Evaluation of the Efficacy of Tofacitinib, a JAK Inhibitor, in Alleviating Sepsis-Induced Multiple Organ Dysfunction Syndrome

Abstract

Sepsis, a life-threatening condition triggered by an uncontrolled response to infection, results in a systemic inflammatory response syndrome (SIRS) and the failure of multiple organs leading to multiple organ dysfunction (MODS). In the present study, we investigated the therapeutic potential of tofacitinib (TOFA), an FDA-approved inhibitor of JAK1 and JAK3 against sepsis, using a mouse model induced by cecal ligation puncture (CLP). Swiss albino mice were employed to replicate the CLP-induced sepsis model and were randomly divided into four groups: control, CLP, 150 mg/kg TOFA, and 300 mg/kg TOFA. Six hours after the last TOFA dose, we collected blood and tissue samples from the liver, lungs, kidneys, and spleen for histological analysis. Blood samples were used to assess granulocyte and lymphocyte percentages. Throughout the experiment, we monitored body weight and short-term survival. Our comparative histological analysis revealed that 150 mg/kg TOFA had a protective effect against multiple organ damage. Conversely, the study highlighted the harmful effects of 300 mg/kg TOFA, primarily due to liver and renal toxicity within this group. In summary, our findings demonstrate that tofacitinib at an optimal dose of 150 mg/kg showed promise as a potential therapeutic intervention for sepsis-induced multiple organ failure. However, caution is warranted when considering higher dosages.

Keywords

sepsis - molecular docking - tofacitinib - multiple organ dysfunction - cecal ligation puncture - histopathology

• References

• 1 Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, … Conference D. (2003). 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. 31
• 2 Chatterjee S, Bhattacharya M, Todi SK. Epidemiology of adult-population sepsis in India: a single center 5 year experience. Indian journal of critical care medicine: peer-reviewed, official publication of Indian Society of Critical Care Medicine 2017; 21: 573
• 3 Delano MJ, Ward PA. The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunological reviews 2016; 274: 330-353
• 4 Scicluna BP, Wiewel MA, Horn J. et al. Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. 2016; 1-11
• 5 Ramírez M. Multiple organ dysfunction syndrome. Current problems in pediatric and adolescent health care 2013; 43: 273-277
• 6 Shapiro N, Howell MD, Bates DW. et al. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Annals of emergency medicine 2006; 48: 583-590
• 7 Fragoulis GE, Mcinnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (United Kingdom) 2019; 58: i43-i54
• 8 Dhillon S. Tofacitinib: A Review in Rheumatoid Arthritis. Drugs 2017; 77: 1987-2001
• 9 Meyer DM, Jesson MI, Li X. et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. Journal of Inflammation 2010; 7: 1-12
• 10 Sandborn WJ, Su C, Sands BE. et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine 2017; 376: 1723-1736
• 11 Behrens F, Blanco R, Kaszuba A. et al. Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors. 2017; 1525-1536
• 12 Ibrahim O, Bayart CB, Hogan S. et al. Treatment of alopecia areata with tofacitinib. JAMA Dermatology 2017; 153: 600-602
• 13 Kim S, Thiessen PA, Bolton EE. et al. ‘PubChem substance and compound databases’. Nucleic Acids Res 2016; 44: D1202-D1213
• 14 O’Boyle NM, Banck M, James CA. et al. Open Babel: An open chemical toolbox. Journal of Cheminformatics 2011; 3: 33
• 15 Berman MH, Westbrook J, Feng Z. et al. ‘The protein data bank’. Nucleic Acids Research 2000; 28: 235-242 Nucleic Acids Research.
• 16 Forster M, Chaikuad A, Bauer SM. et al. Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket. Cell chemical biology 2016; 23: 1335-1340
• 17 Zak M, Hanan EJ, Lupardus P. et al. Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling. Bioorganic & medicinal chemistry letters 2019; 29: 1522-1531
• 18 Yang Z, Lasker K, Schneidman-Duhovny D. et al. UCSF Chimera, MODELLER, and IMP: an integrated modeling system. J Struct Biol 2012; 179: 269-278
• 19 Pettersen EF, Goddard TD, Huang CC. et al. ‘UCSF chimera--a. visualization system for exploratory research and analysis’. Journal of Computational Chemistry 2004; 25: 1605-1612
• 20 Morris GM, Huey R, Lindstrom W. et al. ‘AutoDock4 and AutoDockTools 4: automated docking with selective receptor flexibility’. J Comput Chem 2009; 30: 2785-2791
• 21 Trott O, Olson AJ. ‘AutoDock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading’. J Comput Chem 2010; 31: 455-461
• 22 Wallace AC, Laskowski RA, Thornton JM. ‘LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions’. Protein Engineering 1995; 8: 127-134
• 23 Schindelin J, Arganda-Carreras I, Frise E. et al. Fiji: an open-source platform for biological-image analysis. Nature methods 2012; 9: 676-682
• 24 Banerjee S, Biehl A, Gadina M. et al. JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 2017; 77: 521-546
• 25 Yun Y, Chen J, Wang X. et al. Tofacitinib Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Blocking the JAK-STAT1/STAT3 Signaling Pathway. BioMed Research International 2021; 1-9
• 26 Zhang X, Wang X, Sun L. et al. Tofacitinib reduces acute lung injury and improves survival in a rat model of sepsis by inhibiting the JAK-STAT/NF-κB pathway. Journal of Inflammation 2023; 20: 1-10
• 27 Jarneborn A, Mohammad M, Engdahl C. et al. Tofacitinib treatment aggravates Staphylococcus aureus septic arthritis, but attenuates sepsis and enterotoxin induced shock in mice. Scientific reports 2020; 10: 10891
• 28 De Vries LCS, Duarte JM, De Krijger M. et al. A JAK1 selective kinase inhibitor and tofacitinib affect macrophage activation and function. Inflammatory bowel diseases 2019; 25: 647-660
• 29 Pyo JY, Park JS, Park YB. et al. Delta neutrophil index as a marker for differential diagnosis between flare and infection in febrile systemic lupus erythematosus patients. Lupus 2013; 22: 1102-1109
• 30 Pyo JY, Ha YJ, Song JJ. et al. Delta neutrophil index contributes to the differential diagnosis between acute gout attack and cellulitis within 24 hours after hospitalization. Rheumatology 2017; 56: 795-801
• 31 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama 2016; 315: 801-810
• 32 Boomer JS, To K, Chang KC. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. Jama 2011; 306: 2594-2605
• 33 Venet F, Davin F, Guignant C. et al. Early assessment of leukocyte alterations at diagnosis of septic shock. Shock 2010; 34: 358-363
• 34 Muftuoglu MT, Aktekin A, Ozdemir NC. et al. Liver injury in sepsis and abdominal compartment syndrome in rats. Surgery today 2006; 36: 519-524
• 35 Kanhutu K, Jones P, Cheng AC. et al. Spleen Australia guidelines for the prevention of sepsis in patients with asplenia and hyposplenism in Australia and New Zealand. Internal Medicine Journal 2017; 47: 848-855
• 36 Hotchkiss RS, Tinsley KW, Swanson PE. et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. The Journal of Immunology 2001; 166: 6952-6963
• 37 Uchino S, Kellum JA, Bellomo R. et al. Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. Jama 2005; 294: 813-818
• 38 Tiwari MM, Brock RW, Megyesi JK. et al. Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases. American Journal of Physiology-Renal Physiology 2005; 289: F1324-F1332
• 39 Joshi K, Gupta SRR, Verma S. et al. ‘Virtual screening of plant phytochemicals to discover potent Janus kinase-1 inhibitors against severe COVID-19 and sepsis’. Int. J. Computational Biology and Drug Design 2023; 15: 391-411
• 40 Groner B, von Manstein V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Molecular and Cellular Endocrinology 2017; 451: 1-14
• 41 Elke G, Bloos F, Wilson DC. et al. Identification of developing multiple organ failure in sepsis patients with low or moderate SOFA scores. Critical Care 2018; 22: 1-3
• 42 O’Shea JJ, Schwartz DM, Villarino AV. et al. The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annual Review of Medicine 2015; 66: 311-328