Emerging Concepts in Therapeutic Interventions for Idiopathic Pulmonary Fibrosis

Keywords

idiopathic pulmonary fibrosis - interstitial lung disease - anti-fibrotic - preclinical models - pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common etiology of fibrotic lung disease worldwide. Incidence is 1 to 13 cases per 100,000, with prevalence ranging from 3 to 45 cases per 100,000.[1] Risk factors for disease development include age, male sex, inhalational exposures (including tobacco), comorbidities, and genetic factors.[2] Survival is often quoted as 3 to 5 years; however, this is likely an underestimate due to earlier identification, effective drug therapies, effective lifestyle modifications, including pulmonary rehab, and treatment of comorbidities.[3] [4] [5] [6] [7] [8] [9] While there are only two FDA-approved therapies for IPF, comprehensive preclinical studies have identified exciting and novel therapeutic targets. As a result, several new promising drugs have advanced to clinical trials, which we will summarize in this review ([Fig. 1]; [Table 1]).

Fig. 1 Schematic of critical events in IPF pathogenesis and how therapeutic categories target them. Repetitive epithelial injury leads to maladaptive healing, AEC2 dysfunction, senescence, and apoptosis. Pro-inflammatory cell types, including macrophages, epithelial cells, and fibroblasts, produce profibrotic cytokines which promote fibroblast proliferation, differentiation into myofibroblasts, and activation. Fibroblasts produce excessive ECM, resulting in an imbalance between production and degradation. AEC2, type 2 alveolar epithelial cells; AT2, angiotensin 2 receptor; ATX, autotaxin; cAMP, cyclic adenosine monophosphate; ECM, extracellular matrix; LPAR, lysophosphatidic acid receptor; PDE, phosphodiesterase. (Created in BioRender by Cooley J. [2025] https://BioRender.com/5me0sry.)

Table 1 Select phases II and III trials evaluating the efficacy of targeted therapies in IPF

Drug	Other names	Mechanism of action	Clinical trial	Phase	Status[a]	Primary endpoint	Duration	Primary met?	Background therapy	Notes
Pirfenidone[58] [59]	Esbriet, Pirespa, Etuary	Prevents TGF-β signaling	CAPACITY (1 and 2)	III	FDA approved	Change in predicted FVC	72 wk	Yes	None	CAPACITY 1 only showed benefit at earlier timepoints
			ASCEND			Change in FVC or death	52 wk	Yes	None	Improved progression-free survival and 6MWT decline with pirfenidone treatment
Nintedanib[73]	BIBF 1120, Ofev, Vargatef	Inhibits PDGF, VEGF, and FGF receptors	INPULSIS (1 and 2)	III	FDA approved	Rate of decline in FVC	52 wk	Yes	None
Saracatinib	AZD0530	Inhibits the Src family of tyrosine kinases	STOP-IPF	Ib/IIa	Active, not recruiting	Change in FVC from baseline	24 wk	Pending	None
Pamrevlumab[86]	FG-3019	Monoclonal antibody against CTGF	ZEPHYRUS (1 and 2)	III	Terminated	Change in FVC from baseline	48 wk	No	None; allowed after study initiation for worsening respiratory status	Only ZEPHYRUS-1 results available
Vixarelimab	RG6536	Monoclonal antibody against OSM receptor	NCT05785624	II	Recruiting	Change in FVC from baseline	52 wk	Pending	Stable background therapy allowed
Treprostinil	Tyvaso	Prostacyclin analogue	TETON (1 and 2)	III	Active, not recruiting	Change in FVC from baseline	52 wk	Pending	Stable background therapy allowed
Nerandomilast[114]	BI1015550	PDE4B inhibitor	FIBRONEER-IPF	III	Completed	Change in FVC from baseline	52 wk	Yes	Stable background therapy allowed	Data yet to be formally published
Sildenafil[118] [119]	Revatio, viagra, others	PDE5 inhibitor	STEP-IPF	III	Completed	Increase in 6MWT by 20% or more	12 wk	No	Stable background therapy allowed	Improved arterial oxygen saturation, DLCO, and degree of dyspnea
			INSTAGE-IPF	III	Completed	Change in SGRQ score from baseline	12 wk	No	Combination therapy with nintedanib	DLCO < 35% predicted inclusion criteria
Ifetroban		Thromboxane receptor antagonist	NCT05571059	II	Recruiting	Change in FVC from baseline	52 wk	Pending	Stable background therapy allowed	Patients on anticoagulation and antiplatelet therapy were excluded
Bosentan[132] [133]	Tracleer, stayveer, safebo	Endothelin receptor antagonist	BUILD-1	III	Completed	Change in exercise capacity from baseline	12 mo	No	None	Improved time to death or disease progression in those diagnosed by surgical lung biopsy
			BUILD-3	III	Completed	Time to IPF worsening	Variable	No	None	Patients diagnosed by surgical lung biopsy
Ambrisentan[134]	Letairis, volibris, pulmonext	Endothelin receptor antagonist	ARTEMIS-IPF	III	Terminated	Time to disease progression	Variable	No	None	Interim analysis with increased risk of disease progression in the ambrisentan group
Macitentan[135]	Opsumit	Endothelin receptor antagonist	MUSIC	II	Completed	Change in FVC from baseline	12 mo	No	None	Patients diagnosed by surgical lung biopsy
Ziritaxestat[153]	GLPG1690	Autotaxin inhibitor	ISABELA (1 and 2)	III	Terminated	Rate of decline in FVC	52 wk	No	Stable therapy allowed	Terminated early for lack of efficacy and increased mortality in ziritaxestat groups
Fipaxalparant	HZN-825	LPAR1 antagonist	NCT05032066	II	Terminated	Change in predicted FVC	52 wk	No	Stable therapy allowed	Terminated early, no results released to date
Admilparant[156]	BMS986-278	LPAR1 antagonist	NCT04308681	II	Completed	Change in predicted FVC	26 wk	Yes	Stable therapy allowed	30 and 60 mg doses tested
BG00011[167]		Monoclonal antibody against integrin αvβ6	NCT03573505	IIb	Terminated	Change in FVC from baseline	52 wk	No	Stable therapy allowed	Terminated early; signal for worsening at 26-wk analysis
Bexotegrast	PLN-74809	Inhibitor of integrins αvβ6 and αvβ1	BEACON-IPF	II	Active, not recruiting	Change in FVC from baseline	52 wk	Pending	Stable therapy allowed	Phase IIa INTEGRIS-IPF demonstrated safety and tolerability
DWN12088		Prolyl-tRNA synthetase inhibitor, disrupting collagen translation	NCT05389215	II	Recruiting	Rate of decline in FVC	24 wk	Pending	Stable therapy allowed
Simtuzumab[174]	GS 6624	LOXL2 inhibitor, disrupting collagen crosslinking	RAINIER	II	Terminated	Progression-free survival	Variable	No	Stable therapy allowed	Terminated early for lack of efficacy
GSK3915393		Transglutaminase-2 inhibitor,	TRANSFORM	II	Recruiting	Change in FVC from baseline	26 wk	Pending	Stable therapy allowed
Setanaxib	GKT137831	Nox1 and Nox4 inhibitor	NCT03865927	II	Completed	Change in the concentration of the marker of oxidative stress	24 wk	Pending	Not specified
Buloxibutid	C21	Angiotensin type 2 receptor agonist	ASPIRE-IPF	II	Recruiting	Change in FVC from baseline	52 wk	Pending	Nintedanib allowed	Pirfenidone use is excluded due to drug-drug interactions
Zinpentraxin alfa[238]	rhPTX-2, PRM-151	Recombinant human pentraxin-2	STARSCAPE	III	Terminated	Change in FVC from baseline	52 wk	No	Stable therapy allowed	Terminated early for lack of efficacy

Abbreviations: 6MWT, 6-minute walk test distance; DL_CO, diffusing capacity of the lungs for carbon monoxide; FVC, forced vital capacity; SGRQ, Saint George Respiratory Questionnaire.

Source: Trial parameters from clinicaltrials.gov.

^a At the time of manuscript submission.

Clinically, IPF is defined radiographically and histologically by the presence of usual interstitial pneumonia without evidence of underlying exposure or rheumatologic cause.[10] These findings manifest as progressive reticular changes in the lung, traction bronchiectasis and bronchiolectasis, and ultimately, honeycomb cyst formation.[10] [11] Symptoms manifest as dry cough, dyspnea, and hypoxia. Physiology most frequently demonstrates pulmonary restriction and gas exchange abnormalities with reduced total lung capacity, forced vital capacity (FVC), and low diffusing capacity of the lung for carbon monoxide (DL_CO).[12] Diagnosis is made using careful appraisal of the clinical history, physical exam findings, pulmonary function tests, imaging, and relevant serologic data. When considering other etiologies, surgical lung biopsy may be performed for definitive diagnosis. In a small cohort of patients who received clinical and histopathologic diagnoses from biopsy, a clinical assessment alone was accurate in 62% of patients diagnosed with IPF.[13] Critically, the symptoms and physiologic changes associated with IPF frequently occur prior to formal diagnosis.[14] Clinical progression is tracked by trending patient-reported outcomes, spirometry, DL_CO, 6-minute walk test distance (6MWT), and radiographic evidence of fibrosis, which form the basis for clinical trial outcomes in IPF research.[15]

The pathogenesis of IPF has not been fully elucidated, but the working hypothesis is that a genetically susceptible individual undergoes repetitive epithelial injury, resulting in pro-fibrotic signaling, accumulation of pro-fibrotic fibroblasts, and an imbalance between collagen synthesis and degradation.[2] [16] [17] Preclinical studies utilize in vitro, ex vivo, and in vivo approaches to identify mechanisms driving fibrotic change.[18] [19] [20] [21] In vivo mouse models have been foundational in identifying pathophysiologic mechanisms of fibrosis. In vivo models of pulmonary fibrosis utilize injurious exposures including chemical (bleomycin), radiation, inhalation of damaging substances (silica and asbestos), or genetic modalities to induce fibrosis.[20] [21] The most well-characterized of these models utilizes a single dose of intratracheal bleomycin, a chemotherapeutic agent causing double-stranded DNA breaks.[22] [23] [24] [25] [26] Bleomycin-induced lung injury can be broken into four overlapping phases. After an acute inflammatory phase (days: 0–7), a fibroproliferative phase ensues (days: 3–14), followed by an established fibrotic phase (days: 14–28) which resolves over time (days: 42–56), leaving mice with near normal lung architecture.[21] [24] [26] It shares several phenotypic similarities with IPF during the fibrotic phase, including epithelial cell damage and remodeling, pro-fibrotic signaling, fibroblast proliferation, accumulation of extracellular matrix (ECM), and architectural distortion.[23] When interpreting in vivo studies using bleomycin in mice, the timing of intervention is important. We will use the following nomenclature when describing in vivo mouse studies with bleomycin, consistent with Kolb et al.[23] Inhibiting development of fibrosis will refer to interventions made prior to bleomycin and up to 6 days postbleomycin. Therapeutically reducing fibrosis refers to interventions initiated 7 days or more postbleomycin. However, if an intervention is initiated after 7 days postbleomycin and the analysis occurs at least 6 weeks postbleomycin, we will refer to this as hastening resolution.

Pirfenidone and nintedanib remain the only two FDA-approved therapies for the treatment of IPF. They both slow fibrosis progression and likely have a mortality benefit in IPF, but don't reverse established progressive fibrosis.[8] [27] [28] [29] [30] [31] As of March 2025, review of clinicaltrials.gov demonstrates 9 active and 20 completed phase III clinical trials. This review will explore promising therapeutic avenues, summarizing the (1) targeted mechanisms, (2) preclinical data, and (3) clinical trial results. Exploring the path from bench to bedside will highlight the diverse pathways driving pulmonary fibrosis in preclinical models and identify promising clinical trials.

Growth Factors and Cytokines

Several pro-fibrotic signaling pathways that contribute to epithelial injury, fibroblast recruitment, proliferation, and resilience have been implicated in the pathogenesis of pulmonary fibrosis. Signaling pathways have formed the backbone of pulmonary fibrosis research since the identification of TGF-β as a key mediator of fibrosis.[32] [33] Increased levels of TGF-β have been identified in IPF lungs, and overexpression of TGF-β in animal models (both genetic and through adenoviral delivery) results in the development of fibrosis.[34] [35] [36] [37] [38] TGF-β is produced by several cell types integral to the pathogenesis of IPF, namely damaged alveolar epithelial cells, pro-fibrotic macrophages, and fibroblasts.[38] [39] Upon binding to its receptor, TGF-β activates Smad2 and Smad3 via phosphorylation, allowing for translocation to the nucleus and promoting transcription of several fibrosis-related genes, including collagen synthesis.[40] [41] [42] [43] Loss of Smad3 is protective against the development of bleomycin fibrosis in mice.[44] TGF-β also drives epithelial-to-mesenchymal transition, fibroblast proliferation, differentiation into myofibroblasts, and fibroblast activation.[45] [46] [47] [48] While TGF-β has long been considered a target for IPF, there have been limited clinical studies to date directly targeting TGF-β, largely due to concerns about on target effects outside of lung fibrosis.[49] TRK-250, an inhaled small-interfering RNA (siRNA) molecule blocking TGF-β production, completed phase I trials but has not advanced further.[50]

While the precise mechanism of action has not been fully elucidated, pirfenidone has been shown to decrease expression of TGF-β in vitro and in vivo models of fibrosis, thereby decreasing production of ECM components like collagen, fibronectin, and tenascin-C.[51] [52] [53] [54] Additionally, pirfenidone decreases expression of pro-fibrotic growth factors like platelet-derived growth factor (PDGF) and fibroblast growth factor 2.[53] [55] [56] Pirfenidone has also been shown to decrease the expression of some matrix metalloproteinases (MMP), reduce inflammatory cells and cytokine expression, which have been excellently reviewed elsewhere.[57] Efficacy of pirfenidone in IPF was evaluated in three phase III randomized controlled trials (RCTs), ASCEND and two CAPACITY RCTs.[58] [59] Pooled results demonstrate that at 1 year, placebo-treated patients experienced an FVC decline of 363 mL, pirfenidone-treated patients experienced a decline of 216 mL, and no decline was observed in 59.3% more pirfenidone-treated patients.[60] Treatment was well tolerated, and the most common side effects were gastrointestinal-related and rash.[60] Nebulized pirfenidone is currently being studied as an alternative to the oral agent to reduce side effects, predominantly upper GI distress.[61] A deuterated formulation, deupirfenidone, is also being studied for improved pharmacokinetic and safety profiles in the ELEVATE-IPF trial, with promising early results noted in a press release.[62] [63]

Nintedanib is a tyrosine kinase inhibitor that targets several additional growth factors implicated in IPF, namely PDGF, FGF, and vascular endothelial growth factor (VEGF). PDGF RNA expression is increased in the lungs of IPF patients and is derived from alveolar macrophages and epithelial cells.[64] In response to PDGF stimulation, fibroblasts proliferate, produce collagens, and a-SMA.[64] [65] [66] The FGF family of growth factors has multiple effects on fibroblasts, including fibroblast proliferation and collagen production.[47] [67] FGF-9 and FGF-18 are also known to promote fibroblast survival.[68] VEGF is produced by type II alveolar epithelial cells and fibroblasts in the lung, but its effects on fibrosis are unclear, as some investigators report pro-fibrotic effects and others anti-fibrotic effects.[69] [70] By antagonizing the receptors of PDGF, FGF, and VEGF, nintedanib exerts anti-fibrotic effects. After bleomycin administration in mice, nintedanib inhibited the development of fibrosis and therapeutically reduced fibrosis in a dose-dependent manner.[71] [72] Nintedanib treatment for IPF was evaluated in two phase III RCTs, INPULSIS-1 and 2, which demonstrated that nintedanib reduced the rate of FVC decline in IPF patients (−240 mL/year in placebo group vs. −115 mL/year in nintedanib group).[73] Its primary side effect was diarrhea (19% in the placebo group and 62% in the nintedanib group), which significantly restricts its use clinically.

The Src-family tyrosine kinases modulate several pro-fibrotic signaling pathways, including PDGF, VEGF, FGF, and epidermal growth factor.[74] [75] [76] [77] [78] Saracatanib, a c-Src inhibitor, therapeutically reduced fibrosis after both bleomycin and recombinant-TGF-β adenovirus induced fibrosis in mice.[79] In these animal models, saracatinib demonstrated equal to improved efficacy compared to nintedanib and pirfenidone in therapeutically reducing fibrosis.[79] A phase Ib/IIa trial is currently enrolling to evaluate the safety and efficacy of saracatinib for the treatment of IPF (identifier: NCT04598919).

Connective tissue growth factor (CTGF) is a pro-fibrotic matricellular protein that has been identified as a drug target for IPF. Plasma and lung tissue from patients with IPF have increased levels of CTGF, which directs fibroblasts, epithelial cells, and alveolar macrophages to promote fibrogenesis.[80] [81] CTGF induces fibroblast proliferation and differentiation into myofibroblasts.[82] Both fibroblast-specific CTGF-deletion and inhibition using an anti-CTGF monoclonal antibody inhibited the development of bleomycin-induced fibrosis in mice.[83] [84] Targeted CTGF inhibition as a treatment modality for IPF is being approached through the development of novel monoclonal antibodies. Pamrevlumab exhibited efficacy and safety in treating IPF in the phase II PRAISE trial.[85] Unfortunately, the phase III ZEPHYRUS-1 trial studying pamrevlumab did not meet its primary endpoint of change in FVC at 48 weeks (−330 mL in the placebo group and −260 mL in the pamrevlumab group; p = 0.29).[86] There was no significant difference in adverse events. Another monoclonal antibody targeting CTGF, SHR-1906, demonstrated safety in a phase I trial demonstrated safety, and a phase II trial of the agent is currently underway (identifier: NCT05722964).[87]

Interleukin signaling has been another therapeutic target in IPF. IL-1β, IL-2, IL-6, IL-8, IL-10, IL-11, IL-12, IL17-A, and IL-33 are all increased in the blood or BAL of IPF patients compared to healthy controls, implicating a role for inflammation in the fibrotic lung.[88] [89] These cytokines are largely pro-inflammatory, though some have pro-fibrotic activity as well, and facilitate immune cell recruitment, ECM production, and fibrosis.[88] [90] Despite mouse models demonstrating a robust inflammatory response to bleomycin preceding fibrosis, targeting an inflammatory component of IPF has not proven beneficial, and may even worsen mortality. The PANTHER-IPF study, while limited by its multi-arm protocol and early termination, demonstrated that use of N-acetylcysteine (NAC) combined with the immunomodulatory agents prednisone and azathioprine was associated with an increased risk of death or hospitalization.[91] Additionally, inhibition of TNF-α with etanercept was shown to be an ineffective treatment modality for IPF.[92] Therefore, the use of anti-inflammatory maintenance therapy for IPF appears to be an ineffective strategy. IL-11 and members of the IL-6 family continue to hold promise as therapeutic targets in part due to their pro-fibrotic actions. IL-11 is increased in the lungs of IPF patients and positively correlates with disease severity.[89] In response to IL-11 stimulation, fibroblasts differentiate into myofibroblasts and produce collagen. Exogenous IL-11 administration and fibroblast-specific overexpression of IL-11 in vivo promoted the accumulation of collagen in the lungs of mice.[89] After bleomycin, deletion of an IL-11 receptor subunit inhibited the development of fibrosis in mice.[89] A neutralizing antibody to IL-11 receptor, LASN01, has been developed and has completed a phase I/IIa clinical trial with results pending formal publication (identifier: NCT05331300). Oncostatin M (OSM), a member of the IL-6 family of cytokines, is elevated in bronchoalveolar lavage (BAL) fluid of IPF patients.[93] OSM is not only pro-inflammatory, but also modulates ECM production, drives fibroblast proliferation, and inhibits fibroblast apoptosis.[93] [94] [95] Vixarelimab is a monoclonal antibody against the OSM receptor OSMRß and is being studied in a phase IIa trial in IPF (identifier: NCT05785624).

Cyclic AMP, Cyclic GMP, Endothelin-1, and Thromboxane

Preclinical and clinical studies in IPF have also evaluated drugs classically used for pulmonary hypertension (PH) due to overlapping anti-fibrotic effects. Cyclic adenosine monophosphate (cAMP) is produced by adenylyl cyclase and activates cAMP-dependent protein kinase A (PKA) and exchange protein activated by cAMP, leading to downstream anti-inflammatory and anti-fibrotic effects in the lung.[96] [97] [98] [99] [100] Elevated cAMP levels inhibit TGF-β and Smad signaling, an effect reversed by PKA inhibition, suggesting cAMP and PKA play a critical role in modulating TGF-β signaling.[101] Prostacyclin and its analogues, including treprostinil, activate adenylyl cyclase to produce cAMP.[102] [103] [104] Treprostinil inhibits TGF-β secretion, fibroblast proliferation, myofibroblast differentiation, and collagen deposition and has been shown to inhibit the development of bleomycin-induced fibrosis in mice.[105] [106] In the INCREASE trial, which evaluated inhaled treprostinil for treatment of ILD-associated PH, subgroup analyses showed a non-significant trend toward not only stable, but improved FVC in ILD patients, 28% of whom had IPF.[107] This formed the basis for the TETON trials, two phase III RCTs evaluating the efficacy of inhaled treprostinil in treating IPF, which are currently underway (identifiers: NCT04708782 and NCT05255991).[108]

Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cAMP, cyclic guanosine monophosphate (cGMP), or both cAMP and cGMP. Given the crucial role of cAMP in pulmonary fibrosis, attention has turned to PDE4, a cAMP-specific PDE that increases intracellular cAMP. Nonspecific PDE4 inhibitors have been shown to inhibit development and therapeutically reduce fibrosis in multiple preclinical models of pulmonary fibrosis, including bleomycin.[109] [110] [111] However, the nonspecific PDE4 inhibitors' clinical utility has been hampered by adverse side effects, namely headaches, gastrointestinal, and psychiatric side effects.[112] Targeted PDE4B inhibition offers potent anti-fibrotic effects with a better side effect profile. Specifically, PDE4B inhibition with nerandomilast therapeutically reduced fibrosis in both bleomycin and silica models of pulmonary fibrosis in mice.[98] A phase II RCT of nerandomilast in IPF showed stabilization of FVC at 12 weeks either alone (−81.7 mL in the placebo group and +5.7 mL in the nerandomilast group) or in combination therapy with background anti-fibrotics (−59.2 mL in the placebo group and +2.7 mL in the nerandomilast group).[113] Diarrhea was the most common side effect. Among patients taking background anti-fibrotics, diarrhea occurred in 32% of placebo patients and 37% of nerandomilast patients, and in the absence of background therapy, diarrhea occurred in 16% of placebo patients and 27% of nerandomilast patients. The FIBRONEER trials, two phase III RCTs studying nerandomilast in IPF, have been completed, and while data has yet to be published, press releases report similar clinical benefit as its phase II counterpart.[114]

cGMP is produced by guanylyl cyclase in response to nitric oxide and activates cGMP-dependent protein kinase G to exert anti-fibrotic effects.[115] PDE5 inhibitors like tadalafil and sildenafil are cGMP-specific and are clinically used to treat PH through their effect on vasodilation. Increased cGMP levels, driven by guanylyl cyclase stimulation, inhibit TGF-β-dependent production of collagen in human dermal fibroblasts.[115] [116] Preclinical studies show that sildenafil inhibits fibrosis development in mice after bleomycin, with improved nitric oxide synthase coupling and a reduction in reactive oxidative species (ROS).[117] Clinical trials with sildenafil have proven less promising. STEP-IPF evaluated sildenafil for the treatment of IPF and found no significant improvement in their primary outcome of 6MWT improvement. They did identify minor improvements in DL_CO and quality of life.[118] INSTAGE sought to re-analyze sildenafil in a sicker patient cohort (DL_CO < 35% predicted) and in combination with nintedanib. Using the St. George Respiratory Questionnaire, no improvement in symptomatology was noted compared to nintedanib alone, but this may be limited by patients having more advanced disease at the outset of the study.[119]

Like prostacyclins and PDE5 inhibitors, endothelin receptor antagonists (ERA) are a class of medications approved for the treatment of PH that have also been repurposed for study in pulmonary fibrosis. There are two G-protein-coupled receptor endothelin receptor subtypes found in humans that activate a variety of different downstream pathways, including PKC, AKT, and β-arrestin, and upon activation, can also stimulate IL-11 release through a MAPK-dependent pathway.[120] [121] Endothelin-1 (ET-1) and its precursors are expressed by airway and alveolar epithelial cells, as well as inflammatory cells and alveolar macrophages.[122] [123] ET-1 levels are increased in the serum of IPF patients.[124] ET-1 is known to promote fibroblast chemotaxis, proliferation, and protection against apoptosis while also stimulating ECM deposition.[125] [126] [127] [128] Overexpression of ET-1 drives inflammation and fibrosis in mice, but endothelin antagonism with ERAs has shown mixed responses to bleomycin injury in rat models.[129] [130] [131] Nonetheless, ERAs advanced to clinical trials in IPF. The BUILD-1 trial evaluating bosentan in IPF patients did not demonstrate improvements in the primary endpoint of 6MWT distance at 12 months, but did show a non-significant trend to reduced mortality and disease progression.[132] Subgroup analysis demonstrated a significant mortality benefit in those with surgical biopsy-diagnosed IPF, leading to the BUILD-3 study. In BUILD-3, patients with biopsy-proven IPF were randomized to bosentan therapy or placebo, and no significant difference in the rate of disease progression was identified.[133] ARTEMIS-IPF evaluated ambrisentan therapy but was terminated early due to ambrisentan treatment being associated with increased risk of meeting the primary endpoint of progression as defined by time to death, respiratory hospitalization, or decrease in lung function.[134] Macitentan was studied in the MUSIC trial, where no differences were observed between the treatment and placebo groups.[135] Combined, these trials ended enthusiasm for ERAs as a therapeutic agent for IPF.

Thromboxanes are bioactive metabolites of arachidonic acid, like prostacyclins, and similarly have been studied in IPF. Increases in thromboxane relative to prostacyclin have been documented in IPF-fibroblasts in ex vivo analyses.[136] The thromboxane receptor TBXA2R has increased expression in the lungs of IPF patients, especially fibroblasts, endothelial cells, and smooth muscle cells.[137] Genetic deletion of TBXA2R in mice inhibited the development of fibrosis after bleomycin, and inhibition of TBXA2R with the small molecule inhibitor ifetroban improved fibrosis in multiple mouse models (bleomycin, genetic, and radiation).[137] Ifetroban is now under investigation in a phase II RCT for the treatment of IPF (identifier: NCT05571059). While trials for sildenafil and ERAs have not demonstrated significant clinical efficacy, targeting thromboxane and cAMP signaling remains under investigation and has shown early therapeutic potential in IPF.

Autotaxin, Lysophosphatidic Acid, and Lysophosphatidic Acid Receptor

The autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA receptor (LPAR) axis has shown both promising and dangerous potential for treating IPF. Autotaxin is an excreted enzyme that converts lysophosphatidylcholine to LPA and serves as an LPA chaperone to its receptor LPAR.[138] [139] [140] [141] There are many isoforms of LPA with different saturations and lengths of fatty acid chains, and six isoforms of the G-coupled protein receptors LPAR (LPAR1-6).[139] LPARs have varying affinities for species of LPA, with LPAR1 being the primary binding partner of LPA.[139] ATX-LPA-LPAR signaling can be both pro-inflammatory and pro-fibrotic. In pulmonary fibrosis, this axis participates in crucial events including epithelial cell apoptosis, TGF-b activation, and fibroblast recruitment, activation, and survival through several signaling pathways including the Ras-Raf-MEK-ERK, PI3K, Rho/ROCK, Rac, and phospholipase C pathways.[140] [141] [142] [143] [144] [145] [146] Increased staining for ATX has been demonstrated within the hyperplastic bronchiolar epithelium, alveolar epithelium adjacent to fibroblastic foci, and fibroblasts and alveolar macrophages within the fibrotic interstitium of IPF lungs.[147] Elevated levels of LPA have been measured in the BAL of patients with IPF, and higher levels are associated with worse DL_CO and radiographic fibrosis.[144] [148] Development of bleomycin-induced fibrosis was inhibited with genetic deletion of ATX in macrophages and bronchial epithelial cells, and after therapeutic inhibition of ATX with ziritaxestat and GWJ-A-23.[147] [149] Additionally, ziritaxestat decreased established radiation-induced fibrosis in mice.[140] Similarly, genetic knockout of LPAR1 and LPAR1 inhibition with AM966 both inhibited development of bleomycin-induced fibrosis.[144] [150] An LPAR 1/3 inhibitor was also shown to reduce the development of radiation fibrosis in mice.[151] While phase II clinical trials for ATX inhibitors, cudexestat (RESPIRARE trial) and BBT-877 are yet to be published, ziritaxestat slowed FVC decline at 12 weeks in a phase II RCT.[152] However, two phase III RCTs of ziritaxestat in IPF (ISABELA 1 and 2) were terminated early due to a signal for increased mortality and lack of efficacy.[153] Treatment groups included placebo and ziritaxestat at both lower (200 mg daily) and higher (600 mg daily) doses for at least 52 weeks, and allowed for background therapy with nintedanib or pirfenidone. No difference was observed in the primary endpoint of annual rate of FVC decline (−145 mL with placebo, −174 with low dose, and −125 mL with high dose in ISABELA 1; −177 mL with placebo, −175 mL with low dose, and −174 mL with high dose in ISABELA 2). Secondary endpoints revealed no benefit, and time to first respiratory-related hospitalization was worse in the ziritaxestat group. Importantly, ziritaxestat has a drug-drug interaction with nintedanib, which may have contributed to adverse events. ATX levels were increased in the plasma of treated patients in the ISABELA 1 and 2 trials, suggesting a regulatory feedback loop that could explain the lack of efficacy and adverse effects.[154] Despite the signal for harm with ziritaxestat, LPAR1 inhibition continues to be studied. LPAR1 antagonists in clinical trials include fipaxalparant and admilparant. BMS 986020 demonstrated promising efficacy in a phase II RCT; however, it was terminated early due to inciting hepatobiliary disease.[155] In a phase II RCT of admilparant, patients were randomized to placebo, admilparant 30 mg or 60 mg twice daily, and permitted to continue background nintedanib or pirfenidone. The mean rate of decline in FVC was −2.7, −2.8, and −1.2% in the placebo, 30 and 60 mg groups, respectively.[156] Serious adverse events occurred in 17% of the placebo group, and 11% of both 30 and 60 mg groups. There was an increased frequency of transient day 1 postdose blood pressure reduction with admilparant, but no increased frequency of diarrhea. A more pronounced benefit was seen in a progressive pulmonary fibrosis (PPF) cohort, with the decline in FVC of −4.3, −2.7, and −1.1% in the placebo, 30 mg, and 60 mg groups, respectively. This led to a phase III RCT with admilparant which is underway (identifier: NCT06003426). Despite the failure of ziritaxestat, targeting the ATX-LPA-LPAR axis remains a promising therapeutic strategy.

Extracellular Matrix and Integrins

Excessive deposition and accumulation of ECM is a hallmark feature of IPF. A positive feedback loop exists whereby increased deposition of ECM increases lung stiffness and promotes pro-fibrotic cellular responses via mechanotransduction.[157] Therefore, targeting critical ECM components to break this positive feedback loop holds potential as a therapeutic avenue in IPF.

Integrins are heterodimeric, transmembrane glycoprotein receptors that consist of an α-subunit and a β-subunit.[158] They are cell adhesion signaling proteins, with the unique ability to transduce signals bidirectionally from the intracellular environment to elicit changes in the extracellular environment, and vice versa, allowing cells to sense and respond to ECM mechanical changes.[158] Clinically, integrin inhibitors are commonplace, like abciximab (Reopro), eptifibatide (Integrilin), or tirofiban (Aggrastat), which inhibit αIIbβ3 on platelets and are used during percutaneous coronary interventions, or the pan-α4 inhibitor natalizumab (Tysabri), which is used for multiple sclerosis treatment.[158] [159] [160] Integrins play a pivotal function in IPF, in large part due to their role in TGF-β activation. When inactive, TGF-β is bound to latency-associated peptide and tethered to the ECM.[158] [161] [162] [163] Multiple integrins, including αvβ6 on epithelial cells and αvβ1 on fibroblasts, release TGF-β from its inactive state.[158] [161] [162] αvβ6 protein expression is increased in IPF tissue compared to healthy controls, localizes to epithelial cells overlying fibrotic areas and to areas with active inflammation, and has been associated with increased mortality.[164] [165] Targeting αvβ6 has been a promising option to treat pulmonary fibrosis. Genetic knockout of β6 (preventing formation of αvβ6) protected mice from bleomycin-induced fibrosis, and therapeutic inhibition of αvβ6 after bleomycin inhibits development, therapeutically reduces, and accelerates resolution of fibrosis in mice.[161] [164] [166] Similarly, inhibition of αvβ1 therapeutically reduced fibrosis in mice after bleomycin.[162] A monoclonal antibody against αvβ6 (BG00011) was evaluated in a phase IIb RCT in IPF, but was terminated early due to lack of benefit and increased adverse events, including increased progression, exacerbations, and death in the treatment group compared to placebo.[167] A question remains as to whether monoclonal antibodies can permeate into the dense fibrotic regions of IPF lungs, and if small-molecule inhibitors will therefore prove superior. Bexotegrast, a dual αvβ1 and αvβ6 small molecule inhibitor, targets both epithelial (αvβ6) and fibroblast (αvβ1) integrins mediating TGF-β activation. INTEGRIS-IPF was a phase IIa RCT of patients with IPF receiving once-daily placebo or bexotegrast (40, 80, 160, or 320 mg groups) with or without background nintedanib or pirfenidone over at least 12 weeks.[168] The trial found a similar incidence of adverse events, with the most common side effect being diarrhea, which was primarily seen in patients co-treated with nintedanib. Grade 3 or greater adverse events occurred in 6.5% of placebo-treated patients and 6.7% of bexotegrast-treated patients. FVC decline, CT quantification of fibrosis, and biomarkers all demonstrated a benefit in the bexotegrast groups over the 12-week trial period. A phase IIb/III trial (BEACON-IPF) of bexotegrast in IPF recently stopped enrollment and dosing after recommendations from an independent Data Safety Monitoring Board, but the reasons have yet to be published.[169]

Excessive collagen synthesis, accumulation, maturation, and impaired degradation all contribute to the progression of fibrosis, making targeting collagen an appealing therapeutic strategy. Type 1 collagen is made of two α₁ chains (encoded by COL1A1) and one α₂ chain (encoded by COL1A2). Prepro-polypeptide chains travel to the endoplasmic reticulum (ER) where they undergo posttranslational modification and assembly of a triple helix, then are transported to the Golgi apparatus in the form of pro-collagen for further processing and assembly into secretory vesicles, are secreted, and subsequently undergo extracellular modifications, including collagen crosslinking.[170] Several steps in the collagen biosynthesis and posttranslational modification are under investigation as therapeutic targets for IPF.

Prolyl-tRNA synthetase (PRS) conjugates proline to tRNA during collagen translation.[171] DWN12088, a PRS inhibitor, therapeutically reduced bleomycin-induced fibrosis in mice, which has led to a current phase II RCT to evaluate its safety and efficacy in IPF (identifier: NCT05389215).[171]

Heat shock protein 47 (HSP47) is a collagen-specific chaperone that is essential for the correct folding of pro-collagen fibrils in the ER.[172] HSP47 also plays a role in collagen turnover through collagenase, MMPs, and integrin signaling.[172] A phase II RCT with siRNA targeted HSP47 gene silencing (ND-L02-s0201) did not demonstrate efficacy in patients with IPF (identifier: NCT03538301).

Lysyl oxidase-like 2 (LOXL2) catalyzes collagen crosslinking and has increased expression in fibrotic areas of IPF lung tissue.[173] Preclinical studies showed that inhibition of LOXL2 inhibited development and therapeutically reduced fibrosis after bleomycin treatment in mice.[173] However, a phase II RCT of a LOXL2 inhibiting monoclonal antibody, simtuzumab, in IPF; however, was terminated early for futility.[174] Transglutaminase-2 (also known as tissue transglutaminase), which crosslinks ECM components, is currently being investigated in a phase II RCT with the transglutaminase-2 inhibitor, GSK3915393, in IPF (identifier: NCT06317285).[175]

Senescence

In its basic definition, senescence refers to the arrest of cellular growth and is a key pathologic feature of IPF. In IPF, senescent AEC2s have reduced regenerative capacity, and senescent fibroblasts develop resistance to apoptosis.[176] Senescent cells also secrete pro-fibrotic and pro-inflammatory cytokines, chemokines, growth factors, and proteases, referred to as a senescence-associated secretory phenotype.[176] Senescent fibroblast resistance to apoptosis is in part due to increased expression of anti-apoptotic BCL-2 family members, including BCL-2 and BCL-XL, which have been shown to increase in response to stiffness of fibrotic lungs.[177] BH3 mimetics are drugs that were initially developed as anti-cancer agents, inhibit anti-apoptotic BCL-2 family proteins, and include the BCL-2 specific inhibitor venetoclax and the BCL-2, BCL-XL, and BCL-W inhibitor navitoclax. Navitoclax has been shown to reduce the presence of senescent cells and decrease fibrosis after radiation-induced fibrosis in mice.[178] Furthermore, navitoclax and venetoclax have been shown to inhibit development and therapeutically reduce bleomycin-induced fibrosis in mice.[179] [180] [181] We have recently shown that using a repetitive dosing regimen of bleomycin, which induces PPF, navitoclax stabilized progressive fibrosis by targeting pro-fibrotic fibroblasts for apoptosis.[182] While navitoclax remains a study drug in cancer clinical trials in large part due to its side effect of thrombocytopenia, venetoclax is FDA approved for chronic lymphocytic leukemia and acute myeloid leukemia. A small phase 1 clinical trial evaluating its safety and efficacy in IPF (identifier: NCT05976217) was recently completed, with the results pending publication. The senolytic combination of dasatinib and quercitin has also shown promise as a potential treatment for IPF. Dasatinib is an inhibitor of multiple tyrosine kinases, and quercitin is a natural flavonoid. Together, they have been shown to target senescent cells and inhibit the development of bleomycin fibrosis in mice.[176] A small single-center study evaluated the feasibility of dasatinib plus quercitin in IPF.[183] It demonstrated drug tolerability, and while it did not find changes in disease severity after treatment, it was underpowered. Due to the crucial mechanistic role of senescent cells in IPF, senolytics hold promise as therapeutic agents for IPF.

Reactive Oxygen Species, Unfolded Protein Response, Endoplasmic Reticulum Stress, and Metabolic Stress

Metabolic stress, whether ROS or ER stress, can drive epithelial injury and promote fibrotic responses. ROS are known to stimulate a pro-fibrotic environment through increased release of TGF-β, which in turn stimulates further ROS production.[184] [185] [186] IPF fibroblasts express NADPH oxidase isoform 4 (Nox4) in response to TGF-β, which drives the formation of ROS and facilitates a positive feedback loop promoting fibrogenesis.[187] [188] [189] siRNA knockdown of Nox4 inhibited the development of bleomycin-induced fibrosis in mice.[187] Similarly, Nox1 and Nox4 inhibition with setanaxib (GKT137831) hastened the resolution of bleomycin fibrosis in mice while also decreasing myofibroblast accumulation and improving mortality.[190] Notably, these studies were performed in aged mice, thus more closely mimicking the advanced age of IPF patients. A phase IIb trial of setanaxib was recently completed in IPF patients, and results are pending publication (identifier: NCT03865927).

The ER is a vital cellular organelle involved in protein translation and trafficking. ER stress occurs when these processes are disrupted, particularly in the setting of aberrant protein folding, leading to an unfolded protein response (UPR). UPR was first identified as a pathophysiologic mechanism for fibrosis when mutated surfactant protein C led to misfolding in the ER of alveolar epithelial cells, eventually leading to pulmonary fibrosis.[191] [192] [193] [194] [195] UPR promotes fibrosis by inducing fibroblasts to myofibroblast differentiation and AEC2 apoptosis.[196] [197] [198] IRE1a is an ER sensor that drives UPR. Upon activation, IRE1a auto-phosphorylates, oligomerizes, and cleaves XBP1 mRNA, allowing for translation of XBP1, which drives downstream expression of ER stress genes.[199] In response to lung injury and UPR, IRE1a enhances TGF-β signaling. IRE1a deletion and therapeutic antagonism of IRE1a inhibit the development of bleomycin-induced fibrosis, and even promote type 2 alveolar epithelial cell growth and tissue repair.[200] [201] ORIN1001, which inhibits the RNase activity of IRE1a, is under investigation in a phase Ib clinical trial in IPF patients that is currently suspended (identifier: NCT04643769).

Stem Cells

While preclinical and clinical studies to date have largely focused on halting or slowing fibrosis, stem cells offer a novel method to regenerate damaged tissue. Initial interest in the field focused on mesenchymal stromal cells (MSCs). Animal studies showed that the introduction of MSCs inhibited the development, reduced, and hastened the resolution of bleomycin-induced fibrosis.[202] [203] MSCs function by promoting anti-inflammatory and anti-fibrotic signaling, reducing metabolic stress, and, to a lesser extent, engrafting into the lung.[204] [205] [206] [207] [208] [209] [210] While the phase I AETHER study of adipose-derived MSCs documented safety, a randomized, open-label phase Ib/IIa trial showed improvement in 6MWT distance, DL_CO, and FVC using placental-derived MSCs.[211] [212] Additional phase I trials are ongoing with umbilical cord-derived MSCs, including a phase Ib/IIa trial (identifier: NCT05468502).

Lung-derived spheroid stem cells (LSC) are another option being explored for the treatment of IPF. LSCs can be obtained autologously from lung tissue, generally obtained through biopsy.[213] The tissue is applied to an adherent surface, and migrating cells, termed explant-derived cells, are then collected and cultured in suspension. While in suspension, these cells form spheroids, which are associated with increased expression of progenitor markers.[214] An allogeneic rat model of LSC injection demonstrated reduced inflammation and inhibition of fibrosis development after bleomycin compared to controls, without generating a significant alloimmune response.[214] A phase I RCT is currently recruiting patients to establish the safety of LSCs in humans (identifier: NCT04262167). Stem cells provide an exciting new prospect for IPF therapeutics, but given limited phase II trials and no phase III trials, their therapeutic potential remains in the early stages.

Angiotensin

While the pulmonary renin-angiotensin system (PRAS) has long been an area of study in lung injury and fibrosis, it was brought to the forefront when the COVID-19 pandemic highlighted the significance of bronchoalveolar epithelial expression of angiotensin-converting enzyme 2 (ACE2). ACE2 was implicated in the pathogenesis of disease and in postinfectious fibrotic sequelae of COVID-19.[215] [216] [217] ACE2 is a membrane-bound protein that converts angiotensin I and angiotensin II to Ang-(1-9) and Ang-(1-7), respectively.[218] ACE2 is necessary to maintain homeostasis of PRAS. Decreasing ACE2 activity can lead to elevated angiotensin II levels in the lung, which, upon binding to the angiotensin type 1 receptor (AT₁), leads to alveolar epithelial cell apoptosis.[219] [220] ACE2 has decreased transcript expression and enzymatic activity in biopsy specimens from IPF patients.[221] Apoptotic alveolar epithelial cells in IPF patients release angiotensinogen, which will convert to angiotensin II and drive downstream epithelial apoptosis and promote collagen production by fibroblasts.[222] [223] [224] Exogenous ACE2 co-administered with bleomycin protected against epithelial cell injury, decreased TGF-B expression, decreased a-SMA expression, and inhibited the development of fibrosis in mice.[225] ACE2 null mice experienced exaggerated fibrosis in response to bleomycin.[226] Notably, the ACE2-Ang-(1-7)-Mas pathway leads to increased expression of angiotensin type 2 receptor (AT₂), which, in opposition to AT₁, drives anti-fibrotic responses and is protective against lung injury.[227] [228] [229] [230] [231] Indeed, buloxibutid, an AT₂ agonist, was shown to inhibit bleomycin-induced fibrosis.[232] An open-label phase II trial of buloxibutid for treatment in IPF has been completed (identifier: NCT04533022), and results have not been formally published. The ASPIRE trial is a phase II RCT studying Buloxibutid treatment in IPF, is currently recruiting (identifier: NCT06588686). These studies will provide unique clinical insight into the supportive role ACE2 and AT₂ play in maintaining alveolar integrity to treat IPF.

Pentraxin

Pentraxin-2, also known as serum amyloid P, signals through Fcγ and exerts anti-fibrotic action through modulating pro-fibrotic monocyte-derived macrophages and fibrocytes.[233] [234] IPF patients have lower plasma pentraxin-2, and lower levels correlate with disease severity.[235] Genetic loss of pentraxin-2 in mice results in an exaggerated fibrotic response after bleomycin, while pentraxin-2 treatment inhibits bleomycin and TGF-b-induced fibrosis development.[233] [234] [235] [236] A phase II RCT evaluated recombinant human pentraxin-2 in IPF and found that after 28 weeks, the decline in FVC was −4.8 and −2.5% in the placebo and pentraxin-2 groups, respectively.[237] This led to the phase III RCT STARSCAPE evaluating pentraxin-2 in IPF.[238] However, STARSCAPE was terminated early for futility. At 52 weeks, the decline of FVC in placebo and pentraxin 2 was −215 and −236 mL, respectively.

Discussion

An abundance of preclinical studies have revealed many promising therapeutic targets to help people suffering from IPF. Unfortunately, very few drugs make it to phase II or III clinical trials, and only three drugs have shown efficacy in treating IPF in phase III trials (nintedanib, pirfenidone, and nerandomilast). A major obstacle is that many of these drug therapies are “lost in translation,” and successful in vivo studies are not consistently translating to effective bedside treatments. One major reason behind this failure may be the systems used to evaluate for preclinical efficacy. The translational science toolkit includes in vitro cell culture systems, ex vivo precision-cut lung slices from healthy and diseased animals and humans, in silico modeling or simulation, and in vivo animal models, most often mice. A critical component of preclinical projects is often in vivo mouse work, demonstrating efficacy by improving fibrosis. The most widely used model is single-dose intratracheal bleomycin in young mice (8–12 weeks), which undergoes spontaneous resolution had has limited pathologic overlap with IPF. Risk factors for IPF include genetic predisposition, age, smoking, and other environmental exposures. This starkly contrasts with studies using genetically identical young mice, living in a pathogen-free environment. Additionally, mice lack respiratory bronchioles and spend their lives in the prone position. Mice aged 8 to 12 weeks roughly translate to 20-year-old humans, while mice aged 18 to 24 months roughly translate to 56 to 69-year-old humans, the age at which patients are typically diagnosed with IPF.[21] Therefore, studying “middle-aged” or older mice may offer a better model of IPF than young mice, especially when studying treatment options. Additionally, how investigators utilize this model to test drugs is often inappropriate. Intratracheal bleomycin induces an early, robust inflammatory phase, followed by a fibroproliferative and established fibrotic phases, with subsequent spontaneous resolution.[21] Between 2008 and 2019, single-dose bleomycin was used to investigate 726 potential therapies.[23] The majority (61%) were tested as a preventative of fibrosis, as they were given prior to the establishment of fibrosis. Twenty-three percent were assessed for “therapeutic” effect as treatment was given during the fibroproliferative phase, while 14.5% were tested as both preventative and therapeutic.[23] Prior to 2008, less than 5% of bleomycin drug studies were “therapeutic.”[23] We believe that utilizing more clinically relevant models of progressive fibrosis, like repetitive bleomycin, aged mice, or mice with relevant genetic mutations like MUC5B or TERT mutations, represents a significant paradigm shift that preclinical science must consider adopting, despite the protracted nature of such studies. In the future, utilizing other animal models, like ferrets, which have respiratory bronchioles and develop persistent fibrosis after bleomycin, or West Highland White Terriers, who develop spontaneous PPF, may become more prevalent.[239] [240] Nonetheless, in vivo mouse studies, in particular single-dose bleomycin, have been integral to our understanding of the pathobiology of pulmonary fibrosis.

Selection of primary endpoints also bears consideration when interpreting clinical trials. IPF trials have typically used FVC as the primary endpoint to determine the efficacy of the intervention, comparing the amount of decline at 6 or 12 months to determine progression. The long duration of these studies to identify evidence of progression adds to the high expense of clinical trials in IPF. Recently, it has been proposed that 3-month changes may be predictive of progression and could be used as an endpoint, thereby shortening study duration, which could improve cost and potentially lead to more therapeutic agents being tested.[241] Furthermore, while a relatively easy measure to obtain, the utility of FVC as the primary endpoint has been called into question. As an effort-dependent measurement, there can be variability between measurements. Also, it may not account for all important patient-reported outcomes such as progressive symptoms of dyspnea, cough, or decline in physical function.[15] Moving forward, composite endpoints including FVC, patient-reported outcomes, and potentially novel biomarkers could aid in future clinical trial design.

While several promising therapeutic targets offer potential treatments for IPF, there remain several untapped resources that could prove helpful in improving the lives of people with IPF. First, utilizing new technologies such as artificial intelligence (AI) may be one way to expedite the translation of basic science work to clinical trials. For example, ISM001-005, a first-in-class small molecule inhibitor of TRAF2 and NCK-interacting kinase (TNIK), was designed using generative AI. It has had positive results from its Phase IIa trial per the company's website, though a formal publication is still pending.[242] Second, precision medicine offers new opportunities for people living with IPF. For example, a retrospective analysis of the PANTHER trial, INSPIRE trial, and University of Chicago IPF cohorts found that NAC treatment was beneficial in IPF patients carrying the TOLLIP rs3750920 TT genotype and potentially harmful in those with the rs3750920 CC genotype.[243] Third, comorbidities need to be a focus of future research, as there is a clear interplay between IPF and comorbidities like GERD, PH, and obstructive sleep apnea. For example, inhaled treprostinil has been shown to improve 6MWT in ILD patients with PH.[107] Rather than the “one size fits all” approach used in IPF treatment, delineating effects with certain genotypic or phenotypic variations of IPF could prove exceedingly helpful. Fourth, early diagnosis of people with interstitial lung abnormalities and delineation of which patients will progress is critical and has the potential to allow for early intervention that could halt progressive fibrosis in its tracks. Finally, combination therapy will likely become the standard of care as more therapies become available. Combination therapy is a widely used treatment approach for diseases including COPD, asthma, hypertension, diabetes, HIV, and cancer. Clearly, multiple pathways are involved in the pathogenesis of IPF, as described above. Targeting multiple pathways allows for therapeutic synergy, additive effects, and dose reductions to avoid adverse effects.

The next several years will be an exciting time for IPF drug development. Substantial preclinical data have provided numerous promising candidate pathways, and several encouraging clinical trials are underway. The FIBRONEER trial of nerandomilast in IPF demonstrated efficacy of PDE4B inhibition, becoming the first positive phase III RCT in IPF in a decade.[114] Currently, two other medications (treprostinil and admilparant) are under investigation in phase III RCTs. As detailed above, there are several other targets with strong preclinical rationale and encouraging phase II RCT results. We anticipate several more options to become available for patients within the next decade to help relieve the suffering, economic burden, and early mortality associated with IPF.

• References

• 1 Maher TM, Bendstrup E, Dron L. et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res 2021; 22 (01) 197
• 2 Podolanczuk AJ, Thomson CC, Remy-Jardin M. et al. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J 2023; 61 (04) 2200957
• 3 Raghu G, Chen SY, Yeh WS. et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med 2014; 2 (07) 566-572
• 4 Nathan SD, Shlobin OA, Weir N. et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest 2011; 140 (01) 221-229
• 5 Petnak T, Lertjitbanjong P, Thongprayoon C, Moua T. Impact of antifibrotic therapy on mortality and acute exacerbation in idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Chest 2021; 160 (05) 1751-1763
• 6 Moon SW, Kim SY, Chung MP. et al. Longitudinal changes in clinical features, management, and outcomes of idiopathic pulmonary fibrosis. a nationwide cohort study. Ann Am Thorac Soc 2021; 18 (05) 780-787
• 7 Suissa S, Suissa K. Antifibrotics and reduced mortality in idiopathic pulmonary fibrosis: immortal time bias. Am J Respir Crit Care Med 2023; 207 (01) 105-109
• 8 Behr J, Prasse A, Wirtz H. et al. Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry. Eur Respir J 2020; 56 (02) 1902279
• 9 Hozumi H, Miyashita K, Nakatani E. et al. Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias. Respir Res 2024; 25 (01) 293
• 10 Lynch DA, Sverzellati N, Travis WD. et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med 2018; 6 (02) 138-153
• 11 Lee KS, Han J, Wada N. et al. Imaging of pulmonary fibrosis: an update, from the AJR special series on imaging of fibrosis. AJR Am J Roentgenol 2024; 222 (02) e2329119
• 12 Plantier L, Cazes A, Dinh-Xuan AT, Bancal C, Marchand-Adam S, Crestani B. Physiology of the lung in idiopathic pulmonary fibrosis. Eur Respir Rev 2018; 27 (147) 170062
• 13 Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: A prospective study. Chest 1999; 116 (05) 1168-1174
• 14 Guenther A, Krauss E, Tello S. et al. The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis. Respir Res 2018; 19 (01) 141
• 15 Raghu G, Ghazipura M, Fleming TR. et al. Meaningful endpoints for idiopathic pulmonary fibrosis (IPF) clinical trials: emphasis on ‘feels, functions, survives’. report of a collaborative discussion in a symposium with direct engagement from representatives of patients, investigators, the National Institutes of Health, a patient advocacy organization, and a regulatory agency. Am J Respir Crit Care Med 2024; 209 (06) 647-669
• 16 Mei Q, Liu Z, Zuo H, Yang Z, Qu J. Idiopathic pulmonary fibrosis: an update on pathogenesis. Front Pharmacol 2022; 12: 797292
• 17 Bridges JP, Vladar EK, Kurche JS. et al. Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium. J Clin Invest 2025; 135 (01) e183836
• 18 Kolanko E, Cargnoni A, Papait A, Silini AR, Czekaj P, Parolini O. The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery. Eur Respir Rev 2024; 33 (171) 230127
• 19 Koziol-White C, Gebski E, Cao G, Panettieri Jr RA. Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery. Respir Res 2024; 25 (01) 231
• 20 B. Moore B, Lawson WE, Oury TD, Sisson TH, Raghavendran K, Hogaboam CM. Animal models of fibrotic lung disease. Am J Respir Cell Mol Biol 2013; 49 (02) 167-179
• 21 Jenkins RG, Moore BB, Chambers RC. et al; ATS Assembly on Respiratory Cell and Molecular Biology. An official American Thoracic Society Workshop Report: use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. Am J Respir Cell Mol Biol 2017; 56 (05) 667-679
• 22 Allawzi A, Elajaili H, Redente EF, Nozik-Grayck E. Oxidative toxicology of bleomycin: role of the extracellular redox environment. Curr Opin Toxicol 2019; 13: 68-73
• 23 Kolb P, Upagupta C, Vierhout M. et al. The importance of interventional timing in the bleomycin model of pulmonary fibrosis. Eur Respir J 2020; 55 (06) 1901105
• 24 Redente EF, Black BP, Backos DS. et al. Persistent, progressive pulmonary fibrosis and epithelial remodeling in mice. Am J Respir Cell Mol Biol 2021; 64 (06) 669-676
• 25 Degryse AL, Tanjore H, Xu XC. et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010; 299 (04) L442-L452
• 26 Izbicki G, Segel MJ, Christensen TG, Conner MW, Breuer R. Time course of bleomycin-induced lung fibrosis. Int J Exp Pathol 2002; 83 (03) 111-119
• 27 Fisher M, Nathan SD, Hill C. et al. Predicting life expectancy for pirfenidone in idiopathic pulmonary fibrosis. J Manag Care Spec Pharm 2017; 23 (3-b, suppl): S17-S24
• 28 Margaritopoulos GA, Trachalaki A, Wells AU. et al. Pirfenidone improves survival in IPF: results from a real-life study. BMC Pulm Med 2018; 18 (01) 177
• 29 Rogliani P, Calzetta L, Cavalli F, Matera MG, Cazzola M. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Pulm Pharmacol Ther 2016; 40: 95-103
• 30 Lancaster L, Crestani B, Hernandez P. et al. Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials. BMJ Open Respir Res 2019; 6 (01) e000397
• 31 Nathan SD, Albera C, Bradford WZ. et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med 2017; 5 (01) 33-41
• 32 Shah M, Foreman DM, Ferguson MW. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 1994; 107 (Pt 5): 1137-1157
• 33 Cordeiro MF, Mead A, Ali RR. et al. Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther 2003; 10 (01) 59-71
• 34 Bergeron A, Soler P, Kambouchner M. et al. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Eur Respir J 2003; 22 (01) 69-76
• 35 Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997; 100 (04) 768-776
• 36 Lee CG, Cho SJ, Kang MJ. et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J Exp Med 2004; 200 (03) 377-389
• 37 Warshamana GS, Pociask DA, Fisher KJ, Liu JY, Sime PJ, Brody AR. Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice. Int J Exp Pathol 2002; 83 (04) 183-201
• 38 Khalil N, O'Connor RN, Unruh HW. et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 1991; 5 (02) 155-162
• 39 Enomoto Y, Katsura H, Fujimura T. et al. Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis. Nat Commun 2023; 14 (01) 4956
• 40 Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massagué J. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 2001; 8 (03) 671-682
• 41 Hu B, Wu Z, Phan SH. Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Am J Respir Cell Mol Biol 2003; 29 (3 Pt 1): 397-404
• 42 Meng XM, Huang XR, Xiao J. et al. Disruption of Smad4 impairs TGF-β/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int 2012; 81 (03) 266-279
• 43 Zhao Y, Geverd DA. Regulation of Smad3 expression in bleomycin-induced pulmonary fibrosis: a negative feedback loop of TGF-beta signaling. Biochem Biophys Res Commun 2002; 294 (02) 319-323
• 44 Zhao J, Shi W, Wang YL. et al. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 2002; 282 (03) L585-L593
• 45 Serini G, Gabbiana G. Modulation of alpha-smooth muscle actin expression in fibroblasts by transforming growth factor-beta isoforms: an in vivo and in vitro study. Wound Repair Regen 1996; 4 (02) 278-287
• 46 Degryse AL, Tanjore H, Xu XC. et al. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment. Am J Physiol Lung Cell Mol Physiol 2011; 300 (06) L887-L897
• 47 Xiao L, Du Y, Shen Y, He Y, Zhao H, Li Z. TGF-beta 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front Biosci (Landmark Ed) 2012; 17 (07) 2667-2674
• 48 Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007; 293 (03) L525-L534
• 49 Stewart AG, Thomas B, Koff J. TGF-β: master regulator of inflammation and fibrosis. Respirology 2018; 23 (12) 1096-1097
• 50 Doi H, Atsumi J, Baratz D, Miyamoto Y. A phase I study of TRK-250, a Novel siRNA-based oligonucleotide, in patients with idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv 2023; 36 (06) 300-308
• 51 Ma Z, Zhao C, Chen Q. et al. Antifibrotic effects of a novel pirfenidone derivative in vitro and in vivo. Pulm Pharmacol Ther 2018; 53: 100-106
• 52 Hirano A, Kanehiro A, Ono K. et al. Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge. Am J Respir Cell Mol Biol 2006; 35 (03) 366-377
• 53 Oku H, Shimizu T, Kawabata T. et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008; 590 (1-3): 400-408
• 54 Molina-Molina M, Machahua-Huamani C, Vicens-Zygmunt V. et al. Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells. BMC Pulm Med 2018; 18 (01) 63
• 55 Gurujeyalakshmi G, Hollinger MA, Giri SN. Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol 1999; 276 (02) L311-L318
• 56 Yu W, Guo F, Song X. Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. Pharm Biol 2017; 55 (01) 450-455
• 57 Ruwanpura SM, Thomas BJ, Bardin PG. Pirfenidone: molecular mechanisms and potential clinical applications in lung disease. Am J Respir Cell Mol Biol 2020; 62 (04) 413-422
• 58 Noble PW, Albera C, Bradford WZ. et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377 (9779): 1760-1769
• 59 King Jr TE, Bradford WZ, Castro-Bernardini S. et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2083-2092
• 60 Noble PW, Albera C, Bradford WZ. et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J 2016; 47 (01) 243-253
• 61 West A, Chaudhuri N, Barczyk A. et al. Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial. Thorax 2023; 78 (09) 882-889
• 62 PureTech's Deupirfenidone (LYT-100) Slowed Lung Function Decline in People with Idiopathic Pulmonary Fibrosis. (IPF) as measured by forced vital capacity (FVC), achieving the primary and key secondary endpoints in the ELEVATE IPF phase 2b. Trial 2024;2024. Accessed March 26, 2025 at: https://news.puretechhealth.com/news-releases/news-release-details/puretechs-deupirfenidone-lyt-100-slowed-lung-function-decline
• 63 Chen MC, Korth CC, Harnett MD, Elenko E, Lickliter JD. A randomized phase 1 evaluation of deupirfenidone, a novel deuterium-containing drug candidate for interstitial lung disease and other inflammatory and fibrotic diseases. Clin Pharmacol Drug Dev 2022; 11 (02) 220-234
• 64 Antoniades HN, Bravo MA, Avila RE. et al. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990; 86 (04) 1055-1064
• 65 Takamura N, Renaud L, da Silveira WA, Feghali-Bostwick C. PDGF promotes dermal fibroblast activation via a novel mechanism mediated by signaling through MCHR1. Front Immunol 2021; 12: 745308
• 66 Kishi M, Aono Y, Sato S. et al. Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice. PLoS One 2018; 13 (12) e0209786
• 67 Zhou Y, Ling T, Shi W. Current state of signaling pathways associated with the pathogenesis of idiopathic pulmonary fibrosis. Respir Res 2024; 25 (01) 245
• 68 Joannes A, Brayer S, Besnard V. et al. FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro. Am J Physiol Lung Cell Mol Physiol 2016; 310 (07) L615-L629
• 69 Barratt SL, Flower VA, Pauling JD, Millar AB. VEGF (vascular endothelial growth factor) and fibrotic lung disease. Int J Mol Sci 2018; 19 (05) 1269
• 70 Murray LA, Habiel DM, Hohmann M. et al. Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis. JCI Insight 2017; 2 (16) e92192
• 71 Pan L, Cheng Y, Yang W. et al. Nintedanib ameliorates bleomycin-induced pulmonary fibrosis, inflammation, apoptosis, and oxidative stress by modulating PI3K/Akt/mTOR pathway in mice. Inflammation 2023; 46 (04) 1531-1542
• 72 Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014; 349 (02) 209-220
• 73 Richeldi L, du Bois RM, Raghu G. et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2071-2082
• 74 Hu M, Che P, Han X. et al. Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J Pharmacol Exp Ther 2014; 351 (01) 87-95
• 75 Lu YZ, Liang LM, Cheng PP. et al. VEGF/Src signaling mediated pleural barrier damage and increased permeability contributes to subpleural pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2021; 320 (06) L990-L1004
• 76 Kypta RM, Goldberg Y, Ulug ET, Courtneidge SA. Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell 1990; 62 (03) 481-492
• 77 Kilkenny DM, Rocheleau JV, Price J, Reich MB, Miller GG. c-Src regulation of fibroblast growth factor-induced proliferation in murine embryonic fibroblasts. J Biol Chem 2003; 278 (19) 17448-17454
• 78 Wilde A, Beattie EC, Lem L. et al. EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Cell 1999; 96 (05) 677-687
• 79 Ahangari F, Becker C, Foster DG. et al. Saracatinib, a selective Src kinase inhibitor, blocks fibrotic responses in preclinical models of pulmonary fibrosis. Am J Respir Crit Care Med 2022; 206 (12) 1463-1479
• 80 Yanagihara T, Tsubouchi K, Gholiof M. et al. Connective-tissue growth factor contributes to TGF-β1-induced lung fibrosis. Am J Respir Cell Mol Biol 2022; 66 (03) 260-270
• 81 Kono M, Nakamura Y, Suda T. et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin Chim Acta 2011; 412 (23-24): 2211-2215
• 82 Sonnylal S, Shi-Wen X, Leoni P. et al. Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis Rheum 2010; 62 (05) 1523-1532
• 83 Tam AYY, Horwell AL, Trinder SL. et al. Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension. Int J Biochem Cell Biol 2021; 134: 105961
• 84 Wang Q, Usinger W, Nichols B. et al. Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease. Fibrogenesis Tissue Repair 2011; 4 (01) 4
• 85 Richeldi L, Fernández Pérez ER, Costabel U. et al. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2020; 8 (01) 25-33
• 86 Raghu G, Richeldi L, Fernández Pérez ER. et al; ZEPHYRUS-1 Study Investigators. Pamrevlumab for idiopathic pulmonary fibrosis: the ZEPHYRUS-1 randomized clinical trial. JAMA 2024; 332 (05) 380-389
• 87 Song LL, Zhou HY, Ye PP. et al. A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants. Clin Transl Sci 2023; 16 (12) 2604-2613
• 88 She YX, Yu QY, Tang XX. Role of interleukins in the pathogenesis of pulmonary fibrosis. Cell Death Discov 2021; 7 (01) 52
• 89 Ng B, Dong J, D'Agostino G. et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med 2019; 11 (511) eaaw1237
• 90 He Y, Shen X, Zhai K, Nian S. Advances in understanding the role of interleukins in pulmonary fibrosis (review). Exp Ther Med 2024; 29 (02) 25
• 91 Martinez FJ, de Andrade JA, Anstrom KJ, King Jr TE, Raghu G. Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2093-2101
• 92 Raghu G, Brown KK, Costabel U. et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 2008; 178 (09) 948-955
• 93 Mozaffarian A, Brewer AW, Trueblood ES. et al. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J Immunol 2008; 181 (10) 7243-7253
• 94 Wong S, Botelho FM, Rodrigues RM, Richards CD. Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice. Lab Invest 2014; 94 (09) 1003-1016
• 95 Nagahama KY, Togo S, Holz O. et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol 2013; 49 (04) 582-591
• 96 Sassone-Corsi P. The cyclic AMP pathway. Cold Spring Harb Perspect Biol 2012; 4 (12) a011148
• 97 Lambers C, Boehm PM, Karabacak Y. et al. Combined activation of guanylate cyclase and cyclic AMP in lung fibroblasts as a novel therapeutic concept for lung fibrosis. BioMed Res Int 2019; 2019: 1345402
• 98 Herrmann FE, Hesslinger C, Wollin L, Nickolaus P. BI 1015550 is a PDE4B inhibitor and a clinical drug candidate for the oral treatment of idiopathic pulmonary fibrosis. Front Pharmacol 2022; 13: 838449
• 99 Liu X, Ostrom RS, Insel PA. cAMP-elevating agents and adenylyl cyclase overexpression promote an antifibrotic phenotype in pulmonary fibroblasts. Am J Physiol Cell Physiol 2004; 286 (05) C1089-C1099
• 100 Insel PA, Murray F, Yokoyama U. et al. cAMP and EPAC in the regulation of tissue fibrosis. Br J Pharmacol 2012; 166 (02) 447-456
• 101 Weng L, Wang W, Su X. et al. The Effect of cAMP-PKA activation on TGF-β1-induced profibrotic signaling. Cell Physiol Biochem 2015; 36 (05) 1911-1927
• 102 Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol 2002; 26 (02) 194-201
• 103 Liu X, Li F, Sun SQ. et al. Fibroblast-specific expression of AC6 enhances beta-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010; 298 (06) L819-L829
• 104 Clapp LH, Gurung R. The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: role of membrane versus nuclear receptors. Prostaglandins Other Lipid Mediat 2015; 120: 56-71
• 105 Nikitopoulou I, Manitsopoulos N, Kotanidou A. et al. Orotracheal treprostinil administration attenuates bleomycin-induced lung injury, vascular remodeling, and fibrosis in mice. Pulm Circ 2019; 9 (04) 2045894019881954
• 106 Lambers C, Roth M, Jaksch P. et al. Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation. Sci Rep 2018; 8 (01) 1087
• 107 Waxman A, Restrepo-Jaramillo R, Thenappan T. et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 2021; 384 (04) 325-334
• 108 Nathan SD, Behr J, Cottin V. et al. Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis. BMJ Open Respir Res 2022; 9 (01) e001310
• 109 Cortijo J, Iranzo A, Milara X. et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br J Pharmacol 2009; 156 (03) 534-544
• 110 Sisson TH, Christensen PJ, Muraki Y. et al. Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury. Physiol Rep 2018; 6 (12) e13753
• 111 Kim SW, Lim JY, Rhee CK. et al. Effect of roflumilast, novel phosphodiesterase-4 inhibitor, on lung chronic graft-versus-host disease in mice. Exp Hematol 2016; 44 (05) 332-341.e4
• 112 Kolb M, Crestani B, Maher TM. Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis. Eur Respir Rev 2023; 32 (167) 220206
• 113 Richeldi L, Azuma A, Cottin V. et al; 1305-0013 Trial Investigators. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med 2022; 386 (23) 2178-2187
• 114 Boehringer's nerandomilast meets primary endpoint in pivotal phase-III FIBRONEER-IPF study. 09/16/2024, 2024. Accessed March 26, 2025 at: https://www.boehringer-ingelheim.com/us/topline-results-boehringers-phase-iii-ipf-study
• 115 Schinner E, Wetzl V, Schramm A. et al. Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis. FEBS Open Bio 2017; 7 (04) 550-561
• 116 Beyer C, Zenzmaier C, Palumbo-Zerr K. et al. Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling. Ann Rheum Dis 2015; 74 (07) 1408-1416
• 117 Hemnes AR, Zaiman A, Champion HC. PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 2008; 294 (01) L24-L33
• 118 Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363 (07) 620-628
• 119 Kolb M, Raghu G, Wells AU. et al; INSTAGE Investigators. Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis. N Engl J Med 2018; 379 (18) 1722-1731
• 120 Dagamajalu S, Rex DAB, Gopalakrishnan L. et al. A network map of endothelin mediated signaling pathway. J Cell Commun Signal 2021; 15 (02) 277-282
• 121 Gallelli L, Pelaia G, D'Agostino B. et al. Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases. J Cell Biochem 2005; 96 (04) 858-868
• 122 Giaid A, Polak JM, Gaitonde V. et al. Distribution of endothelin-like immunoreactivity and mRNA in the developing and adult human lung. Am J Respir Cell Mol Biol 1991; 4 (01) 50-58
• 123 Saleh D, Furukawa K, Tsao MS. et al. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines. Am J Respir Cell Mol Biol 1997; 16 (02) 187-193
• 124 Pulito-Cueto V, Genre F, López-Mejías R. et al. Endothelin-1 as a biomarker of idiopathic pulmonary fibrosis and interstitial lung disease associated with autoimmune diseases. Int J Mol Sci 2023; 24 (02) 1275
• 125 Shahar I, Fireman E, Topilsky M. et al. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases. Int J Immunopharmacol 1999; 21 (11) 759-775
• 126 Cambrey AD, Harrison NK, Dawes KE. et al. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994; 11 (04) 439-445
• 127 Dawes KE, Cambrey AD, Campa JS. et al. Changes in collagen metabolism in response to endothelin-1: evidence for fibroblast heterogeneity. Int J Biochem Cell Biol 1996; 28 (02) 229-238
• 128 Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 2009; 41 (04) 484-493
• 129 Hocher B, Schwarz A, Fagan KA. et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 2000; 23 (01) 19-26
• 130 Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156 (2 Pt 1): 600-608
• 131 Mutsaers SE, Marshall RP, Goldsack NR, Laurent GJ, McAnulty RJ. Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Pulm Pharmacol Ther 1998; 11 (2-3): 221-225
• 132 King Jr TE, Behr J, Brown KK. et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177 (01) 75-81
• 133 King Jr TE, Brown KK, Raghu G. et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184 (01) 92-99
• 134 Raghu G, Behr J, Brown KK. et al; ARTEMIS-IPF Investigators*. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158 (09) 641-649
• 135 Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J, Group MS. MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013; 42 (06) 1622-1632
• 136 Cruz-Gervis R, Stecenko AA, Dworski R. et al. Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis. Respir Res 2002; 3 (01) 17
• 137 Suzuki T, Kropski JA, Chen J. et al. Thromboxane-prostanoid receptor signaling drives persistent fibroblast activation in pulmonary fibrosis. Am J Respir Crit Care Med 2022; 206 (05) 596-607
• 138 Perrakis A, Moolenaar WH. Autotaxin: structure-function and signaling. J Lipid Res 2014; 55 (06) 1010-1018
• 139 Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res 2014; 55 (07) 1192-1214
• 140 Salgado-Polo F, Borza R, Matsoukas MT. et al. Autotaxin facilitates selective LPA receptor signaling. Cell Chem Biol 2023; 30 (01) 69-84.e14
• 141 Ninou I, Magkrioti C, Aidinis V. Autotaxin in pathophysiology and pulmonary fibrosis. Front Med (Lausanne) 2018; 5: 180
• 142 Funke M, Zhao Z, Xu Y, Chun J, Tager AM. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol 2012; 46 (03) 355-364
• 143 Xu MY, Porte J, Knox AJ. et al. Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). Am J Pathol 2009; 174 (04) 1264-1279
• 144 Tager AM, LaCamera P, Shea BS. et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 2008; 14 (01) 45-54
• 145 Sakai N, Chun J, Duffield JS. et al. Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor. Kidney Int 2017; 91 (03) 628-641
• 146 Luo YL, Li Y, Zhou W, Wang SY, Liu YQ. Inhibition of LPA-LPAR1 and VEGF-VEGFR2 signaling in IPF treatment. Drug Des Devel Ther 2023; 17: 2679-2690
• 147 Oikonomou N, Mouratis MA, Tzouvelekis A. et al. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 2012; 47 (05) 566-574
• 148 Neighbors M, Li Q, Zhu SJ. et al. Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis. J Lipid Res 2023; 64 (06) 100375
• 149 Desroy N, Housseman C, Bock X. et al. Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a first-in-class autotaxin inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis. J Med Chem 2017; 60 (09) 3580-3590
• 150 Swaney JS, Chapman C, Correa LD. et al. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol 2010; 160 (07) 1699-1713
• 151 Gan L, Xue JX, Li X. et al. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation. Biochem Biophys Res Commun 2011; 409 (01) 7-13
• 152 Maher TM, van der Aar EM, Van de Steen O. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med 2018; 6 (08) 627-635
• 153 Maher TM, Ford P, Brown KK. et al; ISABELA 1 and 2 Investigators. Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis: the ISABELA 1 and 2 randomized clinical trials. JAMA 2023; 329 (18) 1567-1578
• 154 Taneja A, Jentsch G, Delage S. et al. ISABELA studies: plasma exposure and target engagement do not explain the lack of efficacy of ziritaxestat in patients with idiopathic pulmonary fibrosis. Clin Pharmacol Ther 2024; 115 (03) 606-615
• 155 Palmer SM, Snyder L, Todd JL. et al. Randomized, double-blind, placebo-controlled, phase 2 trial of BMS-986020, a lysophosphatidic acid receptor antagonist for the treatment of idiopathic pulmonary fibrosis. Chest 2018; 154 (05) 1061-1069
• 156 Corte TJ, Behr J, Cottin V. et al. Efficacy and safety of admilparant, an LPA₁ antagonist, in pulmonary fibrosis: a phase 2 randomized clinical trial. Am J Respir Crit Care Med 2025; 211 (02) 230-238
• 157 Freeberg MAT, Perelas A, Rebman JK, Phipps RP, Thatcher TH, Sime PJ. Mechanical feed-forward loops contribute to idiopathic pulmonary fibrosis. Am J Pathol 2021; 191 (01) 18-25
• 158 Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov 2022; 21 (01) 60-78
• 159 Lawton JS, Tamis-Holland JE, Bangalore S. et al; Writing Committee Members. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol 2022; 79 (02) 197-215
• 160 Polman CH, O'Connor PW, Havrdova E. et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354 (09) 899-910
• 161 Munger JS, Huang X, Kawakatsu H. et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96 (03) 319-328
• 162 Reed NI, Jo H, Chen C. et al. The αvβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med 2015; 7 (288) 288ra79
• 163 Shi M, Zhu J, Wang R. et al. Latent TGF-β structure and activation. Nature 2011; 474 (7351): 343-349
• 164 Horan GS, Wood S, Ona V. et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 2008; 177 (01) 56-65
• 165 Saini G, Porte J, Weinreb PH. et al. αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease. Eur Respir J 2015; 46 (02) 486-494
• 166 John AE, Graves RH, Pun KT. et al. Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nat Commun 2020; 11 (01) 4659
• 167 Raghu G, Mouded M, Chambers DC. et al. A phase IIb randomized clinical study of an anti-α_vβ₆ monoclonal antibody in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2022; 206 (09) 1128-1139
• 168 Lancaster L, Cottin V, Ramaswamy M. et al; PLN-74809-IPF-202 Trial Investigators. Bexotegrast in patients with idiopathic pulmonary fibrosis: the INTEGRIS-IPF clinical trial. Am J Respir Crit Care Med 2024; 210 (04) 424-434
• 169 Pliant Therapeutics Provides Update on BEACON-IPF, a Phase 2b/3 Trial in Patients with Idiopathic Pulmonary Fibrosis. 02/07/2025, 2025. Accessed March 26, 2025 at: https://ir.pliantrx.com/news-releases/news-release-details/pliant-therapeutics-provides-update-beacon-ipf-phase-2b3-trial
• 170 Staab-Weijnitz CA. Fighting the fiber: targeting collagen in lung fibrosis. Am J Respir Cell Mol Biol 2022; 66 (04) 363-381
• 171 Yoon I, Kim S, Cho M. et al. Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1. EMBO Mol Med 2023; 15 (07) e16940
• 172 Sakamoto N, Okuno D, Tokito T. et al. HSP47: a therapeutic target in pulmonary fibrosis. Biomedicines 2023; 11 (09) 2387
• 173 Barry-Hamilton V, Spangler R, Marshall D. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16 (09) 1009-1017
• 174 Raghu G, Brown KK, Collard HR. et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med 2017; 5 (01) 22-32
• 175 Sanders YY, Liu G. Transglutaminase-2: nature's glue in lung fibrosis?. Am J Respir Cell Mol Biol 2021; 65 (03) 243-244
• 176 Schafer MJ, White TA, Iijima K. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017; 8: 14532
• 177 Lagares D, Santos A, Grasberger PE. et al. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med 2017; 9 (420) eaal3765
• 178 Pan J, Li D, Xu Y. et al. Inhibition of Bcl-2/xl with ABT-263 selectively kills senescent type ii pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. Int J Radiat Oncol Biol Phys 2017; 99 (02) 353-361
• 179 Kim SH, Lee JY, Yoon CM. et al. Mitochondrial antiviral signaling protein is crucial for the development of pulmonary fibrosis. Eur Respir J 2021; 57 (04) 2000652
• 180 Gu L, Surolia R, Larson-Casey JL. et al. Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling. Cell Death Differ 2022; 29 (01) 118-132
• 181 He Y, Li F, Zhang C. et al. Therapeutic effects of the Bcl-2 inhibitor on bleomycin-induced pulmonary fibrosis in mice. Front Mol Biosci 2021; 8: 645846
• 182 Cooley JC, Javkhlan N, Wilson JA. et al. Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI Insight 2023; 8 (03) e163762
• 183 Nambiar A, Kellogg III D, Justice J. et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine 2023; 90: 104481
• 184 Jobling MF, Mott JD, Finnegan MT. et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res 2006; 166 (06) 839-848
• 185 Pociask DA, Sime PJ, Brody AR. Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest 2004; 84 (08) 1013-1023
• 186 Thannickal VJ, Fanburg BL. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. J Biol Chem 1995; 270 (51) 30334-30338
• 187 Hecker L, Vittal R, Jones T. et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 2009; 15 (09) 1077-1081
• 188 Thannickal VJ, Jandeleit-Dahm K, Szyndralewiez C, Török NJ. Pre- evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis. J Cell Mol Med 2023; 27 (04) 471-481
• 189 Huang LS, Jiang P, Feghali-Bostwick C, Reddy SP, Garcia JGN, Natarajan V. Lysocardiolipin acyltransferase regulates TGF-β mediated lung fibroblast differentiation. Free Radic Biol Med 2017; 112: 162-173
• 190 Hecker L, Logsdon NJ, Kurundkar D. et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 2014; 6 (231) 231ra47
• 191 Nogee LM, Dunbar III AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344 (08) 573-579
• 192 Wang WJ, Mulugeta S, Russo SJ, Beers MF. Deletion of exon 4 from human surfactant protein C results in aggresome formation and generation of a dominant negative. J Cell Sci 2003; 116 (Pt 4): 683-692
• 193 Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF. A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 2005; 32 (06) 521-530
• 194 Thurm T, Kaltenborn E, Kern S, Griese M, Zarbock R. SFTPC mutations cause SP-C degradation and aggregate formation without increasing ER stress. Eur J Clin Invest 2013; 43 (08) 791-800
• 195 Maguire JA, Mulugeta S, Beers MF. Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells. Am J Respir Cell Mol Biol 2011; 44 (03) 404-414
• 196 Nguyen H, Uhal BD. The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation. Am J Physiol Lung Cell Mol Physiol 2016; 311 (05) L846-L854
• 197 Delbrel E, Soumare A, Naguez A. et al. HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis. Sci Rep 2018; 8 (01) 17939
• 198 Baek HA, Kim DS, Park HS. et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol 2012; 46 (06) 731-739
• 199 Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I. The structure, activation and signaling of IRE1 and its role in determining cell fate. Biomedicines 2021; 9 (02) 156
• 200 Auyeung VC, Downey MS, Thamsen M. et al. IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2022; 322 (04) L564-L580
• 201 Katzen J, Rodriguez L, Tomer Y. et al. Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells. Proc Natl Acad Sci U S A 2022; 119 (43) e2123187119
• 202 Srour N, Thébaud B. Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med 2015; 4 (12) 1500-1510
• 203 Li DY, Li RF, Sun DX, Pu DD, Zhang YH. Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies. Stem Cell Res Ther 2021; 12 (01) 461
• 204 Ortiz LA, Dutreil M, Fattman C. et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007; 104 (26) 11002-11007
• 205 Germano D, Blyszczuk P, Valaperti A. et al. Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179 (10) 939-949
• 206 Garcia O, Carraro G, Turcatel G. et al. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS One 2013; 8 (08) e71679
• 207 Min F, Gao F, Li Q, Liu Z. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol Med Rep 2015; 11 (04) 2387-2396
• 208 Choi M, Ban T, Rhim T. Therapeutic use of stem cell transplantation for cell replacement or cytoprotective effect of microvesicle released from mesenchymal stem cell. Mol Cells 2014; 37 (02) 133-139
• 209 Cargnoni A, Gibelli L, Tosini A. et al. Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 2009; 18 (04) 405-422
• 210 Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget 2017; 8 (60) 102600-102616
• 211 Glassberg MK, Minkiewicz J, Toonkel RL. et al. Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I safety clinical trial. Chest 2017; 151 (05) 971-981
• 212 Averyanov A, Koroleva I, Konoplyannikov M. et al. First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline. Stem Cells Transl Med 2020; 9 (01) 6-16
• 213 Dinh PC, Cores J, Hensley MT. et al. Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies. Respir Res 2017; 18 (01) 132
• 214 Henry E, Cores J, Hensley MT. et al. Adult lung spheroid cells contain progenitor cells and mediate regeneration in rodents with bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med 2015; 4 (11) 1265-1274
• 215 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271-280.e8
• 216 Bezzerri V, Gentili V, Api M. et al. SARS-CoV-2 viral entry and replication is impaired in cystic fibrosis airways due to ACE2 downregulation. Nat Commun 2023; 14 (01) 132
• 217 Xu J, Xu X, Jiang L, Dua K, Hansbro PM, Liu G. SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis. Respir Res 2020; 21 (01) 182
• 218 Oz M, Lorke DE. Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury. Biomed Pharmacother 2021; 136: 111193
• 219 Wang R, Zagariya A, Ibarra-Sunga O. et al. Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. Am J Physiol 1999; 276 (05) L885-L889
• 220 Papp M, Li X, Zhuang J, Wang R, Uhal BD. Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG II. Am J Physiol Lung Cell Mol Physiol 2002; 282 (04) L713-L718
• 221 Li X, Molina-Molina M, Abdul-Hafez A, Uhal V, Xaubet A, Uhal BD. Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2008; 295 (01) L178-L185
• 222 Li X, Molina-Molina M, Abdul-Hafez A. et al. Extravascular sources of lung angiotensin peptide synthesis in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2006; 291 (05) L887-L895
• 223 Li X, Zhang H, Soledad-Conrad V, Zhuang J, Uhal BD. Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo. Am J Physiol Lung Cell Mol Physiol 2003; 284 (03) L501-L507
• 224 Marshall RP, McAnulty RJ, Laurent GJ. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med 2000; 161 (06) 1999-2004
• 225 Wang L, Wang Y, Yang T, Guo Y, Sun T. Angiotensin-converting enzyme 2 attenuates bleomycin-induced lung fibrosis in mice. Cell Physiol Biochem 2015; 36 (02) 697-711
• 226 Rey-Parra GJ, Vadivel A, Coltan L. et al. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J Mol Med (Berl) 2012; 90 (06) 637-647
• 227 Abadir P, Cosarderelioglu C, Damarla M. et al. Unlocking the protective potential of the angiotensin type 2 receptor (AT₂R) in acute lung injury and age-related pulmonary dysfunction. Biochem Pharmacol 2024; 220: 115978
• 228 Meng Y, Yu CH, Li W. et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol 2014; 50 (04) 723-736
• 229 Shenoy V, Kwon KC, Rathinasabapathy A. et al. Oral delivery of angiotensin-converting enzyme 2 and angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension. Hypertension 2014; 64 (06) 1248-1259
• 230 Kurisu S, Ozono R, Oshima T. et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension 2003; 41 (01) 99-107
• 231 Zheng X, Xu Z, Xu L. et al. Angiotensin II type 2 receptor inhibits M1 polarization and apoptosis of alveolar macrophage and protects against mechanical ventilation-induced lung injury. Inflammation 2025; 48 (01) 165-180
• 232 Rathinasabapathy A, Horowitz A, Horton K. et al. The selective angiotensin II type 2 receptor agonist, compound 21, attenuates the progression of lung fibrosis and pulmonary hypertension in an experimental model of bleomycin-induced lung injury. Front Physiol 2018; 9: 180
• 233 Murray LA, Rosada R, Moreira AP. et al. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS One 2010; 5 (03) e9683
• 234 Pilling D, Roife D, Wang M. et al. Reduction of bleomycin-induced pulmonary fibrosis by serum amyloid P. J Immunol 2007; 179 (06) 4035-4044
• 235 Murray LA, Chen Q, Kramer MS. et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by serum amyloid P. Int J Biochem Cell Biol 2011; 43 (01) 154-162
• 236 Pilling D, Gomer RH. Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice. PLoS One 2014; 9 (04) e93730
• 237 Raghu G, van den Blink B, Hamblin MJ. et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA 2018; 319 (22) 2299-2307
• 238 Richeldi L, Schiffman C, Behr J. et al. Zinpentraxin alfa for idiopathic pulmonary fibrosis: the randomized phase III STARSCAPE trial. Am J Respir Crit Care Med 2024; 209 (09) 1132-1140
• 239 Montesi SB, Gomez CR, Beers M. et al. Pulmonary fibrosis stakeholder summit: a joint NHLBI, three lakes foundation, and pulmonary fibrosis foundation workshop report. Am J Respir Crit Care Med 2024; 209 (04) 362-373
• 240 Laurila HP, Rajamäki MM. Update on canine idiopathic pulmonary fibrosis in West Highland White Terriers. Vet Clin North Am Small Anim Pract 2020; 50 (02) 431-446
• 241 Khan FA, Stewart I, Moss S. et al. Three-month FVC change: a trial endpoint for idiopathic pulmonary fibrosis based on individual participant data meta-analysis. Am J Respir Crit Care Med 2022; 205 (08) 936-948
• 242 Insilico Medicine announces positive topline results of ISM001–055 for the treatment of idiopathic pulmonary fibrosis (IPF) developed using generative AI. 11/12/2024, 2024. Accessed March 26, 2025 at: https://insilico.com/news/tnik-ipf-phase2a
• 243 Oldham JM, Ma SF, Martinez FJ. et al; IPFnet Investigators. TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2015; 192 (12) 1475-1482