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Apoptosis in Lung Fibrosis and Repair^*

^* From the Department of Physiology, Michigan State University, East Lansing, MI.

Correspondence to: Bruce D. Uhal, PhD, Department of Physiology, 3185 Biomedical and Physical Sciences Building, Michigan State University, East Lansing, MI 48824; e-mail: uhal{at}msu.edu.

	Abstract

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
Cell death by apoptosis has fundamental significance in both normal lung homeostasis and a variety of pathologic processes, and for this reason apoptosis in the lung is a rapidly growing area of investigation. Evidence from human lung biopsy specimens and from animal models of lung fibrosis points to important roles for apoptosis in both the pathogenesis and resolution of fibrotic lesions. As more evidence accumulates, the more apparent becomes the paucity of information on the regulation of this mode of cell death in the many different cell types of the lung parenchyma. This discussion will review the current state of knowledge regarding the roles of apoptosis in lung fibrosis and will focus on its role in pathogenesis.

Key Words: apoptosis • fibrosis • lung • pulmonary pathogenesis

	Introduction

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
Interest in the mode of cell death termed apoptosis has grown tremendously in recent years. Electronic searching of the literature with the single search term "apoptosis" reveals a 10-fold increase in the number of manuscripts published on this topic between 1993 and 2000. In the last year, the number reached nearly 10,000 in the MEDLINE index. With specific regard to the lungs, far fewer hits are obtained if the electronic search is narrowed to the terms "apoptosis and lung," but the rate of publication increases even more (40-fold from 1993 to 2000). At least two factors can explain this surge of interest in the process of apoptosis in the lung. First, in contrast to necrosis or "accidental" cell death, apoptosis is an active form of cell death that requires the activation of specific enzymes and other components of signaling pathways, and thus holds great potential for pharmacologic manipulation. Moreover, the discovery of differences in the regulation of apoptosis in various cell types offers the promise that future attempts at pharmacologic control might be achieved in a cell type-specific manner. %Second, and perhaps more importantly, the kinetics of apoptosis are very rapid relative to cell proliferation. For example, measurements of the time required for the sequential stages of apoptosis in hepatocytes in vivo have determined an overall duration of approximately 5 to 6 h from the initiation of signaling to the complete disappearance of the cell.¹ This is in contrast to cell proliferation, in which the time required from initial signaling to cell division is usually 20 to 24 h.² For this reason, the manipulation of apoptosis could be viewed as having an even greater potential for the alteration of cell population size than does control over cell division. This view is supported by the promising gene therapy studies of Roth and colleagues,^{3 4} who are attempting to reverse the growth of lung tumors through the replacement of mutated p53 with the wild-type gene, thus restoring the normal rate of tumor cell apoptosis.

	Roles for Apoptosis in the Lung

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
A large body of literature describes the important roles for apoptosis in lung cancers and their treatment.⁵ However, a growing body of evidence points to other important roles for apoptosis in a variety of normal and abnormal processes in the lung, including postnatal lung development⁶ and in the normal resolution of lung inflammation by the regulated removal of unneeded cells such as granulocytes, without the release of damaging histotoxins.⁷ Dexamethasone has been known for many years to induce apoptosis in some leukocyte subsets, and apoptosis is an important mechanism underlying the anti-inflammatory action of this and other glucocorticoids.⁸ Other studies now support a role for apoptosis in the remodeling of lung tissue after acute lung injury, both for the clearance of excess epithelial stem cells after hyperplastic repair⁹ and for the normal removal of excess mesenchymal cells from resolving lesions.¹⁰ Some evidence also suggests a role for apoptosis in the tissue remodeling that is associated with chronic pulmonary hypertension¹¹ and COPD.¹²

Clearly, apoptosis could be predicted to have detrimental or beneficial effects depending on the cell type and the circumstances. For example, the stimulation of apoptosis in tumor cells would be beneficial as long as it does not extend into the surrounding parenchyma or into the normal cells along a potential metastatic path. In acute lung injury, apoptosis of granulocytes might be beneficial, but apoptosis of cells within the endothelial or epithelial barriers could lead to barrier collapse and edema,¹³ unless these cells are in excess (eg, immediately after hyperplastic repair).¹⁴ The future design of strategies to manipulate apoptosis therefore should consider not only cell-type specificity, but also issues of timing and location as well.

	Apoptosis and Lung Fibrosis

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
The focus of this discussion, however, is fibrotic lung disease, and complimentary lines of evidence suggest that apoptosis of specific lung cell types is involved in both the pathogenesis and the resolution of fibrotic lesions. A prominent feature of the fibrotic lung is the proliferation and accumulation of mesenchymal cells, which include abnormal fibroblast populations that emerge in the interstitium but may migrate into the alveolar spaces,¹⁵ and endothelial cells, which evolve during the neovascularization of nascent fibrotic foci.¹⁰ In patients who recover from fibrotic lung disease, these excess cells are removed by processes that, although not completely understood, likely include apoptosis.^{9 10} Given the poor prognosis of patients who are unfortunate to receive diagnoses of one of the more aggressive forms of interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF) or usual interstitial pneumonia, the elucidation of the factors responsible for the removal of these cells should be a high priority for research.

On the other hand, a growing and somewhat larger group of studies now supports the notion that apoptosis contributes to the pathogenesis of lung fibrosis as well as to its resolution. Somewhat by convention, apoptosis has been viewed as a mechanism of cell death that generally does not lead to tissue scarring, in contrast to necrosis.¹⁶

Apoptosis in Fibrotic Human Lung
Observations from human lung biopsy specimens are beginning to challenge that view, at least as it relates to scarring of the lungs. In 1996, Kuwano et al¹⁷ found heavy labeling of fragmented DNA (a marker of apoptosis) in bronchiolar and alveolar epithelial cells (AECs) within lung biopsy specimens from patients with IPF. Several years later, this finding was confirmed by Uhal et al,¹⁸ who extended the analysis to include simultaneous double-labeling of fragmented DNA and the myofibroblast marker -smooth muscle actin (SMA). In biopsy specimens from patients with IPF and chronic hypersensitivity pneumonitis, fragmented DNA within the alveolar epithelium was found most frequently in regions that were immediately adjacent to -SMA-positive interstitial cells interspersed within a heavy collagen deposition. Thus, epithelial apoptosis colocalizes with regions of the heaviest myofibroblast activity and collagen accumulation, at least in patients with IPF or chronic hypersensitivity pneumonitis.

These results were consistent with earlier studies of primary lung fibroblasts that were isolated from the same biopsy specimens.¹⁹ The fibroblasts isolated from fibrotic lung specimens, which also were -SMA-positive in culture, produced factors capable of killing AECs by apoptosis in vitro. This finding is in contrast to those from studies of normal human lung fibroblasts, which produce mitogens for the alveolar epithelium such as hepatocyte growth factor and keratinocyte growth factor.²⁰ In subsequent work, the human fibroblast-derived factors that are responsible for the killing of AECs in vitro were identified as angiotensin (ANG) peptides.²¹ This finding in turn is consistent with earlier demonstrations that ANGII is a potent inducer of apoptosis in AECs²² and with other works demonstrating that myofibroblasts in the failing heart²³ and other organs²⁴ also synthesize ANG peptides. Very recently, the observation of fragmented DNA within AECs of fibrotic human lung was reconfirmed by Barbas-Filho et al²⁵ in a study of 19 patients with IPF/usual interstitial pneumonia. Together, the studies are consistent with a role for epithelial apoptosis as a contributor to the fibrogenic process, but the amount of mechanistic information to be gained from studies of biopsy materials is limited at best.

Apoptosis and Lung Fibrogenesis in Animal Models
On the other hand, considerable literature from animal models supports the notion that apoptosis of alveolar and/or bronchiolar epithelial cells is a mechanism that can lead to a fibrogenic response. In many respects, this literature revives a relatively old theory, first put forth by Haschek and Witschi,²⁶ that contends that the fibrotic response is driven by the severity of adjacent epithelial injury, rather than by inflammation per se, through the elimination of the many "antifibrotic" functions of the epithelium. These functions include, but are not limited to the following: constitutive synthesis of inhibitors of lung fibroblast proliferation such as prostaglandin E₂; the synthesis of urokinase-type plasminogen activator and the degradation of fibrin exuded from damaged capillaries; the constitutive synthesis of matrix metalloproteinases of the subtypes known to degrade interstitial collagens; and the provision of a physical barrier that protects underlying interstitial cells from mitogens that are released by activated alveolar macrophages (for review, see Simon²⁷ ). This hypothesis is attractive because, among other reasons, it can account for the failure of anti-inflammatory or immunosuppressive therapies to help patients with IPF²⁸ in the absence of a strategy to restore epithelial integrity. Moreover, it also is consistent with the tendency of strong inducers of epithelial apoptosis (eg, antineoplastic agents such as bleomycin, adriamycin, and methotrexate) to induce lung fibrosis.

Although the early studies of Witschi²⁹ and Adamson and Bowden³⁰ did not investigate apoptosis, their findings revealed a strong correlation between nonspecific damage to the epithelium and subsequent collagen deposition, regardless of the extent of inflammation. More recent studies have found that the induction of apoptosis in the epithelium is sufficient to initiate a fibrotic response. In investigations of the mouse lung, Hagimoto et al³¹ showed that intratracheal instillation of an antibody that activates the "death receptor" Fas induced the apoptosis of bronchial and AECs (both of which express Fas constitutively) and initiated a fibrotic response detectable one week later. Earlier that year, the same research group showed that the induction of lung fibrosis by intratracheal instillation of bleomycin is associated with the up-regulation of Fas on the epithelium and the concomitant induction of epithelial apoptosis as a prelude to fibrogenesis.³² Moreover, knockout mice deficient in the receptor Fas were found to be resistant to the profibrotic effect of bleomycin, suggesting that Fas-induced apoptosis plays an essential role in the development of the fibrotic response.³³

As a group, those results support the hypothesis proposed by Witschi²⁹ and Adamson and Bowden³⁰ that the integrity of the epithelium is a key determinant in the pathway to fibrosis. This interpretation depends, however, on the specificity of the apoptosis inducer (ie, bleomycin or Fas-activating antibody) for epithelial cells, a premise that was not established in those studies. The argument could be made, for example, that the activation of Fas stimulated apoptosis not only in the epithelium but also in inflammatory cell populations, and that the death of certain inflammatory cells initiated the fibrogenic response. Despite this limitation, these studies clearly demonstrated that apoptosis was indeed induced and preceded the accumulation of collagens.

From that perspective, a more fundamental question is whether the blockade of the apoptosis, regardless of which lung cell types it affects, could prevent the subsequent fibrotic response. To date, the two studies that have attempted to address this issue have obtained essentially identical and affirmative results. In a study of lung fibrogenesis in rats, Wang et al³⁴ found that the accumulation of lung collagens after the intratracheal administration of bleomycin could be blocked with equal potency by the ANG-converting enzyme (ACE) inhibitor captopril or by daily intraperitoneal injections of N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone (ZVADfmk), a broad-spectrum inhibitor of caspases (cysteine proteases), which are required for the induction of apoptosis. Captopril had been shown earlier by Uhal et al³⁵ to be capable of blocking Fas-induced apoptosis in human AECs in vitro and, in primary cultures of rat AECs, either Fas-induced or bleomycin-induced apoptosis.³⁴

The in vivo results of the study by Wang et al³⁴ were confirmed the following year by Kuwano and coworkers³⁶ through a study of bleomycin-induced lung fibrosis in mice, to which the same caspase inhibitor (ZVADfmk) was administered by aerosol. In this study, and in that by Wang et al,³⁴ ZVADfmk significantly inhibited both bleomycin-induced epithelial apoptosis and the subsequent accumulation of lung collagens, regardless of the route of drug delivery. The blockade of collagen deposition in vivo by an inhibitor of apoptosis suggests that the fibrotic response is secondary to the apoptotic death of certain lung cell types, which is consistent with the theories put forth by Witschi²⁹ and Adamson and Bowden.³⁰

	The Path From Apoptosis to Fibrosis: What Is the Link?

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
The successful blockade of bleomycin-induced collagen deposition by the ACE inhibitor (ACEI) captopril also confirmed the findings of earlier studies by Molteni et al³⁷ and Ward et al,³⁸ who had shown years before that ACEIs and related compounds had potent antifibrotic potential in lung fibrosis models induced by monocrotaline or by gamma irradiation. In light of the finding that captopril also blocked apoptosis of AECs,³⁵ Wang et al³⁹ hypothesized that apoptosis in AECs might somehow be dependent on the production of ANGII by the epithelial cell. This hypothesis was proven correct by the demonstration that the activation of Fas either on primary cultures of rat AECs or on the human A549 cell line caused a significant increase in the messenger RNA for angiotensinogen (ANGEN) and the release of ANGII into the cell culture medium.³⁹ Moreover, the apoptosis of either cell type could be completely abrogated by ACEIs, by ANGII receptor antagonists, by antibodies capable of neutralizing ANGII, or by antisense oligonucleotides that block the ANGEN messenger RNA translation.³⁹ Together, these results demonstrated that the apoptosis of AECs in response to Fas requires the autocrine production of ANGII.

More recent work by Wang et al⁴⁰ showed that the same requirement for ANGII production and receptor interaction occurs during the apoptosis of AECs in response to tumor necrosis factor (TNF)-. An initial report⁴¹ that TNF- does not induce apoptosis in AECs was later found to be erroneous by two independent research groups^{40 42} that used more sensitive detection methods. The induction of AEC apoptosis by TNF- occurs at physiologically relevant concentrations of the cytokine and is greatly potentiated by agents that evoke oxidative stress, such as ethanol.⁴² Moreover, TNF--induced apoptosis of AECs, like that in response to Fas, also was blocked by ACEIs, by ANGII receptor antagonists, or by antisense oligonucleotides against ANGEN messenger RNA.⁴⁰

These findings have led to the hypothesis that the apoptosis of AECs, regardless of the initiating stimulus, might involve the autocrine synthesis of ANGII and its subsequent binding to epithelial ANGII receptors as required steps in the execution of apoptosis.⁴³ Consistent with this theory, investigations of AEC apoptosis in response to the antiarrhythmic agent amiodarone⁴⁴ or the catecholamine norepinephrine⁴⁵ also found that AEC apoptosis could be completely abrogated by ACEIs or by ANGII receptor antagonists. Although the transcription of the precursor molecule ANGEN was not addressed in those studies, the notion that ANGEN could play a central role as a regulator of apoptosis is supported by the observations that the ANGEN promoter contains an acute-phase response element and thus is rapidly responsive to a variety of cytokines.⁴⁶ Moreover, ANGEN gene transcription is well-documented as a mediator of apoptosis in cardiac myocytes.⁴⁷

In cells of both the heart and kidney, the ANGII produced from proteolytic processing of ANGEN is well-documented to be an inducer of transforming growth factor (TGF)-ß1 expression.⁴⁸ ANGII also is a known inducer of the expression of platelet-derived growth factor (PDGF)-A chain, PDGF receptors, and, through the induction of TGF-ß1 and its receptors, collagen gene expression as well.⁴⁹ In experimental models of lung fibrogenesis, an important role for TGF-ß1 as a "downstream" effector of collagen gene expression has been demonstrated by a variety of approaches, including by the administration of TGF-ß-soluble receptors⁵⁰ and TGF-ß gene transfer to the lung.⁵¹ Similarly, profibrotic roles for PDGF-A and its receptors also have been suggested by a variety of investigations of lung fibrogenesis in humans and animals.⁵² Although the regulation of TGF-ß and PDGF by ANG has not yet been confirmed specifically in lung tissue, it seems reasonable to suspect that the same mechanisms that regulate these genes in the heart and kidney are likely to be found to be active in the lung as well.

	Summary

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 
Although cell death by apoptosis is generally thought to provide a mechanism of cell removal without tissue scarring, investigations of both human lung biopsy specimens and small animal models of lung fibrogenesis have found apoptotic cells associated with fibrotic foci. Animal studies have shown that the induction of apoptosis, particularly within lung epithelial cells, is sufficient to initiate a fibrogenic response, and that blockade of the apoptosis can prevent subsequent collagen deposition. In the case of AECs, recent evidence indicates that the induction of apoptosis requires the de novo synthesis of ANGII. For this reason, apoptosis of AECs can be prevented by ACEIs, ANG receptor antagonists, or other agents capable of blocking ANG synthesis or function. These same agents also have documented antifibrotic potential in animal models. It has been speculated that at least part of the antifibrotic effect of these agents can be attributed to their ability to prevent the apoptotic death of the epithelial layer. On the basis of related studies of cardiac and renal fibrosis, it is speculated that the blockage of the ANGII synthesis that accompanies the apoptotic response is also likely to reduce the activation of genes that up-regulate collagen expression and mesenchymal cell proliferation. A more definitive proof of this principle is now underway with cell type-specific apoptosis inhibitors, antisense oligonucleotides that block the function of ANGEN, and mice that are deficient in specific genes of the renin-ANG system.

	Footnotes

 
Abbreviations: ACE = angiotensin-converting enzyme; ACEI = angiotensin-converting enzyme inhibitor; AEC = alveolar epithelial cell; ANG = angiotensin; ANGEN = angiotensinogen; IPF = idiopathic pulmonary fibrosis; PDGF = platelet-derived growth factor; SMA = smooth muscle actin; TGF = transforming growth factor; TNF = tumor necrosis factor; ZVADfmk = N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone

This research was supported by Public Health Service grant HL-45136 and by the Michigan State University Foundation.

	References

TOP Abstract Introduction Roles for Apoptosis in... Apoptosis and Lung Fibrosis The Path From Apoptosis... Summary References

 

1. Bursch, W, Patte, S, Putz, B, et al (1990) Determination of the length of the histological stages of apoptosis in normal liver and altered hepatic fool of rats. Carcinogenesis 11,847-853
2. Uhal, BD Cell cycle kinetics in the alveolar epithelium. Am J Physiol 1997;272,L1031-L1045
3. Roth, JA, Nguyen, D, Lawrence, DD, et al Retrovirus- mediated. wild-type p53 gene transfer to tumors of patients with lung cancer. Nat Med 1996;2,985-991
4. Pearson, AS, Spitz, FR, Swisher, SG, et al Upregulation of the proapoptotic mediators bax and bak following adenovirus-mediated p53 gene transfer in lung cancer cells. Clin Cancer Res 2000;6,887-890
5. Wilman, KG New p53-based anti-cancer therapeutic strategies. Med Oncol 1998;15,222-228
6. Schittney, J, Djonov, V, Fine, A, et al Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol 1998;18,786-793
7. Haslett, C Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med 1999;160,S5-S11
8. Meagher, L, Cousin, JM, Seckl, R, et al Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996;156,4422-4428
9. Bardales, RH, Xie, SS, Schaefer, RF, et al Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury. Am J Pathol 1997;149,845-852
10. Polunovsky, V, Chen, B, Henke, C, et al Role of mesenchymal cell death in lung remodeling after injury. J Clin Invest 1993;92,388-397
11. Durmowicz, AG, Stenmark, KR Mechanisms of structural remodeling in chronic pulmonary hypertension. Pediatr Rev 1999;20,e91-e102
12. Segura, L, Pardo, A, Gaxiola, M, et al Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117,684-694
13. Uhal, BD Fas and apoptosis in the alveolar epithelium: holes in the dike [editorial]? Am J Physiol 2001;281,L326-L327
14. Fehrenbach, H, Kasper, M, Koslowski, R, et al Alveolar epithelial type II cell apoptosis in vivo during resolution of keratinocyte growth factor-induced hyperplasia in the rat. Histochem Cell Biol 2000;11,49-61
15. Selman, M Pulmonary fibrosis: human and experimental disease. Rojkind, M eds. Connective tissue in health and disease 1990,123-188 CRC Press Boca Raton, FL.
16. Eastman, A Apoptosis: a product of programmed and unprogrammed cell death. Toxicol Appl Pharmacol 1993;121,160-164
17. Kuwano, K, Kunitake, R, Kawasaki, M, et al p21 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1996;154,477-483
18. Uhal, BD, Joshi, I, Ramos, C, et al Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 1998;275,L1192-L1199
19. Uhal, BD, Joshi, I, True, A, et al Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. Am J Physiol 1995;269,L819-L828
20. Panos, RJ, Rubin, JS, Csaky, KG, et al Keratinocyte growth factor and hepatocyte growth factor/scatter factor ar heparin-binding growth factors for alveolar type II cells in fibroblast conditioned medium. J Clin Invest 1993;92,969-977
21. Wang, R, Ramos, C, Joshi, I, et al Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. Am J Physiol 1999;277,L1158-L1164
22. 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,L885-L889
23. Katwa, LC, Campbell, SE, Tyagi, SC, et al Cultured myofibroblasts generate angiotensin peptides de novo. J Mol Cell Cardiol 1997;2,I375-I386
24. Weber, KT Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol 1997;17,467-491
25. Barbas-Filho, J, Ferreira, M, Sesso, A, et al Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). J Clin Pathol 2001;54,132-138
26. Haschek, WM, Witschi, HP Pulmonary fibrosis: a possible mechanism. Toxicol Appl Pharmacol 1979;51,75-487
27. Simon, RH Alveolar epithelial cells in pulmonary fibrosis Phan, SH Thrall, RS eds. Pulmonary fibrosis (vol 80) 1995,511-540 Dekker New York, NY.
28. Selman, M, King, TE, Pardo, A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134,136-151
29. Witschi, H Responses of the lung to toxic injury. Environ Health Perspect 1990;85,5-13
30. Adamson, IYR, Bowden, DH Pulmonary injury and repair: organ culture studies of murine lung after oxygen. Arch Pathol Lab Med 1976;100,640-643
31. Hagimoto, N, Kuwano, K, Miyazaki, H, et al Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of FAS antigen. Am J Respir Cell Mol Biol 1997;17,272-278
32. Hagimoto, N, Kuwano, K, Nomoto, Y, et al Apoptosis and expression of FAS/FAS ligand mRNA in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 1997;16,91-101
33. Kuwano, K, Hagimoto, N, Kawasaki, M, et al Essential roles of the Fas/Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 1999;104,13-19
34. Wang, R, Ibarra-Sunga, O, Pick, R, et al Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol 2000;279,L143-L151
35. Uhal, BD, Gidea, C, Bargout, R, et al Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol 1998;275,L1013-L1017
36. Kuwano, K, Kunitake, R, Maeyama, T, et al Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. Am J Physiol 2001;280,L316-L325
37. Molteni, A, Ward, W, Ts’ao, C, et al Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. Proc Soc Exp Biol Med 1985;180,112-120
38. Ward, W, Molteni, A, Ts’ao, C, et al The effect of captopril on benign and malignant reactions in irradiated rat skin. Br J Radiol 1990;63,349-354
39. Wang, R, Zagariya, A, Ang, E, et al Fas-induced apoptosis of alveolar epithelial cells requires angiotensin II generation and receptor interaction. Am J Physiol 1999;277,L1245-L1250
40. Wang, R, Alam, G, Zagariya, A, et al Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. J Cell Physiol 2000;185,253-259
41. Mallampalli, RM, Peterson, E, Carter, A, et al TNF- increases ceramide without inducing apoptosis in alveolar type II epithelial cells. Am J Physiol 1999;276,L481-L490
42. Brown, LA, Harris, F, Guidot, D Chronic ethanol ingestion potentiates TNF--mediated oxidative stress and apoptosis in rat type II cells. Am J Physiol 2001;281,L377-L386
43. Filippatos, G, Lalude, O, Ramaswaran, N, et al Regulation of apoptosis by vasoactive peptides. Am J Physiol 2001;,L749-L761
44. Bargout, R, Jankov, A, Dincer, E, et al Amiodarone induces apoptosis in human and rat alveolar epithelial cells in vitro. Am J Physiol 2000;278,L1039-L1044
45. Dincer, H, Gangopadhyay, N, Wang, R, et al Norepinephrine induces alveolar epithelial apoptosis mediated by , ß and angiotensin receptor activation. Am J Physiol Lung Cell Mol Physiol 2001;281,L624-L630
46. Brasier, A, Junyi, L, Copland, A Transcription factors modulating angiotensinogen gene expression in hepatocytes. Kidney Int 1994;46,1564-1566
47. Leri, A, Claudia, PP, Li, Q, et al Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system, and decreases the Bc1–2-to-Bax protein ratio in the cell. J Clin Invest 1998;101,1326-1342
48. Kupfahl, C, Pink, D, Friedrich, K, et al Angiotensin II directly increases transforming growth factor ß1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 2000;46,463-475
49. Klahr, S, Morrissey, J Angiotensin II and gene expression in the kidney. Am J Kidney Dis 1998;31,171-176
50. Wang, Q, Wang, W, Hyde, D, et al Reduction of bleomycin-induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax 1999;54,805-812
51. Gauldie, J, Sime, P, 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
52. Antoniades, HN, Bravo, M, Avila, RE, et al Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990;86,1055-1064

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