Potential Therapeutic Initiatives for Fibrogenic Lung Diseases
1995; Elsevier BV; Volume: 108; Issue: 3 Linguagem: Inglês
10.1378/chest.108.3.848
ISSN1931-3543
AutoresRonald H. Goldstein, Alan Fine,
Tópico(s)Neonatal Respiratory Health Research
ResumoFibrotic process affecting the lung and other tissues is characterized by stimulation of fibroblast proliferation and connective tissue deposition. Conventional therapy consisting of glucocorticoids or cytotoxic agents is usually ineffective in blocking progression of disease. Potential new therapies have emerged from the use of animal models of pulmonary fibrosis and recent advances in the cellular and molecular biology of inflammatory reactions. Such therapies involve the use of substances directed against the action of certain growth factors, cytokines, or oxidants that are elaborated during the fibrotic reaction. In this article, we review possible therapeutic applications of these advances. Fibrotic process affecting the lung and other tissues is characterized by stimulation of fibroblast proliferation and connective tissue deposition. Conventional therapy consisting of glucocorticoids or cytotoxic agents is usually ineffective in blocking progression of disease. Potential new therapies have emerged from the use of animal models of pulmonary fibrosis and recent advances in the cellular and molecular biology of inflammatory reactions. Such therapies involve the use of substances directed against the action of certain growth factors, cytokines, or oxidants that are elaborated during the fibrotic reaction. In this article, we review possible therapeutic applications of these advances. epithelial lining fluid granulocyte macrophage colony-stimulating factor interleukin IL-1 receptor antagonist idiopathic pulmonary fibrosis nicotinamide adenosine dinucleotide prostaglandin E2 transforming growth factor-β tumor necrosis factor-α Diseases characterized by the laying down of excess connective tissue affect many organs and tissues of the body. Although other connective tissue elements increase, the stimulation of fibroblasts to proliferate and deposit excess type I collagen is the most prominent feature of the fibrosing process. This accumulation of collagen disrupts normal organ function. In the heart, longstanding systemic hypertension results in replacement of myocardial muscle cells by fibrous tissue with resultant diastolic dysfunction and heart failure.1Weber KT Sun Y Tyagi SC et al.Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms..J Mol Cell Cardiol. 1994; 26: 279-292Abstract Full Text PDF PubMed Scopus (435) Google Scholar After abdominal surgery, adhesions may cause intestinal obstruction. In the eye, fibrous opacification of the cornea impairs vision. Cutaneous sclerosis may occur locally, as after burns, or it may be widespread as part of progressive systemic sclerosis. In the liver, the scarring of cirrhosis often results in disruption of structure and function. Although antifibrotic therapy is of potential benefit in any of these conditions, this review will focus on diseases that cause widespread fibrosis in the lungs. Many conditions of both known and unknown etiology may produce excess connective tissue deposition in the lungs.2Crouch E. Pathobiology of pulmonary fibrosis..Am J Physiol. 1990; 259: L159-84PubMed Google Scholar This disorder is variously known as interstitial pulmonary fibrosis or fibrosing alveolitis. These processes may develop over a course measured in days, as in ARDS or over a course measured in years as in the pneumoconioses or idiopathic pulmonary fibrosis (IPF). During the last 3 decades, careful study of human lungs and of animal models of interstitial pulmonary fibrosis by histologic study, ultrastructure, and BAL using the techniques of cell and molecular biology has cast new light on the pathogenesis of these disorders. The initial injury results in damage to the alveolar epithelium or capillary endothelium. An inflammatory response follows that is initially predominantly neutrophilic but soon goes on to a predominance of lymphocytes and macrophages. Unlike many inflammatory processes in the lungs such as pneumococcal pneumonia, resolution does not follow. Effector substances released during inflammation may injure the lung or perpetuate the inflammation by acting as chemoattractants for inflammatory cells. Products of inflammation such as oxidants and proteases may further damage the lungs. Type II alveolar epithelial cells dedifferentiate, replicate, and spread out to replace the sloughed type I alveolar cells. Fibroblasts proliferate in the alveolar walls and in the respiratory airspaces in response to growth factors and deposit new connective tissue that is primarily type I collagen. The accumulation of collagen disrupts function and there is evidence that inhibition of collagen deposition attenuates the physiologic disturbance.3Riley DJ Kerr JS Berg RA et al.Prevention of bleomycin-induced pulmonary fibrosis in the hamsters by cis-4-hydroxypro-line-1-proline..Am Rev Respir Dis. 1981; 123: 388-393PubMed Google Scholar Fibrosing lung diseases may have serious consequences. The onset of the fibroproliferative phase of ARDS heralds a poor outcome. IPF has a 5-year survival of about 50%.4du Bois RM. Idiopathic pulmonary fibrosis..Annu Rev Med. 1993; 44: 441-450Crossref Scopus (18) Google Scholar Current therapy for IPF includes use of corticosteroids and antimetabolites.5Johnson MA Kwan S Snell NJ et al.Randomised controlled trial compared prednisolone alone with cyclophosphamide with low dose prednisolone in combination in cryptogenic fibrosing alveolitis..Thorax. 1989; 44: 280-288Crossref PubMed Scopus (275) Google Scholar, 6Raghu G Depaso WJ Cain K et al.Azathioprine combined with prednisone in the treatment of pulmonary fibrosis: a prospective double-blind randomized, placebo-controlled clinical trial..Am Rev Respir Dis. 1991; 144: 291-296Crossref PubMed Scopus (397) Google Scholar, 7Dayton CS Schwartz DA Helmers RA et al.Outcome of subjects with idiopathic pulmonary fibrosis who fail corticsteroid therapy: implications for further studies..Chest. 1993; 103: 69-73Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 8Baughman RP Lower EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis..Chest. 1992; 102: 1090-1094Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Other agents used with variable results include colchicine,9Peters SG McDougall JC Douglas WW et al.Colchicine in the treatment of pulmonary fibrosis..Chest. 1993; 103: 101-104Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar cyclosporine,10Moolman JA Bardin PG Rossouw DJ et al.Cyclosporin as a treatment for interstitial lung disease of unknown aetiology..Thorax. 1991; 46: 592-595Crossref PubMed Scopus (78) Google Scholar and penicillamine.11Jimenez SA Sigal SH. A 15-year prospective study of treatment of rapidly progressive systemic sclerosis with D-penicillamine..J Rheumatol. 1991; 18: 1496-1503PubMed Google Scholar Single lung transplantation holds considerable promise as a treatment for IPF. However, the selection criteria for transplant candidates, the availability of suitable donor lungs, and the costs will likely limit its use. A potential therapeutic agent could act at any of the steps in the pathogenetic pathway that results in fibrosis. Among such agents might be drugs that limit proteolytic or oxidative damage, inhibit the migration of inflammatory cells in the lung, or interfere with the action of inflammatory mediators or with the biosynthesis of collagen. It is not clear whether normal healing can occur after inhibition of collagen deposition; restoring structural integrity may require repair of alveolar epithelium, capillary endothelium, and associated connective tissue matrix. Methods of targeting medications to particular tissues, including the lung, may be important. In the lung, aerosolization offers the opportunity of delivering potent drugs in small amounts with limited systemic side effects, although the delivery of an adequate dose of a drug to the respiratory airspaces may be limiting. Besides the usual aerosol systems, other approaches may be necessary such as delivery of bioactive proteins via viral expression vectors. An adenoviral vector system that contains the transmembrane conductance regulatory protein is in clinical trials for administration to patients with cystic fibrosis.12Rosenfeld MA Yoshimura K Trapnell BC et al.In vivo transfer of the human cystic fibrosis transmembrane conductance regulatory gene to the airway epithelium..Cell. 1992; 68: 143-155Abstract Full Text PDF PubMed Scopus (866) Google Scholar,13Rich DP Couture LA Cardoza LM et al.Development of recombinant adenoviruses of gene therapy of cystic fibrosis..Hum Gene Ther. 1993; 4: 461-476Crossref PubMed Scopus (152) Google Scholar One problem with new therapies for pulmonary fibrosis will be deciding how to measure their efficacy. Pulmonary function tests and standard chest radiographs will be useful but may not be sufficiently sensitive or specific, particularly in early disease with minimal impairment or advanced disease with poor gas exchange. High-resolution CT scans will be more sensitive but not specific. Several biologic markers of inflammation and fibrogenesis are available. When measured in blood, urine, or BAL fluid, they identify specific changes in the inflammatory and repair process.14Standiford TJ Rolfe MW Kunkel SL et al.Macrophage inflammatory protein-1 alpha expression in interstitial lung disease..J Immunol. 1993; 151: 2852-2863PubMed Google Scholar, 15Ozaki T Hayaski H Tani K et al.Neutrophil chemotactic factors in the respiratory tract of patients with chronic airway diseases or idiopathic pulmonary fibrosis.Am Rev Respir Dis. 1992; 145: 85-91Crossref PubMed Scopus (62) Google Scholar, 16Stone PJ Lucey EC Snider GL et al.Effect of diet on urinary excretion of desmosine and hydroxylysyl pyridinoline..Am J Respir Crit Care Med. 1994; 149: 174-177Crossref PubMed Scopus (29) Google Scholar, 17Kawamura M Yamasawa F Ishizaka A et al.Serum concentration of 7S collagen and prognosis in patients with the adult respiratory distress syndrome..Thorax. 1994; 49: 144-146Crossref PubMed Scopus (29) Google Scholar, 18Low RB Giancola MS King Jr, TE et al.Serum and bronchoalveolar lavage of N-terminal type III procollagen peptides in idiopathic pulmonary fibrosis..Am Rev Respir Dis. 1992; 146: 701-706Crossref PubMed Scopus (41) Google Scholar, 19Shijubo N Imai K Aoki S et al.Circulating intercellular adhesion molecule-1 (ICAM-1) antigen in sera of patients with idiopathic pulmonary fibrosis..Clin Exp Immunol. 1992; 89: 58-62Crossref PubMed Scopus (78) Google Scholar, 20Satoh H Kamma H Ogata T et al.Clinical significance of serum levels of a carbohydrate antigen, sialyl SSEA-1, in patients with fibrosing lung disease..Am Rev Respir Dis. 1991; 144: 1177-1181Crossref PubMed Scopus (16) Google Scholar Included are collagen-related peptides,17Kawamura M Yamasawa F Ishizaka A et al.Serum concentration of 7S collagen and prognosis in patients with the adult respiratory distress syndrome..Thorax. 1994; 49: 144-146Crossref PubMed Scopus (29) Google Scholar,18Low RB Giancola MS King Jr, TE et al.Serum and bronchoalveolar lavage of N-terminal type III procollagen peptides in idiopathic pulmonary fibrosis..Am Rev Respir Dis. 1992; 146: 701-706Crossref PubMed Scopus (41) Google Scholar adhesion molecules,19Shijubo N Imai K Aoki S et al.Circulating intercellular adhesion molecule-1 (ICAM-1) antigen in sera of patients with idiopathic pulmonary fibrosis..Clin Exp Immunol. 1992; 89: 58-62Crossref PubMed Scopus (78) Google Scholar alveolar epithelial cell antigens,20Satoh H Kamma H Ogata T et al.Clinical significance of serum levels of a carbohydrate antigen, sialyl SSEA-1, in patients with fibrosing lung disease..Am Rev Respir Dis. 1991; 144: 1177-1181Crossref PubMed Scopus (16) Google Scholar and other relevant cytokines. Animal models are useful to characterize the mechanisms involved in the development of IPF and to examine the efficacy of specific therapeutic interventions. In each of these models, acute lung injury follows the administration of a noxious agent. After resolution of the resulting intense inflammatory reaction, remodeling of the lung and excess connective tissue accumulation occurs stereotypically after injury. These models may mimic human lung fibrosis that results from a specific injury such as following ARDS or exposure to chemotherapeutic agents. Because human IPF is usually a chronic, insidious disorder, the application of observations derived from animal models of IPF to human disease may have limited relevance. An animal model that behaves similarly to human IPF would aid in the assessment of new therapies. Perhaps a transgenic approach would be useful in this regard. For example, overexpression of human transforming growth factor-α in respiratory epithelial cells results in pulmonary fibrosis in transgenic mice.21Korfhagen TR Swantz RJ Wert SE et al.Respiratory epithelial cell expression of human transforming growth factor-α induces lung fibrosis in transgenic mice..J Clin Invest. 1994; 93: 1691-1699Crossref PubMed Scopus (169) Google Scholar Studies in cell culture employing homogeneous cell populations have greatly contributed to the understanding of the molecular events involved in tissue injury and repair. The results of these studies have suggested possible interventions that could disrupt or modify critical cellular events necessary for connective tissue accumulation in the lung. Because these studies use simple biologic systems, their relevance to the pathogenesis of a disease process occurring in a complex structure like the lung is uncertain. For example, certain effector substances such as tumor necrosis factor-α (TNF-α) have direct actions on fibroblasts in vitro but cause different responses when functioning as part of a complex inflammatory reaction. This may result from induction of other effector substances or their receptors or from interactions with other cell types. Nevertheless, several novel therapies now being considered for fibrotic illness derive from observations gleaned from experiments in cell culture. We will discuss the potential therapeutic applications derived from such studies to the treatment of IPF. A working model for activation of collagen deposition in fibrotic processes involves an initial cellular injury associated with a marked inflammatory infiltrate and the elaboration of cytokines, including interleukin 1 (IL-1), TNF-α, and platelet-derived growth factor. These mediators amplify the cellular injury and stimulate fibroblast proliferation. Subsequently, an extracellular matrix is deposited coincident with the appearance of certain fibrogenic cytokines, including transforming growth factor-β (TGF-β) and insulin-related growth factors. Additional work is needed to characterize the specific adhesion molecules that mediate the migration of leukocytes into lung. The same can be said for the influence of other inflammatory cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF), other interleukins, particularly IL-4, IL-6, and IL-10, and prostaglandins in the process. Other events may also contribute to the disorder, including alterations in the antioxidant barrier, regional blood flow, coagulation, protease activation, and hypoxic conditions. Studies employing animal models suggest that interruption of the initial inflammatory events using inhibitors to specific cytokines prevents the subsequent accumulation of collagen.22Piquet PF Vesin C Grau GE et al.Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica..Cytokine. 1993; 5: 57-61Crossref PubMed Scopus (193) Google Scholar, 23Piguet PF Vesin C. Treatment by recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice..Eur Respir J. 1994; 7: 515-518Crossref PubMed Scopus (270) Google Scholar, 24Piguet PF Grau GE de Kossodo S. Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin..Exp Lung Res. 1993; 19: 579-587Crossref PubMed Scopus (41) Google Scholar Whether such an approach is applicable to human IPF is unclear. IL-Iß and TNF-α increase in the lung and the BAL fluid in some patients with fibrosis.25Zhang Y Lee TC Guillemin B et al.Enhanced IL-1ß and tumor necrosis factor-α release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure..J Immunol. 1993; 150: 4188-4196PubMed Google Scholar These mediators may have a role in initiating and sustaining the fibrogenic injury. Alveolar macrophages derived from patients with IPF and asbestosis release increased quantities of IL-lß and TNF-α as compared with normal controls.25Zhang Y Lee TC Guillemin B et al.Enhanced IL-1ß and tumor necrosis factor-α release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure..J Immunol. 1993; 150: 4188-4196PubMed Google Scholar The activity of IL-1 likely depends on the concentration of the effector and its inhibitor, the IL-1 receptor antagonist (IL-1ra), in the inflammatory milieu. Macrophages release both IL-1 and the IL-lra. The IL-1/lra ratio increased in supernatants obtained from cultured macrophages derived from patients with IPF 26Kline JN Schwartz DA Monick MM et al.Relative release of interleukin-1ß and interleukin-1 receptor antagonist by alveolar macrophages: a study in asbestos-induced lung disease, sarcoidosis and idiopathic pulmonary fibrosis..Chest. 1993; 104: 47-53Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Epithelial cells in the lungs of patients with IPF, particularly hyperplastic type II pneumocytes, contain high levels of TNF-α.27Piguet PF Ribaux C Karpuz V et al.Expression and localization of tumor necrosis factor-α and its mRNA in idiopathic pulmonary fibrosis..Am J Pathol. 1993; 143: 651-655PubMed Google Scholar,28Nash JRG Mclaughlin PJ Butcher D et al.Expression of tumour necrosis factor-α in crytogenic fibrosing alveolitis..Histopathology. 1993; 22: 343-347Crossref PubMed Scopus (83) Google Scholar In contrast, the release of these mediators from macrophages derived from patients with sarcoidosis did not correlate with the clinical status in patients with sarcoidosis.29Pueringer RJ Schwartz DA Dayton CS et al.The relationship between alveolar macrophages TNF, IL-1, and PGE2 release, alveolitis, and disease severity in sarcoidosis..Chest. 1993; 103: 832-838Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Nevertheless the administration of IL-lra22Piquet PF Vesin C Grau GE et al.Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica..Cytokine. 1993; 5: 57-61Crossref PubMed Scopus (193) Google Scholar or anti-TNF-α antibodies30Piquet PF Collart MA Grau GE et al.Requirement for tumor necrosis factor for development of silica induced pulmonary fibrosis..Nature. 1990; 344: 245-247Crossref PubMed Scopus (516) Google Scholar or a soluble TNF-α receptor23Piguet PF Vesin C. Treatment by recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice..Eur Respir J. 1994; 7: 515-518Crossref PubMed Scopus (270) Google Scholar inhibited the development of fibrosis in bleomycin- or silica-treated mice. Interestingly, the soluble TNF-α receptor was effective in the treatment of established fibrosis in mice,23Piguet PF Vesin C. Treatment by recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice..Eur Respir J. 1994; 7: 515-518Crossref PubMed Scopus (270) Google Scholar suggesting that TNF-α is also active during later stages of lung injury. Tetrandrine, a bisbenylisoquine alkaloid, inhibits silica-induced fibrosis in rodents, perhaps by decreasing IL-1 production.31Kang JH Lewis DM Castranova V et al.Inhibitory action of tetrandrine on macrophage production of interleukin-1 (IL-1)-like activity in thymocyte proliferation..Exp Lung Res. 1992; 18: 715-729Crossref Scopus (41) Google Scholar The activity of IL-1 and TNF-α may be interdependent because inhibitors directed against either one appear to block the fibrotic response. GM-CSF induces the differentiation of myeloid stem cells to granulocytes and macrophages. In the lung, GM-CSF generated by T lymphocytes, macrophages, fibroblasts, endothelial cells, and epithelial cells acts on regional inflammatory cells. 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Such a control system could limit connective tissue accumulation during certain inflammatory reactions. The administration of GM-CSF to mice decreased bleomycin-induced fibrosis, whereas the administration of anti-GM-CSF antibodies increased the deposition of collagen.24Piguet PF Grau GE de Kossodo S. Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin..Exp Lung Res. 1993; 19: 579-587Crossref PubMed Scopus (41) Google Scholar Although these data suggest that GM-CSF would be useful as an antifibrogenic substance, the subcutaneous administration of GM-CSF to rats produced fibroblast proliferation and induction of α-smooth muscle actin in fibroblasts.36Rubbia-Brandt L Sappino A-P Gabbiani G. Locally applied GM-CSF induces the accumulation of α-smooth muscle actin containing myofibroblasts..Virchows Arch B. 1991; 60: 73-82Crossref Scopus (143) Google Scholar This myofibroblast phenotype is typically found in fibrotic lesions in the lung.37Vyalov SL Gabbiani G Kapanci Y. Rat alveolar myofibroblasts acquire α-smooth muscle actin expression during bleomycin-induced pulmonary fibrosis..Am J Pathol. 1993; 143: 1754-1765PubMed Google Scholar If GM-CSF proves to have antifibrotic properties, the present cost of GM-CSF would make the clinical use of GM-CSF in chronic IPF prohibitive. It may be useful in a rapidly progressing fibrogenic lesion as in ARDS. The TGF-ß cytokines are 25-kDa proteins that, because of their cellular effects, play a central role in the development of IPF and other fibrosing diseases. Accordingly, inhibition of TGF-ß action may be an important target for treating IPF. TGF-ß is a potent activator of collagen formation by lung fibroblasts in vitro and following subcutaneous implantation.38Krummel TM Michna BA Thomas BL et al.Transforming growth factor-ß (TGF-ß) induced fibrosis in a fetal wound model..J Pediatr Surg. 1988; 23: 647-652Abstract Full Text PDF PubMed Scopus (191) Google Scholar TGF-ß activates expression of genes that encode connective tissue proteins and protease inhibitors, and inhibits expression of genes that encode for proteases.39Ignotz RA Massagué J. Transforming growth factor-ß stimulates the expression of fibronectin and collagen and their encorporation into the extracellular matrix..J Biol Chem. 1986; 261: 4337-4345PubMed Google Scholar, 40Fine A Goldstein RH. 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