189
Views
35
CrossRef citations to date
0
Altmetric
Review

Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy

, , &
Pages 1671-1686 | Published online: 25 Feb 2005

Bibliography

  • American Thoracic Society/EuropeanRespiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am. Respir: Crit. Care Med. (2002) 165(2):277–304.
  • •This statement proposes a new classification system for the IIPs based largely on differences in prognoses and responses to therapy in patients with different histopathological patterns. The level of evidence for the recommendations in this statement is primarily that of expert opinion developed by consensus.
  • THANNICKAL VJ, TOEWS GB,WHITE ES, LYNCH jp 3rd,MARTINEZ FJ: Mechanisms of pulmonary fibrosis. Ann. Rev Med. (2004) 55:395–417.
  • •A conceptual framework for biological mechanisms of tissue fibrosis based on understanding host responses to injury. Histopathological variability is explained by differences in host (intrinsic) factors such as age and genetic susceptibility and in environmental (extrinsic) factors that modulate inflammatory and repair responses.
  • 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(2):136–151.
  • ••An excellent review that challenges theconcept that inflammation is a prerequisite for the development of IIIP/IPE These authors propose that fibrosis may result from both inflammation-dependent and -independent pathways.
  • COLLARD HR, KING TE Jr: Demystifying idiopathic interstitialpneumonia. Arch. Intern. Med. (2003) 163(1):17–29.
  • FLAHERTY KR, TRAVIS WD, COLBY TV et al.: Histopathologic variability in usual and nonspecific interstitial pneumonias. Am. I Respir: Crit. Care Med. (2001) 164(9):1722–1727.
  • ••This study was the first to document theco-existence of different histopathological patterns in the same lung, and often in the same lobe, of patients with
  • KATZENSTEIN AL, ZISMAN DA, LITZKY LA, NGUYEN BT,KOTLOFF RM: Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am. j Surg. Pathol (2002) 26(12):1567–1577.
  • NATHAN C: Points of control in inflammation. Nature (2002) 420(6917):846–852.
  • LAWRENCE T, GILROY DW, COLVILLE-NASH PR,WILLOUGHBY DA: Possible new role for NF-kappaB in the resolution of inflammation. Nat. Med. (2001) 7(12):1291–1297.
  • WAHL SM, HUNT DA,WAKEFIELD LM et al.: Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc. Natl. Acad. Sci. USA (1987) 84(16):5788–5792.
  • GRANDE JP: Role of transforming growth factor-beta in tissue injury and repair. Proc. Soc. Exp. Biol. Med. (1997) 214(1):27–40.
  • CARRINGTON CB, GAENSLER EA, COUTU RE, FITZGERALD MX, GUPTA RG: Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl. J. Med. (1978) 298(15):801–809.
  • TURNER-WARWICK M, BURROWS B, JOHNSON A: Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival. Thorax (1980) 35(8):593–599.
  • FLAHERTY KR, TOEWS GB,TRAVIS WD et at Clinical significance of histological classification of idiopathic interstitial pneumonia. Ear: Respir. J. (2002) 19(2):275–283.
  • •This study demonstrated that patients with histopathological UIP on lung biopsy had increased mortality and poor responses to steroids, whereas patients with NSIP were more likely to respond or remain stable on prednisone therapy.
  • WATTERS LC, KING TE,SCHWARZ MI et al: A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am. Rev Respir. Dis. (1986) 133(1):97–103.
  • FLAHERTY KR, TOEWS GB,LYNCH JP 3rd et al.: Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am. I Med. (2001) 110(4):278–282.
  • RAGHU G, DEPASO WJ, CAIN K et al: Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am. Rev Respir. Dis. (1991) 144(2):291–296.
  • JOHNSON MA, KWAN S, SNELL NJ et al.: Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenicfibrosing alveolitis. Thorax (1989) 44(4)280–288.
  • ZISMAN DA, LYNCH JP 3rd,TOEWS GB et al.: Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids.Chest (2000) 117(6):1619–1626.
  • RAGHU G, BROWN KK,BRADFORD WZ et al.: A placebo-controlled trial of interferon gamma-lb in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. (2004) 350(2):125–133.
  • ••A multi-centre, prospective, randomised,placebo-controlled clinical trial of a potential antifibrotic agent in a large well-defined group of patients with IPE Treatment with IFN-yll, did not affect the primary end point of disease-free survival. This study has spurred interest in conducting other drug trials, including a second Phase III trial of IFN-yi, in patients with less severe disease and with overall survival time from randomisation as the primary end point.
  • MURPHY KM, OUYANG W, FARRAR JD et al.: Signaling and transcription in T helper development. Ann. Rev Iminunol (2000) 18:451–494.
  • WALLACE WA, RAMAGE EA, LAMB D, HOWIE SE: A Type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA). Clin. Exp. Iminunol (1995) 101(3):436–441.
  • PRIOR C, HASLAM PL: In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases. Clin. Exp. Iminunol (1992) 88(2):280–287.
  • ROSENBLOOM J, FELDMAN G, FREUNDLICH B, JIMENEZ SA: Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon. Association with a coordinate decrease in types I and III procollagen messenger RNA levels. Arthritis Rheum. (1986) 29(7):851–856.
  • ELIAS JA, JIMENEZ SA,FREUNDLICH B: Recombinant gamma, alpha, and beta interferon regulation of human lung fibroblast proliferation. Am. Rev. Respic Dis. (1987) 135(1):62–65.
  • ELIAS JA, FREUNDLICH B, ADAMS S, ROSENBLOOM J: Regulation of human lung fibroblast collagen production by recombinant interleukin-1, tumor necrosisfactor, and interferon-gamma. Ann. NY Acad. ScL (1990) 580:233–244.
  • ULLOA L, DOODY J, MASSAGUE J: Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature (1999) 397(6721):710–713.
  • FLANDERS KC, SULLIVAN CD, FUJII M et al.: Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am. J. Pathol (2002) 160(3):1057–1068.
  • ROBERTS AB, PIEK E, BOTTINGER EP et al.: Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest (2001) 120(1 Suppl.):43S–47S.
  • GURUJEYALAKSHMI G, GIRI SN: 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(5):791–808.
  • VENKATESAN N, ROUGHLEY PJ, LUDWIG MS: Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta(1) and interferon-gamma. Am. I Physiol Lung Cell Mol Physiol (2002) 283(4):L806–L814.
  • CHEN ES, GREENLEE BM, WILLS-KARP M, MOLLER DR: Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin. Am. J. Respir. Cell Ma Biol. (2001) 24(5):545–555.
  • ZIESCHE R, HOFBAUER E, WITTMANN K, PETKOV V,BLOCK LH: A preliminary study of long-term treatment with interferon gamma-lb and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl. I Med. (1999) 341(17):1264–1269.
  • HONORE I, NUNES H,GROUSSARD O et al.: Acute respiratory failure after interferon-gamma therapy of end-stage pulmonary fibrosis. Am. J. Respir. Grit. Care Med. (2003) 167(7):953–957.
  • DI SARIO A, BENDIA E,SVEGLIATI BARONI G et al: Effect ofpirfenidone on rat hepatic stellate cell proliferation and collagen production. Hepatol (2002) 37(5):584–591.
  • HEWITSON TD, KELYNACK KJ, TAIT MG et al.: Pirfenidone reduces in vitro rat renal fibroblast activation andmitogenesis. Nephrol (2001) 14(6)453–460.
  • IYER SN, HYDE DM, GIRI SN: Anti-inflammatory effect of pirfenidone in the bleomycin-hamster model of lung inflammation. Inflammation (2000) 24(5):477–491.
  • OKU H, NAKAZATO H, HORIKAWA T, TSURUTA Y, SUZUKI R: Pirfenidone suppresses tumor necrosis factor-alpha, enhances interleukin-10 and protects mice from endotoxic shock. Eur: .1. Pharmacol (2002) 446(1–3):167–176.
  • HALE ML, MARGOLIN SB, KRAKAUER T, ROY CJ, STILES BG: Pirfenidone blocks the in vitro and in vivo effects of staphylococcal enterotoxin B. Infect. Inman. (2002) 70(6):2989–2994.
  • NAKAZATO H, OKU H, YAMANE S, TSURUTA Y, SUZUKI R: A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur. Phannacol (2002) 446(1-3):177–185.
  • IYER SN, WILD JS, SCHIEDT MJ et al.: Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. I Lab. Clin. Med. (1995) 125(6):779–785.
  • KEHRER JP, MARGOLIN SB:Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett. (1997) 90(2-3):125–132.
  • DOSANJH AK, WAN B,THRONDSET W, SHERWOOD S, MORRIS RE: Pirfenidone: a novel antifibrotic agent with implications for the treatment of obliterative bronchiolitis. Transplant. Proc. (1998) 30(5):1910–1911.
  • SHIMIZU T, KURODA T, HATA S et al.: Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int. (1998) 54(1):99–109.
  • AL-BAYATI MA, XIE Y, MOHR FC, MARGOLIN SB, GIRI SN: Effect of pirfenidone against vanadate-induced kidney fibrosis in rats. Biochem. Phannacol (2002) 64(3):517–525.
  • TADA S, NAKAMUTA M, ENJOJI M et al.: Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats. Clin. Exp. Phannacol Physiol (2001) 28(7):522–527.
  • GARCIA L, HERNANDEZ I, SANDOVAL A et al: Pirfenidone effectively reverses experimental liver fibrosis. Hepatol (2002) 37(6):797–805.
  • WALLER JR, MURPHY GJ, METCALFE MS et al.: Effects of pirfenidone on vascular smooth muscle cell proliferation and intimal hyperplasia following arterial balloon injury. Transplant. Proc. (2001) 33(7-8):3816–3818.
  • MIRIC G, DALLEMAGNE C, ENDRE Z et al.: Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br.Pharmacol (2001) 133(5):687–694.
  • RAGHU G, JOHNSON WC,LOCKHART D, MAGETO Y: Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am. J. Respir. Grit. Care Med. (1999) 159(4 Pt 1):1061–1069.
  • NAGAI S, HAMADA K,SHIGEMATSU M et al.: Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern. Med. (2002) 41(12):1118–1123.
  • GAHL WA, BRANTLY M, TROENDLE J et al.: Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Ma Genet. Metab. (2002) 76(3):234–242.
  • ANGULO P, MACCARTY RL, SYLVESTRE PB et al.: Pirfenidone in the treatment of primary sclerosing cholangitis. Dig. Dis. Sci. (2002) 47(1):157–161.
  • SCHIFFRIN EL: Vascular and cardiac benefits of angiotensin receptor blockers. Am. J. Med. (2002) 113(5):409–418.
  • MARSHALL RP, MCANULTY RJ, LAURENT GJ: Angiotensin II is mitogenic for human lung fibroblasts via activation of the Type 1 receptor. Am. Respic Crit. Care Med. (2000) 161(6):1999–2004.
  • WANG R, RAMOS C, JOSHI I et al: Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. Am. Physiol (1999) 277(6 Pt 1):L1158–L1164.
  • UHAL BD, GIDEA C, BARGOUT R et al.: Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am. I Physiol (1998) 275(5 Pt 1):L1013–L1017.
  • KETTELER M, NOBLE NA,BORDER WA: Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration toglomerulosclerosis? Ann. Rev Physiol (1995) 57:279–295.
  • NGUYEN L, WARD WE TS'AO CH, MOLTENI A: Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism. Proc. Soc. Exp. Biol. Med. (1994) 205(1):80–84.
  • CANDAN F, ALAGOZLU H: Captopril inhibits the pulmonary toxicity of paraquat in rats. Hum. Exp. Toxicol (2001) 20(12):637–641.
  • MOLTENI A, MOULDER JE,COHEN EF et al: Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II Type 1 receptor blocker. Int. I Radial-. Biol. (2000) 76(4):523–532.
  • FANG X, ZHU Y, HU X, LIU Y: [Losartan in the rat model of bleomycin-induced pulmonary fibrosis and its impact on the expression of monocyte chemoattractant protein-1 and basic fibroblast growth factor]. Zhonghua lie He He Hu Xi Za Zhi (2002) 25(5):268–272.
  • YU L, NOBLE NA, BORDER WA: Therapeutic strategies to halt renal fibrosis. Carr. Opin. Pharmacol (2002) 2(2):177–181.
  • CARRILLO G, ESTRADA A, MEJIA M et al.: Inhaled beclomethasone and colchicine versus inhaled beclomethasone, colchicine and captopril in patients with idiooathic pulmonary fibrosis. Am.' Respic Grit. Care Med. (2000) 161(3):A528 (Abstract).
  • RAGHU G, SAFRIN S, WEYCKER D et al.: Association of statins and angiotensin-converting enzyme inhibitor use with survival and disease progression in patients with idiopathic pulmonary fibrosis (IPF). Am. I Respir: Crit. Care Med. (2004) 169(7):A706 (Abstract).
  • UGUCCIONI M, PULSATELLI L, GRIGOLO B et al: Endothelin-1 in idiopathic pulmonary fibrosis. I. Gin. Pathol (1995) 48(4):330–334.
  • GIAID A, MICHEL RP, STEWART DJ et al.: Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet (1993) 341(8860):1550–1554.
  • SALEH D, FURUKAWA K, TSAO MS et al.: Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible
  • ••involvement of proinflammatory cytokines. Am. J. Respir. Cell Ma Biol. (1997) 16(2):187–193.
  • CAMBREY AD, HARRISON NK, DAWES KE et al: Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am. Respir. Cell MoL Biol. (1994) 11(4):439–445.
  • ODOUX C, CRESTANI B, LEBRUN G et al.: Endothelin-1 secretion by alveolar macrophages in systemic sclerosis.Am. J. Respir. Grit. Care Med. (1997) 156(5):1429–1435.
  • PEACOCK AJ, DAWES KE, SHOCK A et al.: Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. Am. I Respir: Cell MM. Biol. (1992) 7(5):492–499.
  • SHAHAR I, FIREMAN E, TOPILSKY M et al.: Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases. Int. J. Immunopharmacol (1999) 21(11):759–775.
  • XU S, DENTON CP, HOLMES A et al: Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts. J. Cardiovasc. PharmacoL (1998) 31 (Suppl. 1):S360–S363.
  • MAYER DC, LEINWAND LA: Sarcomeric gene expression and contractility in myofibroblasts. J. Cell Biol. (1997) 139(6):1477–1484.
  • GASULL X, BATALLER R, GINES P et al.: Human myofibroblastic hepatic stellate cells express Ca(2+)-activated K(+) channels that modulate the effects of endothelin-1 and nitric oxide. .I. Hepatol (2001) 35(6):739–748.
  • SHICHIRI M, SEDIVYJM, MARUMO F, HIRATA Y: Endothelin-1 is a potent survival factor for c-Myc-dependent apoptosis. MM. Endocrinol (1998) 12(2):172–180.
  • SHI-WEN X, DENTON CP,DASHWOOD MR et al: Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. Invest. Dermatol (2001) 116(3):417–425.
  • SAITO H, NAKAMURA H, KATO S et al.: Percutaneous in vivo gene transfer to the peripheral lungs using plasmid-liposome complexes. Am. I Physiol Lung Cell Ma Physiol (2000) 279(4):L651–L657.
  • HOCHER B, SCHWARZ A, FAGAN KA et al.: Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am. I Respir: Cell MM. Biol. (2000) 23(1):19–26.
  • PARK SH, SALEH D, GIAID A, MICHEL RP: Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am. I Respir. Grit. Care Med. (1997) 156(2 Pt 1):600–608.
  • MUTSAERS SE, MARSHALL RP, GOLDSACK NR, LAURENT GJ, MCANULTY RJ: Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Palm. Pharmacol Ther: (1998) 11(2-3):221–225.
  • NGUYEN QT, COLOMBO F, ROULEAU JL, DUPUIS J, CALDERONE A: LU135252, an endothelin(A) receptor antagonist did not prevent pulmonary vascular remodelling or lung fibrosis in a rat model of myocardial infarction. Br. J. Pharmacol (2000) 130(7):1525–1530.
  • RUBIN LJ, BADESCH DB, BARST RJ et al.: Bosentan therapy for pulmonary arterial hypertension. N EngL I Med. (2002) 346(12):896–903.
  • BORDER WA, NOBLE NA: Transforming growth factor beta in tissue fibrosis. N Engl. [Med. (1994) 331(19):1286–1292.
  • BROEKELMANN TJ, LIMPER AH, COLBY TV, MCDONALD JA: Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl. Acad. Sci. USA (1991) 88(15):6642–6646.
  • KHALIL N, O'CONNOR RN,UNRUH HW et al.: Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. I Respic Cell MM. Biol. (1991) 5(2):155–162.
  • MASSAGUE J, BLAIN SW, LO RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Ce//(2000) 103(2):295–309.
  • SHULL MM, ORMSBY I, KIER AB et al: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature (1992) 359(6397):693–699.
  • ••This study identifies TGF-I31 a criticalintmunoregulatory factor in vi vo by downregulating inflarnrnatory responses in uninjured tissues. This suggests an important homeostatic, immune-suppressor role for this pro-fibrotic cytokine.
  • LEOF EB, PROPER JA, GETZ MJ, MOSES HL: Transforming growth factor type beta regulation of actin mRNA. Cell. Physiol (1986) 127(1):83–88.
  • BATTEGAY EJ, RAINES EW, SEIFERT RA, BOWEN-POPE DF, ROSS R: TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell (1660) 63(3):515–524.
  • FINLAY GA, THANNICKAL VJ, FANBURG BL, PAULSON KE: Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor. Biol. Chem. (2000) 275(36):27650–27656.
  • ROSENBAUM J, BLAZEJEWSKI S, PREAUX AM et al: Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts. Gastroenterology (1995) 109(6):1986–1996.
  • THANNICKAL VJ, ALDWEIB KD, RAJAN T, FANBURG BL: Upregulated expression of fibroblast growth factor (FGF) receptors by transforming growth factor-beta 1 (TGF-betal) mediates enhanced mitogenic responses to FGFs in cultured human lung fibroblasts.Biochem. Biophys. Res. Commun. (1998) 251(2):437–441.
  • ZHANG HY, PHAN SH: Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am. Respir. Cell MM. Biol. (1999) 21(6):658–665.
  • JELASKA A, KORN JH: Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum. (2000) 43(10):2230–2239.
  • HOROWITZ JC, LEE DY, WAGHRAY M et al.: Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta], in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. j Biol. Chem. (2004) 279(2):1359–1367.
  • •This study provides mechanistic insights into anti-apoptotic/pro-survival phenotypic expression of myofibroblasts in response to TGF-I31 signalling.
  • DESMOULIERE A, GEINOZ A, GABBIANI F, GABBIANI G: Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts.Cell Biol. (1993) 122(1):103–111.
  • •This is one of the first studies to show that TGF-I31 is potent inducer of myofibroblast differentiation.
  • THANNICKAL VJ, LEE DY, WHITE ES et al.: Myofibroblast differentiation by transforming growth factor-betal is dependent on cell adhesion and integrin signaling via focal adhesion kinase. " Biol. Chem. (2003) 278(14):12384–12389.
  • ••This study demonstrates a critical role formatrix-derived signals via the activation of focal adhesion kinase in the stable differentiation and maintenance of the myofibroblast phenotype. This suggests that therapeutic targeting of non-Smad-dependent pathways may be feasible in blocking pro-fibrotic effects of TGF-I31 without interfering with its important homeostatic functions.
  • SIME PJ, XING Z, GRAHAM FL, CSAKY KG, GAULDIE J: Adenovector-mediated gene transfer of active transforming growth factor-betal induces prolonged severe fibrosis in rat lung.Clin. Invest. (1997) 100(4):768–776.
  • IGNOTZ RA, MASSAGUE J:Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J. Biol. Chem. (1986) 261(9)4337–4345.
  • ZHANG K, REKHTER MD,GORDON D, PHAN SH: Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am. Pathol (1994) 145(1):114–125.
  • •In an animal model of pulmonary fibrosis, the emergence of myofibroblasts is strongly correlated with ECM production.
  • HEINO J, IGNOTZ RA, HEMLER ME, CROUSE C, MASSAGUE J: Regulation of cell adhesion receptors by transforming growth factor-beta. Concomitant regulation of integrins that share a common beta 1 subunit. J. Biol. Chem. (1989) 264(1):380–388.
  • THANNICKAL VJ, FANBURG BL: Activation of an H202-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. Biol. Chem. (1995) 270(51):30334–30338.
  • •This study demonstrates the ability of TGF-I31-differentiated myofibroblasts to secrete extracellular H202, a potential mechanism for oxidative stress in late stages of UIP/IPE characterised by a relative paucity of classic inflammatory cells.
  • THANNICKAL VJ, ALDWEIB KD, FANBURG BL: Tyrosine phosphorylation regulates H202 production in lung fibroblasts stimulated by transforming growth factor betal. J. Biol. Chem. (1998) 273(36):23611–23615.
  • HAMILTON JA, WOJTA J, GALLICHIO M, MCGRATH K, FILONZI EL: Contrasting effects of transforming growth factor-beta and IL-1 on the regulation of plasminogen activator inhibitors in human synovial fibroblasts.Immunol (1993) 151(10):5154–5161.
  • SCHNAPER HW, KOPP JB, PONCELET AC et al.: Increased expression of extracellular matrix proteins and decreased expression of matrix proteases after serial passage of glomerular mesangial cells." Cell Sci. (1996) 109\(Pt 10):2521–2528.
  • TOMASEK JJ, GABBIANI G, HINZ B, CHAPONNIER C, BROWN RA: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev Ma Cell. Biol. (2002) 3(5):349–363.
  • FAVA RA, OLSEN NJ, POSTLETHWAITE AE et al.: Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia. I Exp. Med. (1991) 173(5):1121–1132.
  • POSTLETHWAITE AE, KESKI-OJA J, MOSES HL, KANG AH: Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta." Exp. Med. (1987) 165(1):251–256.
  • GIRT SN, HYDE DM, HOLLINGER MA: Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax (1993) 48(10):959–966.
  • WANG Q, WANG Y, HYDE DM et al: Reduction of bleomycin induced lung fibrosis by transforming growth factor betasoluble receptor in hamsters. Thorax (1999) 54(9):805–812.
  • SHIMIZUKAWA M, EBINA M, NARUMI K et al: Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycin. Am. I Physiol Lung Cell Ma Physiol (2003) 284(3)1526–L532.
  • DERYNCK R, ZHANG YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature (2003) 425(6958):577–584.
  • ROBERTS AB, DERYNCK R: Meeting report: signaling schemes for TGF-beta. Sci. STKE (2001) 2001(113):PE43.
  • ZHAO J, SHI W, WANG YL et al: Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am. I Physiol Lung Cell Ma Physiol (2002) 282(3):L585–L593.
  • NAKAO A, FUJII M, MATSUMURA R et al.: Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. Clin. Invest. (1999) 104(1):5–11.
  • •This study demonstrates that blockade of TGF-I3 post-receptor signalling at the level of Smad activation protects against fibrotic responses to tissue injury in vivo.
  • SIRIWARDENA D, KHAW PT, KING AJ et al.: Human antitransforming growth factor beta(2) monoclonal antibody-a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study.Ophthalmology (2002) 109(3):427–431.
  • WARD MR, SASAHARA T, AGROTIS A et al.: Inhibitory effects of tranilast on expression of transforming growth factor-beta isoforms and receptors in injured arteries. Atherosclerosis (1998) 137(2):267–275.
  • IVELL R, EINSPANIER A: Relaxin peptides are new global players. Trends Endocrinol Metab. (2002)\ 13(8):343–348.
  • HSU SY, NAKABAYASHI K, NISHI S et al.: Activation of orphan receptors by the hormone relaxin. Science (2002) 295(5555):671–674.
  • BARTSCH O, BARTLICK B, IVELL R: Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Ma Hum. Reprod. (2001) 7(9):799–809.
  • UNEMORI EN, BECK LS, LEE WP et al: Human relaxin decreases collagenaccumulation in vivo in two rodent modelsof fibrosis.j Invest. Dermatcl. (1993) 101(3):280–285.
  • UNEMORI EN, PICKFORD LB, SALLES AL 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.Clin. Invest. (1996) 98(12):2739–2745.
  • PALEJVVALA S, STEIN DE, WEISS G et al.: Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology (2001) 142(8):3405–3413.
  • DSCHIETZIG T, BARTSCH C, RICHTER C et al.: Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ. Res. (2003) 92(1):32–40.
  • GARBER SL, MIROCHNIK Y, BRECKLIN CS et al.: Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int. (2001) 59(3):876–882.
  • SAMUEL CS, ZHAO C, BATHGATE RA et al.: Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. Faseb. 1(2003) 17(1):121–123.
  • KENYON NJ, WARD RW, LAST JA: Airway fibrosis in a mouse model of airway inflammation. Miami Appl. Pharmacy]. (2003) 186(2):90–100.
  • SEIBOLD JR, KORN JH, SIMMS R et al.: Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. (2000) 132(11):871–879.
  • PIGUET PF: Is 'tumor necrosis factor' the major effector of pulmonary fibrosis? Ear. Cytckine Netw. (1990) 1(4):257–258.
  • PIGUET PF, RIBAUX C, KARPUZ V, GRAU GE, KAPANCI Y: Expression and localization of tumor necrosis factor-alpha and its mRNA in idiopathic pulmonary fibrosis. Am. J. Pathcl (1993) 143(3):651–655.
  • NASH JR, MCLAUGHLIN PJ,BUTCHER D, CORRIN B: Expression of tumour necrosis factor-alpha in cryptogenic fibrosing alveolitis. Histcpathclogy (1993) 22(4):343–347.
  • WHYTE M, HUBBARD R,MELICONI R et al.: Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms. Am. I Respic Crit. Care Med. (2000) 162(2 Pt 1):755–758.
  • MIYAZAKI Y, ARAKI K, VESIN C et al.: Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. I Clin. Invest. (1995) 96(1):250–259.
  • SIME PJ, MARR RA, 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-betal and myofibroblasts. Am. I Pathcl (1998) 153(3):825–832.
  • SOLIS-HERRUZO JA, BRENNER DA, CHOJKIER M: Tumor necrosis factor alpha inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. I Bic] Chem. (1988) 263(12):5841–5845.
  • KAHARI VM, CHEN YQ, SU MW, RAMIREZ F, UITTO J: Tumor necrosis factor-alpha and interferon-gamma suppress the activation of human Type I collagen gene expression by transforming growth factor-beta 1. Evidence for two distinct mechanisms of inhibition at the transcriptional and posttranscriptional levels. I Clin. Invest. (1990) 86(5):1489–1495.
  • SIWIK DA, CHANG DL, COLUCCI WS: Interleukin-lbeta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ. Res. (2000) 86(12):1259–1265.
  • GREENWEL P, TANAKA S, PENKOV D et al.: Tumor necrosis factor alpha inhibits Type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mel Cell. Bic] (2000) 20(3):912–918.
  • HAN YP, TUAN TL, WU H,HUGHES M, GARNER WL: TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMPI Cell Sci. (2001) 114(Pt 1):131–139.
  • RAPALA KT, VAHA-KREULA MO, HEINO JJ, VUORIO El, LAATO MK: Tumor necrosis factor-alpha inhibits collagen synthesis in human and ratgranulation tissue fibroblasts. Experientia (1996) 52(1):70–74.
  • KON A, VINDEVOGHEL L, KOUBA DJ et al.: Cooperation between SMAD and NF-kappaB in growth factor regulated Type VII collagen gene expression. Oncygene (1999) 18(10):1837–1844.
  • CHOU DH, LEE W, MCCULLOCH CA: TNF-alpha inactivation of collagen receptors: implications for fibroblast function and fibrosis. I Immune] (1996) 156(11):4354–4362.
  • ABRAHAM DJ, SHIWEN X, BLACK CM et al.: Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts. I Bic] Chem. (2000) 275(20):15220–15225.
  • WANG R, ALAM G, ZAGARIYA A et al.: Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. I Cell. Physic] (2000) 185(2):253–259.
  • PIGUET PF, COLLART MA, GRAU GE, KAPANCI Y, VASSALLI P: Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. I Exp. Med. (1989) 170(3):655–663.
  • PIGUET PF, VESIN C: Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur: Respic 1 (1994) 7(3):515–518.
  • PIGUET PF, COLLART MA, GRAU GE, SAPPINO AP, VASSALLI P: Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature (1990) 344(6263):245–247.
  • ORTIZ LA, LASKY J, LUNGARELLA G et al.: Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am. I Respic Cell Mel Bic] (1999) 20(4):825–833.
  • LIU JY, BRASS DM, HOYLE GW, BRODY AR: TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers. Am. J. Pathcl (1998) 153(6):1839–1847.
  • KUROKI M, NOGUCHI Y,SHIMONO M et al.: Repression of bleomycin-induced pneumopathy by TNE I Immune] (2003) 170(1):567–574.
  • FUJITA M, SHANNON JM,MORIKAWA O et al.: Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta. Am. .1 Respir: Cell Ma Biol. (2003) 29(6):669–676.
  • FELDMANN M, MAINI RN: Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Ann. Rev Immunol (2001) 19:163–196.
  • NIDEN A, KOSS M, BOYLEN CT, WILCOX A: An open label pilot study to determine the potential efficacy of TNFR:Fc (Enbrel, Etanercept) in the treatment of usual interstitial pneumonitis. Am. I Respir: Grit. Care Med. (2002) 165(8):A728 (Abstract).
  • IHN H: Pathogenesis of fibrosis: role of TGF-beta and CTGF. Carr: Opin. Rheumatol (2002) 14(6):681–685.
  • ALLEN JT, KNIGHT RA, BLOOR CA, SPITERI MA: Enhanced insulin-like growth factor binding protein-related protein 2 (Connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am. .1 Respir: Cell Ma Biol. (1999) 21(6):693–700.
  • PAN LH, YAMAUCHI K, UZUKI M et al.: Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF Eur: Respir: (2001) 17(6):1220–1227.
  • SATO S, HASEGAWA M, TAKEHARA K: Serum levels of interleukin-6 and interleultin-10 correlate with total skin thickness score in patients with systemic sclerosis. I Dermatol ScL (2001) 27(2):140–146.
  • DUNCAN MR, FRAZIER KS, ABRAMSON S et al.: Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP FASEB. (1999) 13(13):1774–1786.
  • BONNIAUD P, MARGETTS PJ,KOLB M et al.: Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis. Am. .1 Respir: Grit. Care Med. (2003) 168(7):770–778.
  • ITO Y, ATEN J, BENDE RJ et al.: Expression of connective tissue growth factor in human renal fibrosis. Kidney Int. (1998) 53(4):853–861.
  • LEASK A, ABRAHAM DJ: The role of connective tissue growth factor, amultifunctional matricellular protein, in fibroblast biology. Biochem. Cell Biol. (2003) 81(6):355–363.
  • LASKY JA, ORTIZ LA, TONTHAT B et al.: Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis. Am.' Physiol (1998) 275(2 Pt 1):L365–L371.
  • MACNEE W RAHMAN I: Oxidants/antioxidants in idiopathic pulmonary fibrosis. Thorax (1995) 50\(Suppl. 1):S53–S58.
  • RAHMAN I, SKWARSKA E, HENRY M et al.: Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis. Free Radic. Biol. Med. (1999) 27(1-2):60–68.
  • CANTIN AM, NORTH SL, FELLS GA, HUBBARD RC, CRYSTAL RG: Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.' Clin. Invest. (1987) 79(6):1665–1673.
  • CANTIN AM, HUBBARD RC, CRYSTAL RG: Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am. Rev. Respir: Dis. (1989) 139(2):370–372.
  • PHELPS DT, DENEKE SM, DALEY DL, FANBURG BL: Elevation of glutathione levels in bovine pulmonary artery endothelial cells by N-acetylcysteine. Am. Respir: Cell Ma Biol. (1992) 7(3):293–299.
  • BOROK Z, BUHL R, GRIMES GJ et al: Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet (1991) 338(8761):215–216.
  • MEYER A, BUHL R, MAGNUSSEN H: The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Lid. Respir. (1994) 7(3):431–436.
  • WHITE AC, THANNICKAL VJ, FANBURG BL: Glutathione deficiency in human disease.' Nutr. Biochem. (1994) 5:218–226.
  • RINALDO J, GOLDSTEIN RH, SNIDER GL: Modification of oxygen toxicity after lung injury by bleomycin in hamsters. Am. Rev Respir: Dis. (1982) 126(6):1030–1033.
  • NAKASHIMA JM, LEVIN JR,HYDE DM, GIRI SN: Repeated exposures to enzyme-generated oxidants cause alveolitis, epithelial hyperplasia, and fibrosis in hamsters. Am. I Pathol (1991) 139(6):1485–1499.
  • SHAHZEIDI S, SARNSTRAND B, JEFFERY PK, MCANULTY RJ, LAURENT GJ: Oral N-acetylcysteine reduces bleomycin-induced collagen deposition in the lungs of mice.Respir. (1991) 4(7):845–852.
  • BEHR J, MAIER K, DEGENKOLB B, KROMBACH F, VOGELMEIER C: Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am. I Respir: Grit. Care Med. (1997) 156(6):1897–1901.
  • •An interesting preliminary report of an antioxidant strategy for the treatment of human subjects with IPE
  • TANZI RE, PETRUKHIN K, CHERNOV I et al: The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat. Genet. (1993) 5(4):344–350.
  • BREWER GJ: Copper control as an antiangiogenic anticancer therapy: lessons from treating Wilson's disease. Exp. Biol. Med. (Maywood) (2001) 226(7):665–673.
  • BREWER GJ: Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation. I Cell Ma Med. (2003) 7(1):11–20.
  • BREWER GJ, ULLENBRUCH MR, DICK R, OLIVAREZ L, PHAN SH: Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice. I Lab. Clin. Med. (2003) 141(3):210–216.
  • WILBORN J, BAILIE M, COFFEY M et al.: Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis. I. Gin. Invest. (1996) 97(8):1827–1836.
  • BOROK Z, GILLISSEN A, BUHL R et al: Augmentation of functional prostaglandin E levels on the respiratory epithelial surface by aerosol administration of prostaglandin E. Am. Rev Respir: Dis. (1991) 144(5):1080–1084.
  • WILBORN J, CROFFORD LJ, BURDICK MD et al: Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. I Clin. Invest. (1995) 95(4):1861–1868.
  • •This study suggests that fibroblasts isolated UIP/IPF lung may bephenotypically altered in a relatively stable manner despite ex vivo cell culture.
  • LAMA V, MOORE BB,CHRISTENSEN P, TOEWS GB, PETERS-GOLDEN M: Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am. Respir. Cell Mel. Biel (2002) 27(6):752–758.
  • KOHYAMA T, ERTL RE VALENTI V et al.: Prostaglandin E(2) inhibits fibroblast chemotaxis. Am. I Physiel. Lung Cell Mel Physiel. (2001) 281(5)11257–L1263.
  • MIO T, LIU XD, ADACHI Y et al: Human bronchial epithelial cells modulate collagen gel contraction by fibroblasts.Am. J. Physiel. (1998) 274(1 Pt 1):L119–L126.
  • KOLODSICK JE, PETERS-GOLDEN M, LARIOS J et al.: Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation.Am.Respir. Cell Mel Biel (2003) 29(5):537–544.
  • HOLGATE ST, PETERS-GOLDEN M, PANETTIERI RA, HENDERSON WR Jr:Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. I Allergy Clin. Immune]. (2003) 111(1 Suppl.):S18-S34;Discussion S34–S16.
  • PETERS-GOLDEN M, BAILIE M, MARSHALL T et al.: Protection from pulmonary fibrosis in leukotriene-deficient mice. Am.j Respir. Grit. Care Med. (2002) 165 (2): 229–235.
  • MOORE BB, PETERS-GOLDEN M, CHRISTENSEN PJ et al: Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2. Am. I Physiel.Lung Cell Mel. Physiel. (2003) 284(2)1342–L349.
  • MOORE BB, PAINE R 3rd,CHRISTENSEN PJ et al.: Protection from pulmonary fibrosis in the absence of CCR2 signaling. Immune]. (2001) 167(8):4368–4377.
  • CHARBENEAU RP, CHRISTENSEN PJ, CHRISMAN CJ et al.: Impaired synthesis of prostaglandin E2 by lung fibroblasts and alveolar epithelial cells from GM-CSF-/-mice: implications for fibroproliferation.Am. I Physiel. Lung Cell Mel Physiel. (2003) 284(6)11103–L1111.
  • SAVAGE DG, ANTMAN KH: Imatinth mesylate-a new oral targeted therapy. N Eng]. Med. (2002) 346(9):683–693.
  • HADDAD JJ: VX-745. VertexPharmaceuticals. Carr. Opin. Investig. Drugs (2001) 2(8):1070–1076.
  • COHEN P: The origins of protein phosphorylation. Nat. Cell Biel. (2002) 4(5):E127–E130.
  • COHEN P: Protein kinases-the major drug targets of the twenty-first century? Nat. Rev Drug Discev. (2002) 1(4):309–315.
  • TONG L, PAV S, WHITE DM et al: A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat. Struct. Biel (1997) 4(4):311–316.
  • UNDERWOOD DC, OSBORN RR, BOCHNOWICZ S et al.: SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am. I Physiel. Lung CellPhysiel. (2000) 279(5)1895–L902.
  • MATSUOKA H, ARM T, MORI M et al:A p38 MAPK inhibitor, FR-167653,ameliorates murine bleomycin-induced pulmonary fibrosis. Am. I Physiel. Lung Cell Physiel. (2002) 283(1)1103–L112.
  • KINNMAN N, GORIA O, WENDUM D et al.: Hepatic stellate cell proliferation is anearly platelet-derived growth factor-mediated cellular event in rat cholestatic liver injury. Lab. Invest. (2001) 81(12):1709–1716.
  • FLAHERTY KR, MUMFORD JA, MURRAY S et al.: Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia.Am. I Respir. Crit. Care Med. (2003) 168(5):543–548.
  • YOSHIDA K, KUWANO K, HAGIMOTO N et al: MAP kinase activation and apoptosis in lung tissues from patients with idiopathic pulmonary fibrosis.Pathel (2002) 198(3):388–396.
  • •This is the first study to show that MAPKs are differentially activated in epithelial versus mesenchymal cells in lungs ofUIP/IPF patients.

Websites

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.