Download PDF
Pneumologie 2003; 57(2): 91-97
DOI: 10.1055/s-2003-37153
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Die Bedeutung von Zytokinen und Wachstumsfaktoren bei fibrosierenden Lungenerkrankungen

The Role of Cytokines and Growth Factors in Fibroproliferative Lung DiseaseM.  Kolb1 , M.  Schmidt1
  • 1Medizinische Klinik der Julius-Maximilian-Universität Würzburg, Schwerpunkt Pneumologie (Direktor: Prof. Dr. G. Ertl)
DanksagungDie wissenschaftliche Arbeit des Erstautors wird gefördert durch die Stiftung Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft, Canadian Institute of Health Research und die Parker B. Francis Foundation.
Further Information

Publication History

Eingereicht: 31. Juli 2002

Nach Überarbeitung angenommen: 4. November 2002

Publication Date:
11 February 2003 (online)

Also available at
   Permissions and Reprints

Zusammenfassung

Ein neues pathogenetisches Konzept zur Fibrogenese hat die Hypothese aufgestellt, dass es sich bei der Fibrose um „pathologische Wundheilung” oder gestörtes „Remodeling” handelt und Entzündungsvorgänge sekundär sind. Zytokine sind bei diesem Prozess maßgeblich involviert und ein attraktives Ziel für pharmakologische Interventionen. TGFβ hat als profibrotischer Wachstumsfaktor eine Schlüsselstellung und kann auf verschiedenen Wegen inaktiviert oder in seiner Wirkung abgeschwächt werden. Diese Übersichtsarbeit erläutert die Grundlagen der pathobiologischen Abläufe und stellt ihre potenzielle klinische Bedeutung dar.

Abstract

A new hypothesis of the pathogenesis of fibroproliferative lung disease suggests that fibrosis is caused by abnormal and excessive wound healing and pathologic tissue remodelling. Inflammation is possibly an epiphenomenon. Cytokines are critical players in the pathologic process and attractive targets for pharmacological intervention. TGFβ is a key profibrotic growth factor, a variety of approaches are known to modify and inhibit its activity. This article reviews the basic pathological concepts of pulmonary fibrogenesis and outlines its potential clinical benefit.

Literatur

  • 1 Lympany P A, du Bois R M. Diffuse lung disease: product of genetic susceptibility and environmental encounters.  Thorax. 1997;  52 92-94
    PubMedGoogle Scholar
  • 2 Gross T J, Hunninghake G W. Idiopathic pulmonary fibrosis.  N Engl J Med. 2001;  345 517-525
    CrossrefPubMedGoogle Scholar
  • 3 Ryu J H, Colby T V, Hartman T E. Idiopathic pulmonary fibrosis: current concepts.  Mayo Clin Proc. 1998;  73 1085-1101
    PubMedGoogle Scholar
  • 4 American Thoracic Society . Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).  Am J Respir Crit Care Med. 2000;  161 646-664
    Google Scholar
  • 5 Selman M, King T E, Pardo A. Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy.  Ann Intern Med. 2001;  134 136-151
    CrossrefPubMedGoogle Scholar
  • 6 Sime P J, Gauldie J. Mechanisms of scarring. In: Evans TWHC (editor). ARDS in adults. London: Chapman & Hall Medical 1996: 215-231
    Google Scholar
  • 7 Sheppard D. Pulmonary fibrosis: a cellular overreaction or a failure of communication?.  J Clin Invest. 2001;  107 1501-1502
    PubMedGoogle Scholar
  • 8 Gauldie J, Kolb M, Sime P J. A new direction in the pathogenesis of idiopathic pulmonary fibrosis?.  Respir Res. 2002;  3 1
    CrossrefPubMedGoogle Scholar
  • 9 Lasky J A, Brody A R. Interstitial fibrosis and growth factors.  Environ Health Perspect. 2000;  108 Suppl 4 751-762
    PubMedGoogle Scholar
  • 10 Allen J T, Spiteri M A. Growth factors in idiopathic pulmonary fibrosis: relative roles.  Respir Res. 2002;  3 13
    CrossrefPubMedGoogle Scholar
  • 11 Kunkel S L. Chemotactic cytokines: the chemokine family. In: Phan S (editor). Pulmonary fibrosis. New York: Marcel Dekker 1995: 579-597
    Google Scholar
  • 12 Gauldie J, Sime P J, Xing Z. et al . Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis.  Curr Top Pathol. 1999;  93 35-45
    PubMedGoogle Scholar
  • 13 Remick D. Cytokines and pulmonary fibrosis. In: Pulmonary fibrosis. New York: Marcel Dekker 1995: 599-626
    Google Scholar
  • 14 Khalil N, O'Connor R N. Cytokine regulation of pulmonary fibrosis: TGFbeta. In: Pulmonary fibrosis. New York: Marcel Dekker 1995: 627-645
    Google Scholar
  • 15 Keane M P, Strieter R M. The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease.  Respir Res. 2002;  3 5
    CrossrefPubMedGoogle Scholar
  • 16 Ward P A, Hunninghake G W. Lung inflammation and fibrosis.  Am J Respir Crit Care Med. 1998;  157 S123-S129
    PubMedGoogle Scholar
  • 17 Dinarello C A. Interleukin-1.  Cytokine Growth Factor Rev. 1997;  8 253-265
    CrossrefPubMedGoogle Scholar
  • 18 Rochester C L, Elias J A. Cytokines and cytokine networking in the pathogenesis in interstitial and fibrotic lung disorders.  Semir Respir Crit Care Med. 1994;  14 389-416
    PubMedGoogle Scholar
  • 19 Boyle J E, Lindroos P M, Rice A B. et al . Prostaglandin-E2 counteracts interleukin-1beta-stimulated upregulation of platelet-derived growth factor alpha-receptor on rat pulmonary myofibroblasts.  Am J Respir Cell Mol Biol. 1999;  20 433-440
    PubMedGoogle Scholar
  • 20 Phan S H, Kunkel S L. Lung cytokine production in bleomycin-induced pulmonary fibrosis.  Exp Lung Res. 1992;  18 29-43
    PubMedGoogle Scholar
  • 21 Thrall R S, Scalise P J. Bleomycin. In: Phan SH (editor). Pulmonary Fibrosis. New York: Marcel Dekker 1995: 231-292
    Google Scholar
  • 22 Pan L H, Ohtani H, Yamauchi K. et al . Co-expression of TNF alpha and IL-1 beta in human acute pulmonary fibrotic diseases: an immunohistochemical analysis.  Pathol Int. 1996;  46 91-99
    PubMedGoogle Scholar
  • 23 Johnston C J, Piedboeuf B, Rubin P. et al . Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha mRNA levels in fibrosis-resistant and sensitive mice after thoracic irradiation.  Radiat Res. 1996;  145 762-767
    PubMedGoogle Scholar
  • 24 Lee Y M, Hybertson B M, Cho H G. et al . Platelet-activating factor contributes to acute lung leak in rats given interleukin-1 intratracheally.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L75-L80
    PubMedGoogle Scholar
  • 25 Hybertson B M, Lee Y M, Repine J E. Phagocytes and acute lung injury: dual roles for interleukin-1.  Ann NY Acad Sci. 1997;  832 266-273
    PubMedGoogle Scholar
  • 26 Kolb M, Margetts P J, Anthony D C. et al . Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis.  J Clin Invest. 2001;  107 1529-1536
    CrossrefPubMedGoogle Scholar
  • 27 Kotecha S, Wilson L, Wangoo A. et al . Increase in interleukin (IL)-1 beta and IL-6 in bronchoalveolar lavage fluid obtained from infants with chronic lung disease of prematurity.  Pediatr Res. 1996;  40 250-256
    CrossrefPubMedGoogle Scholar
  • 28 Sporn M B, Roberts A B. Peptide growth factors and their receptors. New York: Springer 1991
    Google Scholar
  • 29 Tufvesson E, Westergren-Thorsson G. Alteration of proteoglycan synthesis in human lung fibroblasts induced by interleukin-1beta and tumor necrosis factor-alpha.  J Cell Biochem. 2000;  77 298-309
    CrossrefPubMedGoogle Scholar
  • 30 Ortiz L A, Lasky J, Hamilton Jr R F. et al . Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice.  Exp Lung Res. 1998;  24 721-743
    PubMedGoogle Scholar
  • 31 Sime P J, Marr R A, Gauldie D. et al . Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts.  Am J Pathol. 1998;  153 825-832
    CrossrefPubMedGoogle Scholar
  • 32 Ziegenhagen M W, Schrum S, Zissel G. et al . Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis.  J Investig Med. 1998;  46 223-231
    PubMedGoogle Scholar
  • 33 O'Kane S, Ferguson M W. Transforming growth factor beta s and wound healing.  Int J Biochem Cell Biol. 1997;  29 63-78
    CrossrefPubMedGoogle Scholar
  • 34 Letterio J J, Roberts A B. TGF-beta: a critical modulator of immune cell function.  Clin Immunol Immunopathol. 1997;  84 244-250
    CrossrefPubMedGoogle Scholar
  • 35 Munger J S, 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;  96 319-328
    CrossrefPubMedGoogle Scholar
  • 36 Fish J E, Peters S P. Airway remodeling and persistent airway obstruction in asthma.  J Allergy Clin Immunol. 1999;  104 509-516
    CrossrefPubMedGoogle Scholar
  • 37 Mutsaers S E, Bishop J E, McGrouther G. et al . Mechanisms of tissue repair: from wound healing to fibrosis.  Int J Biochem Cell Biol. 1997;  29 5-17
    CrossrefPubMedGoogle Scholar
  • 38 Border W A, Noble N A. Transforming growth factor beta in tissue fibrosis.  N Engl J Med. 1994;  331 1286-1292
    CrossrefPubMedGoogle Scholar
  • 39 Rubin P, Johnston C J, Williams J P. et al . A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis [see comments].  Int J Radiat Oncol Biol Phys. 1995;  33 99-109
    CrossrefPubMedGoogle Scholar
  • 40 Sime P J, Xing Z, Graham F L. et al . Adenovector-mediated gene transfer of active transforming growth factor- beta1 induces prolonged severe fibrosis in rat lung.  J Clin Invest. 1997;  100 768-776
    CrossrefPubMedGoogle Scholar
  • 41 Anscher M S, Kong F M, Andrews K. et al . Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis.  Int J Radiat Oncol Biol Phys. 1998;  41 1029-1035
    CrossrefPubMedGoogle Scholar
  • 42 Fabisiak J P, Kelley J. Platelet derived growth factor. In: Kelley J (editor). Cytokines of the lung. New York: Marcel Dekker 1993: 3-39
    Google Scholar
  • 43 Rice A B, Moomaw C R, Morgan D L. et al . Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats.  Am J Pathol. 1999;  155 213-221
    PubMedGoogle Scholar
  • 44 Lasky J A, Tonthat B, Liu J Y. et al . Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats.  Am J Respir Crit Care Med. 1998;  157 1652-1657
    PubMedGoogle Scholar
  • 45 Bostrom H, Willetts K, Pekny M. et al . PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.  Cell. 1996;  85 863-873
    CrossrefPubMedGoogle Scholar
  • 46 Chung K F, Barnes P J. Cytokines in asthma.  Thorax. 1999;  54 825-857
    PubMedGoogle Scholar
  • 47 Barrios R, Pardo A, Ramos C. et al . Upregulation of acidic fibroblast growth factor during development of experimental lung fibrosis.  Am J Physiol. 1997;  273 L451-L458
    PubMedGoogle Scholar
  • 48 Liebler J M, Picou M A, Qu Z. et al . Altered immunohistochemical localization of basic fibroblast growth factor after bleomycin-induced lung injury.  Growth Factors. 1997;  14 25-38
    PubMedGoogle Scholar
  • 49 Kadono T, Kikuchi K, Kubo M. et al . Serum concentrations of basic fibroblast growth factor in collagen diseases.  J Am Acad Dermatol. 1996;  35 392-397
    CrossrefPubMedGoogle Scholar
  • 50 Stern J B, Fierobe L, Paugam C. et al . Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients.  Crit Care Med. 2000;  28 2326-2333
    PubMedGoogle Scholar
  • 51 Anscher M S, Peters W P, Reisenbichler H. et al . Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer.  N Engl J Med. 1993;  328 1592-1598
    CrossrefPubMedGoogle Scholar
  • 52 Vogel E, Kolb M, Mueller J. et al . BAL levels of the profibrotic cytokines TGFbeta and PDGF in patients with interstitial lung disease.  Eur Respir J. 2000;  14 369S
    PubMedGoogle Scholar
  • 53 Piguet P F, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice.  Eur Respir J. 1994;  7 515-518
    CrossrefPubMedGoogle Scholar
  • 54 Piguet P F, Vesin C, Grau G E. et al . Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica.  Cytokine. 1993;  5 57-61
    CrossrefPubMedGoogle Scholar
  • 55 Entzian P, Zahringer U, Schlaak M. et al . Comparative study on effects of pentoxifylline, prednisolone and colchicine in experimental alveolitis.  Int J Immunopharmacol. 1998;  20 723-735
    CrossrefPubMedGoogle Scholar
  • 56 Zabel P, Entzian P, Dalhoff K. et al . Pentoxifylline in treatment of sarcoidosis.  Am J Respir Crit Care Med. 1997;  155 1665-1669
    CrossrefPubMedGoogle Scholar
  • 57 Iyer S N, Gurujeyalakshmi G, Giri S N. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.  J Pharmacol Exp Ther. 1999;  291 367-373
    PubMedGoogle Scholar
  • 58 van den Berg W B. Anti-cytokine therapy in chronic destructive arthritis.  Arthritis Res. 2001;  3 18-26
    CrossrefPubMedGoogle Scholar
  • 59 Wang Q, Wang Y, Hyde D M. et al . Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters.  Thorax. 1999;  54 805-812
    PubMedGoogle Scholar
  • 60 Giri S N, Hyde D M, Braun R K. et al . Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis.  Biochem Pharmacol. 1997;  54 1205-1216
    CrossrefPubMedGoogle Scholar
  • 61 Giri S N, Hyde D M, Hollinger M A. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice.  Thorax. 1993;  48 959-966
    CrossrefPubMedGoogle Scholar
  • 62 Kolb M, Margetts P J, Galt T. et al . Transient Transgene Expression of Decorin in the Lung Reduces the Fibrotic Response to Bleomycin.  Am J Respir Crit Care Med. 2001;  163 770-777
    PubMedGoogle Scholar
  • 63 Molteni A, Moulder J E, Cohen E F. et al . Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker.  Int J Radiat Biol. 2000;  76 523-532
    CrossrefPubMedGoogle Scholar
  • 64 Gurujeyalakshmi G, Hollinger M A, Giri S N. Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level.  Am J Physiol. 1999;  276 L311-L318
    PubMedGoogle Scholar
  • 65 Gurujeyalakshmi G, Hollinger M A, Giri S N. Regulation of transforming growth factor-beta1 mRNA expression by taurine and niacin in the bleomycin hamster model of lung fibrosis.  Am J Respir Cell Mol Biol. 1998;  18 334-342
    PubMedGoogle Scholar
  • 66 Ziesche R, Hofbauer E, Wittmann K. et al . A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.  N Engl J Med. 1999;  341 1264-1269
    CrossrefPubMedGoogle Scholar
  • 67 Franklin T J. Therapeutic approaches to organ fibrosis.  Int J Biochem Cell Biol. 1997;  29 79-89
    CrossrefPubMedGoogle Scholar
  • 68 Marshall R P, McAnulty R J, Laurent G J. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor.  Am J Respir Crit Care Med. 2000;  161 1999-2004
    PubMedGoogle Scholar
  • 69 Yoshida M, Sakuma-Mochizuki J, Abe K. et al . In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis.  Biochem Biophys Res Commun. 1999;  265 503-508
    CrossrefPubMedGoogle Scholar
  • 70 Bienkowski R S, Gotkin M G. Control of collagen deposition in mammalian lung.  Proc Soc Exp Biol Med. 1995;  209 118-140
    PubMedGoogle Scholar
  • 71 Gurujeyalakshmi G, Giri S N. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression.  Exp Lung Res. 1995;  21 791-808
    PubMedGoogle Scholar
  • 72 Raghu G, Johnson W C, Lockhart D. et al . Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study.  Am J Respir Crit Care Med. 1999;  159 1061-1069
    CrossrefPubMedGoogle Scholar
  • 73 Unemori E N, Pickford L B, Salles A L. et al . Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.  J Clin Invest. 1996;  98 2739-2745
    PubMedGoogle Scholar
  • 74 Seibold J R, Korn J H, Simms R. et al . Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.  Ann Intern Med. 2000;  132 871-879
    PubMedGoogle Scholar

Dr. med. M. Kolb

Medizinische Universitätsklinik · Schwerpunkt Pneumologie

Josef-Schneider-Str. 11

97080 Würzburg

Email: kolb_m@klinik.uni-wuerzburg.de