Das akute Lungenversagen – Pulmonale Reparatur und therapeutische Optionen

Zusammenfassung

Das akute respiratorische distress syndrome (ARDS) ist charakterisiert durch inflammatorisch bedingtes Lungenödem, hyaline Membranen, diffusen endothelialen und epithelialen Schaden sowie Fibrose. Ein Überleben impliziert Lungenreparatur. Diese Übersicht fast den aktuellen Wissenstand in Bezug auf Reparatur sowie genetische Faktoren zusammen, die Einfluss nehmen auf Letalität und Schweregrad des ARDS.

Summary

The acute respiratory distress syndrome (ARDS) is characterized by inflammation evoked pulmonary edema, hyaline membranes, diffuse endothelial and epithelial injury, and fibrosis. For survival to occur lung repair is required. This review explores recent advances in the field of fibroproliferation with emphasis on cellular and soluble factors, mechanisms involved in lung repair, and genetic factors which influence severity and survival in ARDS.

ARDS - extrazelluläres Proteasom - Lungenumbau - Polymorphismen - Lungenreparatur - Therapie

ARDS - extracellular proteasome - lung repair - polymorphisms - prognosis - therapy

Kernaussagen

• 30–70  % der ARDS–Patienten überleben unter qualifizierter Therapie einschließlich extrakorporalem Lungenersatz in spezialisierten Zentren.

• Überleben Patienten das ARDS, sind im Langzeitverlauf in vielen Fällen nur noch geringe pulmonale Veränderungen und Funktionseinschränkungen nachweisbar.

• Es gibt bislang keine kausale bzw. spezifische Therapie, pulmonale Reparaturmechanismen positiv zu beeinflussen – das ist jedoch Ziel aktueller Forschung.

• Migration, Proliferation und Regeneration von Pneumozyten Typ II und deren Sekretion von extrazellulären Enzymen in den Alveolarraum sind essenzielle Elemente pulmonaler Reparatur.

• Die Einwanderung atemwegsresidenter, transdifferenzierter mesenchymaler Zellen sowie pluripotenter Knochenmarkszellen in den Alveolarraum und Apoptose von Pneumozyten trägt wesentlich zur Wiederherstellung alveolärer Integrität bei.

• In der Reparaturphase des ARDS gelangen enzymatische „Fressmaschinen” in den geschädigten Alveolarraum, um dort hyaline Membranen abzuräumen.

• Alveolarmakrophagen sezernieren Mediatoren und Wachstumsfaktoren, die zu einer proliferativen Antwort von Fibroblasten und glatten Muskelzellen führen.

• Wesentliches Schlüsselelement in der Lungenfibrose ist TGF–β.

• Auch das lokale Gerinnungssystem an der Alveolaroberfläche spielt eine wichtige Rolle in der Entwicklung der Lungenfibrose.

• Inzidenz und Krankheitsverlauf werden durch die individuelle genetische Konstellation erheblich beeinflusst.

Literatur

• 1 Deja M. et al. . Evidence–based therapy of severe acute respiratory distress syndrome: an algorithm–guided approach.  J Int Med Res. 2008;  36 211-21
• 2 Herridge MS. et al. . One–year outcomes in survivors of the acute respiratory distress syndrome.  N Engl J Med. 2003;  348 683-93
• 3 Gattinoni L. et al. . Lung structure and function in different stages of severe adult respiratory distress syndrome.  Jama. 1994;  271 1772-9
• 4 Demling RH.. Current concepts on the adult respiratory distress syndrome.  Circ Shock. 1990;  30 297-309
• 5 Marshall R, Bellingan G, Laurent G.. The acute respiratory distress syndrome: fibrosis in the fast lane.  Thorax. 1998;  53 815-7
• 6 Gattinoni L. et al. . Inflammatory pulmonary edema and positive end–expiratory pressure: correlations between imaging and physiologic studies.  J Thorac Imaging. 1988;  3 59-64
• 7 Klein JJ. et al. . Pulmonary function after recovery from the adult respiratory distress syndrome.  Chest. 1976;  69 350-5
• 8 Richardson JV. et al. . Late pulmonary function in survivors of adult respiratory distress syndrome.  South Med. 1976;  69 740
• 9 Simpson DL. et al. . Long–term follow–up and bronchial reactivity testing in survivors of the adult respiratory distress syndrome.  Am Rev Respir Dis. 1978;  117 449-54
• 10 Elliott CG, Morris AH, Cengiz M.. Pulmonary function and exercise gas exchange in survivors of adult respiratory distress syndrome.  Am Rev Respir Dis. 1981;  123 492-5
• 11 McHugh LG. et al. . Recovery of function in survivors of the acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1994;  150 90-4
• 12 Castro CY.. ARDS and diffuse alveolar damage: a pathologist's perspective.  Semin Thorac Cardiovasc Surg. 2006;  18 13-9
• 13 Karayannis G. et al. . Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure.  Heart Fail Rev. 2008;  44 91-8
• 14 White HD.. Remodelling of the heart after myocardial infarction.  Aust N Z J Med. 1992;  22 601-6
• 15 Brilla CG, Maisch B.. Regulation of the structural remodelling of the myocardium: from hypertrophy to heart failure.  Eur Heart J. 1994;  15 45-52
• 16 Meduri GU.. Late adult respiratory distress syndrome.  New Horiz. 1993;  1 563-77
• 17 Geiser T.. Mechanisms of alveolar epithelial repair in acute lung injury – a translational approach.  Swiss Med Wkly. 2003;  133 586-90
• 18 Dos Santos CC.. Advances in mechanisms of repair and remodelling in acute lung injury.  Intensive Care Med. 2008;  34 619-30
• 19 Elkington PT, Friedland JS.. Matrix metalloproteinases in destructive pulmonary pathology.  Thorax. 2006;  61 259-66
• 20 Schonbeck U, Mach F, Libby P.. Generation of biologically active IL–1 beta by matrix metalloproteinases: a novel caspase–1–independent pathway of IL–1 beta processing.  J Immunol. 1998;  161 3340-6
• 21 Ito A. et al. . Degradation of interleukin 1beta by matrix metalloproteinases.  J Biol Chem. 1996;  271 14657-60
• 22 Ricou B. et al. . Matrix metalloproteinases and TIMP in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  154 346-52
• 23 Torii K. et al. . Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.  Am J Respir Crit Care Med. 1997;  155 43-6
• 24 Lanchou J. et al. . Imbalance between matrix metalloproteinases (MMP–9 and MMP–2) and tissue inhibitors of metalloproteinases (TIMP–1 and TIMP–2) in acute respiratory distress syndrome patients.  Crit Care Med. 2003;  31 536-42
• 25 Pardo A. et al. . Increased expression of gelatinases and collagenase in rat lungs exposed to 100 % oxygen.  Am J Respir Crit Care Med. 1996;  154 1067-75
• 26 Pugin J. et al. . The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome.  Crit Care Med. 1999;  27 304-12
• 27 Armstrong L. et al. . Changes in collagen turnover in early acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;  160 1910-5
• 28 Suzuki K. et al. . Protective role of activated protein C in lung and airway remodeling.  Crit Care Med. 2004;  32 262-5
• 29 Porter RM, Lane EB.. Phenotypes, genotypes and their contribution to understanding keratin function.  Trends Genet. 2003;  19 278-85
• 30 Kotton DN. et al. . Bone marrow–derived cells as progenitors of lung alveolar epithelium.  Development. 2001;  128 5181-8
• 31 Yamada M. et al. . Bone marrow–derived progenitor cells are important for lung repair after lipopolysaccharide–induced lung injury.  J Immunol. 2004;  172 1266-72
• 32 Rojas M. et al. . Bone marrow–derived mesenchymal stem cells in repair of the injured lung.  Am J Respir Cell Mol Biol. 2005;  33 145-52
• 33 Kuwano K, Hagimoto N, Nakanishi Y.. The role of apoptosis in pulmonary fibrosis.  Histol Histopathol. 2004;  19 867-81
• 34 Li HP. et al. . The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin–induced pulmonary fibrosis in rats.  Respirology. 2004;  9 25-32
• 35 Desmouliere A. et al. . Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar.  Am J Pathol. 1995;  146 56-66
• 36 Horowitz JC. et al. . Constitutive activation of prosurvival signaling in alveolar mesenchymal cells isolated from patients with nonresolving acute respiratory distress syndrome.  Am J Physiol Lung Cell Mol Physiol. 2006;  290 415-25
• 37 Budinger GR, Chandel NS.. The role of cell suicide or apoptosis in the pathophysiology of acute lung injury.  Intensive Care Med. 2001;  27 1091-3
• 38 Wang R. et al. . Fas–induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction.  Am J Physiol. 1999;  277 1245-50
• 39 Hagimoto N. et al. . TGF–beta 1 as an enhancer of Fas–mediated apoptosis of lung epithelial cells.  J Immunol. 2002;  168 6470-8
• 40 Sookhai S. et al. . A novel therapeutic strategy for attenuating neutrophil–mediated lung injury in vivo.  Ann Surg. 2002;  235 285-91
• 41 Braude S. et al. . Adult respiratory distress syndrome after allogeneic bone–marrow transplantation: evidence for a neutrophil–independent mechanism.  Lancet. 1985;  1 1239-42
• 42 Clark JG, Kuhn 3rd. C. Bleomycin–induced pulmonary fibrosis in hamsters: effect of neutrophil depletion on lung collagen synthesis.  Am Rev Respir Dis. 1982;  126 737-9
• 43 Sixt SU, Beiderlinden M, Jennissen HP, Peters J.. Extracellular proteasome in the human alveolar space: a new housekeeping enzyme?.  Am J Physiol Lung Cell Mol Physiol. 2007;  292 1280-8
• 44 Sixt SU, Dahlmann B.. Extracellular, circulating proteasomes and ubiquitin – Incidence and relevance. Biochim Biophys Acta 2008
• 45 Hashimoto S. et al. . Neutrophil elastase activity in acute lung injury and respiratory distress syndrome.  Respirology. 2008;  44 581-4
• 46 Shih JY. et al. . Elevated serum levels of mucin–associated antigen in patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1997;  156 1453-7
• 47 Rose MC, Voynow JA.. Respiratory tract mucin genes and mucin glycoproteins in health and disease.  Physiol Rev. 2006;  86 245-78
• 48 Reynolds HY.. Lung inflammation and fibrosis: an alveolar macrophage–centered perspective from the 1970s to 1980s.  Am J Respir Crit Care Med. 2005;  171 98-102
• 49 Shimabukuro DW, Sawa T, Gropper MA.. Injury and repair in lung and airways.  Crit Care Med. 2003;  31 524-31
• 50 Dayer JM. et al. . Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells.  J Clin Invest. 1986;  77 645-8
• 51 Portnoy J. et al. . Alveolar type II cells inhibit fibroblast proliferation: role of IL–1alpha.  Am J Physiol Lung Cell Mol Physiol. 2006;  290 307-16
• 52 Ishida Y. et al. . Absence of IL–1 receptor antagonist impaired wound healing along with aberrant NF–kappaB activation and a reciprocal suppression of TGF–beta signal pathway.  J Immunol. 2006;  176 5598-606
• 53 Kolb M. et al. . Transient expression of IL–1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis.  J Clin Invest. 2001;  107 1529-36
• 54 Fahy RJ. et al. . The acute respiratory distress syndrome: a role for transforming growth factor–beta 1.  Am J Respir Cell Mol Biol. 2003;  28 499-503
• 55 Pittet JF. et al. . TGF–beta is a critical mediator of acute lung injury.  J Clin Invest. 2001;  107 1537-44
• 56 Matthay MA, Robriquet L, Fang X.. Alveolar epithelium: role in lung fluid balance and acute lung injury.  Proc Am Thorac Soc. 2005;  2 206-13
• 57 Carmeliet P. et al. . Physiological consequences of loss of plasminogen activator gene function in mice.  Nature. 1994;  368 419-24
• 58 Xu ZH. et al. . Pulmonary edema induced by angiotensin I in rats.  Jpn J Pharmacol. 1998;  76 51-6
• 59 Yamamoto T. et al. . Angiotensin II–induced pulmonary edema in a rabbit model.  Jpn J Pharmacol. 1997;  73 33-40
• 60 Kiely DG. et al. . Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.  Cardiovasc Res. 1997;  33 201-8
• 61 Chesnutt AN. et al. . Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance.  Am J Respir Crit Care Med. 1997;  156 840-5
• 62 Marshall RP. et al. . Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.  Thorax. 2000;  55 143-6
• 63 Wang R. et al. . Human lung myofibroblast–derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides.  Am J Physiol. 1999;  277 1158-64
• 64 Marshall RP. et al. . Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2002;  166 646-50
• 65 Adamzik M. et al. . ACE I/D but not AGT (–6)A/G polymorphism is a risk factor for mortality in ARDS.  Eur Respir J. 2007;  29 482-8
• 66 Goodman RB. et al. . Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  154 602-11
• 67 Blackwell TS, Christman JW.. The role of nuclear factor–kappa B in cytokine gene regulation.  Am J Respir Cell Mol Biol. 1997;  17 3-9
• 68 Barnes PJ, Karin M.. Nuclear factor–kappaB: a pivotal transcription factor in chronic inflammatory diseases.  N Engl J Med. 1997;  336 1066-71
• 69 Madjdpour L. et al. . Acid–induced lung injury: role of nuclear factor–kappaB.  Anesthesiology. 2003;  99 1323-32
• 70 Schwartz MD. et al. . Nuclear factor–kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome.  Crit Care Med. 1996;  24 1285-92
• 71 Adamzik M. et al. . Insertion/deletion polymorphism in the promoter of NFKB1 influences severity but not mortality of acute respiratory distress syndrome.  Intensive Care Med. 2007;  33 1199-203
• 72 Adamzik M. et al. . Factor V Leiden mutation is associated with improved 30–day survival in patients with acute respiratory distress syndrome.  Crit Care Med. 2008;  36 1776-9
• 73 Tsangaris I. et al. .The impact of the PAI–1 4G/5G polymorphism on the outcome of patients with ALI/ARDS. Thromb Res 2008
• 74 Hildebrand F. et al. . Association of IL–8–251A/T polymorphism with incidence of Acute Respiratory Distress Syndrome (ARDS) and IL–8 synthesis after multiple trauma.  Cytokine. 2007;  37 192-9
• 75 Gong MN. et al. . Interleukin–10 polymorphism in position –1082 and acute respiratory distress syndrome.  Eur Respir J. 2006;  27 674-81
• 76 Wunderink RG. et al. . Tumor necrosis factor gene polymorphisms and the variable presentation and outcome of community–acquired pneumonia.  Chest. 2002;  121
• 77 Gong MN. et al. . –308GA and TNFB polymorphisms in acute respiratory distress syndrome.  Eur Respir J. 2005;  26 382-9
• 78 Bajwa EK. et al. . Pre–B–cell colony–enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome.  Crit Care Med. 2007;  35 1290-5
• 79 Gong MN. et al. . Polymorphisms in the mannose binding lectin–2 gene and acute respiratory distress syndrome.  Crit Care Med. 2007;  35 48-56
• 80 Floros J, Kala P.. Surfactant proteins: molecular genetics of neonatal pulmonary diseases.  Annu Rev Physiol. 1998;  60 365-84
• 81 Lin Z. et al. . Polymorphisms of human SP–A, SP–B, and SP–D genes: association of SP–B Thr131Ile with ARDS.  Clin Genet. 2000;  58 181-91
• 82 Koh H. et al. . Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome.  Respirology. 2008;  44 281-4
• 83 Zhai R. et al. . Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS.  Thorax. 2007;  62 718-22
• 84 Chapman HA.. Disorders of lung matrix remodeling.  J Clin Invest. 2004;  113 148-57
• 85 Ranieri VM. et al. . Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.  Jama. 1999;  282 54-61
• 86 Amato MB. et al. . Beneficial effects of the "open lung approach" with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation.  Am J Respir Crit Care Med. 1995;  152 1835-46
• 87 Ibrahim EH. et al. . The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting.  Chest. 2000;  118 146-55
• 88 Leibovici L. et al. . The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection.  J Intern Med. 1998;  244 379-86
• 89 Wiedemann HP. et al. . Comparison of two fluid–management strategies in acute lung injury.  N Engl J Med. 2006;  354 2564-75
• 90 Guerin C. et al. . Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.  Jama. 2004;  292 2379-87
• 91 Papazian L. et al. . Comparison of prone positioning and high–frequency oscillatory ventilation in patients with acute respiratory distress syndrome.  Crit Care Med. 2005;  33 2162-71
• 92 Imai Y, Kuba K, Penninger JM.. The discovery of angiotensin–converting enzyme 2 and its role in acute lung injury in mice.  Exp Physiol. 2008;  93 543-8
• 93 Imai Y. et al. . Angiotensin–converting enzyme 2 protects from severe acute lung failure.  Nature. 2005;  436 112-6
• 94 Marceau F, Regoli D.. Bradykinin receptor ligands: therapeutic perspectives.  Nat Rev Drug Discov. 2004;  3 845-52
• 95 Kuba K. et al. . A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury.  Nat Med. 2005;  11 875-9
• 96 Gao F. et al. . Statins and sepsis.  Br J Anaesth. 2008;  100 288-98
• 97 Chalmers JD. et al. . Prior statin use is associated with improved outcomes in community–acquired pneumonia.  Am J Med. 2008;  121
• 98 McAuley DF. et al. . Clinically relevant concentrations of beta2–adrenergic agonists stimulate maximal cyclic adenosine monophosphate–dependent airspace fluid clearance and decrease pulmonary edema in experimental acid–induced lung injury.  Crit Care Med. 2004;  32 1470-6
• 99 Sakuma T. et al. . Beta–adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs.  Am J Respir Crit Care Med. 1997;  155 506-12
• 100 Vincent JL. et al. . Drotrecogin alfa (activated) treatment in severe sepsis from the global open–label trial ENHANCE: further evidence for survival and safety and implications for early treatment.  Crit Care Med. 2005;  33 2266-77
• 101 Bernard GR. et al. . Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
• 102 Dellinger RP. et al. . Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.  Crit Care Med. 1998;  26 15-23
• 103 Baker SE, Hockman RH.. Inhaled iloprost in pulmonary arterial hypertension.  Ann Pharmacother. 2005;  39 1265-74
• 104 Barnett CF, Machado RF.. Sildenafil in the treatment of pulmonary hypertension.  Vasc Health Risk Manag. 2006;  2 411-22
• 105 Gattinoni L. et al. . Treatment of acute respiratory failure with low–frequency positive–pressure ventilation and extracorporeal removal of CO2.  Lancet. 1980;  2 292-4
• 106 Lewandowski K.. Extracorporeal membrane oxygenation for severe acute respiratory failure.  Crit Care. 2000;  4 156-68
• 107 Beiderlinden M. et al. . Treatment of severe acute respiratory distress syndrome: role of extracorporeal gas exchange.  Intensive Care Med. 2006;  32 1627-31
• 108 Beiderlinden M, Kuehl H, Boes T, Peters J.. Prevalence of pulmonary hypertension associated with severe acute respiratory distress syndrome: predictive value of computed tomography.  Intensive Care Med. 2006;  32 852-7
• 109 Steinberg KP. et al. . Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.  N Engl J Med. 2006;  354 1671-84
• 110 Peter JV. et al. . Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta–analysis.  Bmj. 2008;  336 1006-9