Idiopathic pulmonary fibrosis:Pathophysiological data

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Published Mar 21, 2018
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Vol. 95 No. 8 (2017): Issue Aug 2017

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Khadija Ayed
Raja Serairi Beji
Saloua Jameleddine

Abstract

Idiopathic pulmonary fibrosis is the most common of the idiopathic interstitial pneumonias.
The role of inflammation in idiopathic pulmonary fibrosis (IPF) is controversial. If inflammation were critical to the disease process, lung pathology would demonstrate an influx of inflammatory cells, and that the disease would respond to immunosuppression.
The classic pathology does not display substantial inflammation, and no modulation of the immune system is effective as treatment. Recent data suggest that the pathophysiology of the disease is more a product of fibroblast dysfunction than of dysregulated inflammation. The concept of epithelial-mesenchymal cell transition has recently received much attention; this transition appears to play a greater role in the pathogenesis than inflammation.
It’s suggested that inflammation is indeed a critical factor in IPF and proposed five potential nontraditional mechanisms for the role of inflammation in the pathogenesis of IPF: the direct inflammatory hypothesis, the matrix hypothesis, the growth factor–receptor hypothesis, the plasticity hypothesis, and the vascular hypothesis.

Keywords:

Idiopathic pulmonary fibrosis; pathophysiology; alveolar repair

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References

  1. Nalysunk L, Cid-Ruzafa J, Rotella P, EsserDrik. Incidence and prevalence of idiopathic pulmonary fibrosis : review of literature. EurRespir Rev 2012; 21: 126, 355-61.
  2. Blackwell TS, Tager AM, Borok Z, Moore BB, Schwartz DA, David A et al. Future directions in idiopathic pulmonary fibrosis research. American Journal of Respiratory and Critical Care Medecine 2014;189: 2, 214-22.
  3. Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136-51.
  4. Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/ fibroblastic cross-talk disorder. Respir Res 2002; 3: 3-10.
  5. Horowitz JC, Thannickal VJ. Epithefial-mesenchymal interactions in pulmonary fibrosis. SemRespirClin Care Med 2006; 27: 600-12.
  6. Falfan-Valencia R, Camarena A, Juarez A, Becerril C, Montano M, Cisneros J, et al. Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis. Hum Genet 2005; 118: 235-44.
  7. Grutters JC, Du Bois RM. Genetics of fibrosing lung diseases. EurRespir 1 2005; 25: 915-27.
  8. Fang KC. Mesenchymal regulation of alveolar repair in pulmonary fibrosis. Am J Respir Cell MolBiol 2000; 23: 142-5.
  9. Golan-GerstlR, Wallach-Dayan SB, Amir G, Breuer R. Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis. Am J Respir Cell MolBiol 2007; 36: 270-5.
  10. Nunes H: pathogénie de la fibrose pulmonaire idiopathique: nouveaux concepts. Rev Mal Respir 2003; 20: 6S100-6S102.
  11. Antoniou KM, Pataka A, Bouros D, et al. Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis. PulmPharmacolTher 2007; 20(5): 453-61.
  12. Cool CD, Groshong SD, Rai PR, Henson PM, Stewart JS, Brown KK. Fibroblast foci are not discrete sites of lung injury or repair: the fibcoblast reticulum. Am J RespirCrit Care Med 2006; 174: 654-8.
  13. Myers IL, Katzenstein AL. Fibroblasts in focus. Am J RespirCrit Care Med 2006; 174: 623-4.
  14. King TE, Jr, Schwatz MI, Brown K, Tooze JA, Colby TV, Waldron JA, Jr, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J RespirCrit Care Med 2001; 164: 1025-32.
  15. Pierce EM, Carpenter K, Jakubzick C, Kunkel SL, Flaherty KR, Martinez FJ, et al. Therapeutic targeting of CC ligand 21 or CC chemokine receptor 7 abrogates pulmonary fibrosis induced by the adoptive transfer of human pulmonary fibroblasts to immunodeficient mice. Am J Pathol 2007; 170: 1152-64.
  16. Phillips RI, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, et al. Circulating fibcocytes traffic to the lungs in response to CXCL 12 and mediate fibrosis. J Clin Invest 2004; 114: 438-46.
  17. Lama VN, Phan SH. The extrapulmonary origin of fibroblasts: stem/ progenitor cells and beyond. Proc Am ThoracSoc 2006; 3: 373-6.
  18. Willis BC, DuBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am ThoracSoc 2006; 3: 377-82.
  19. Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, et al. Caveolin- 1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med 2006; 203: 2895-906.
  20. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 2009; 175: 3-16.
  21. Kalluri R, Weimberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420-8.
  22. Cordier JF. Fibrose pulmonaire idiopathique. Presse Med 2010 ; 39: 85-92.
  23. Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002; 122 : 286S-9.
  24. Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 2006; 3: 364-72.
  25. Nunes H: pathogénie de la fibrose pulmonaire idiopathique: nouveaux concepts. Rev Mal Respir 2003; 20: 6S100-2.
  26. Petrovski S, Todd JL, Durheim MT, Wang Q, Chien JW, Kelly FL, et al.An exome sequencing study to assess the role of rare genetic variation in pulmonary fibrosis. Am J RespirCrit Care Med 2017; 5: 325-31.
  27. Guzy RD, Li L, Smith C, Dorry SJ, Koo HY, Chen L, et al.Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling.J BiolChem 2017; 292: 10364-78.
  28. Lu YY, Zhao XK, Yu L, Qi F, Zhai B, Gao CQ, Ding Q.Interaction of Src and alpha-V integrin regulates fibroblast migration and modulateslung fibrosis in a preclinical model of lung fibrosis.Sci Rep. 2017;7: 46357-68.
  29. Pittenger MF, Mackay AM, Beck SC, et al. Multiline age potential of adult human mesenchymal stem cells. Science 1999; 284: 143-7.
  30. Gerson SL. Mesenchymal stem cells: no longer second class marrow citizens. Nat Med 1999; 5: 262-4.
  31. Pereira RF, Halford KW, O'Hara MD, et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. ProcNatlAcadSci USA 1995; 92: 4857-61.
  32. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71-4.
  33. Lama VN, Phan SH. The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am ThoracSoc 2006; 3: 373-6.
  34. Antoniou KM, Papadaki HA, Soufla G, Kastrinaki MC, Damianaki A, Koutala H, et al. Investigation of bone marrow mesenchymal stem cells (BM MSCs) involvement in idiopathic pulmonary fibrosis (IPF). Respiratory Medicine 2010; 104: 1535-42.
  35. Shahar I, Fireman E, Topilsky M, Grief J, Schwarz Y, Kivity S, et al. Effect of endothelin- 1 on alpha-smooth muscle action expression and on alveolar fibroblasts proliferation in interstitial lung diseases. Int J Immunopharmacol 1999; 21: 759-75.
  36. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou- Gharios G, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Aktdependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. MolBiol Cell 2004; 15: 2707-19.
  37. Goto T, Yanaga F, O htsuki I. Studies on the endothelin-l-induced contraction of rat granulation tissue pouch mediated by myofibroblasts. BiochimBiophysActa 1998; 1405: 55-66.
  38. Shi-Wen X, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, et al. Endothelin- 1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J BiolChem 2004; 279: 23098-103.
  39. Jain R, Shaul PW, Borok Z, Willis BC. Endothelin- 1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-betal. Am J Respir Cell MolBiol2007; 37: 38-47.
  40. Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD, et al. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 1990; 172: 1741-8.
  41. Giaid A, Michel RP, Stewart DJ, Sheppard M, Comn B, Hamid Q. Expression of endothelin- 1 in lungs of patients with cryptogenic fibrosingalveolitis. Lancet 1993; 341: 1550-4.
  42. Saleh D, Furukawa K, Tsao MS, Maghazachi A, Comn B, Yanagisawa M, et al. Elevated expression of endothelin-I and endothelinconverting enzyme-I in idiopathic pulmonary fibrosis: possible involvement of pro-inflammatory cytokines. Am J Respir Cell MolBiol 1997; 16: 187-93.
  43. Mutsaers SE, Foster ML, Chambers RC, Laurent GJ, McAnulty ILI. Increased endothelin- 1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats. Am J Respir Cell MolBiol 1998; 18: 611-9.
  44. Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling : role of endothelin- 1. J Invest Dermato 2001; 116: 417-25.
  45. Duronio V, Clark-Lewis I, Federsppiel B, Wieler JS, Schrader JW. Tyrosine phosphorylation of receptor beta-subunits and common substratesin response to interleukin-3 and granulocyte/macrophage colony-stimulating factor. J BiolChem 1992; 267: 21856-63.
  46. Hocher B, Schwarz A, Fagan KA, Thone-Reineke C, El-Hag K, Kusserow H, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell MolBiol 2000; 23: 19-26.
  47. Park SH, Saleh D, Giaid A, and Michel RP. Increased endothelin-I in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J RespirCrit Care Med 1997; 156: 600-8.
  48. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 2009; 175: 3-16.
  49. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420-8.
  50. Agostini C, Gurrieri C. chemokine/cytokine cocktail in idiopathic pulmonary fibrosis. Proc Am ThoracSoc 2006; 3: 357-63.
  51. Parks WC, Shapiro SD: Matrix metalloproteinases in lung biology. Respir Res 2001; 2: 10-9.
  52. 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: 136-51.
  53. Selman M, Ruiz V, Cabrera S, Segura L, Ramirez R, Barrios R, Pardo A : TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradativelungmicro-environnement. Am J Physiol Lung Cel Mol Physiol 2000; 279: L562-74.
  54. Ramos C, Montano M, Garcia Alvarez J, Ruiz V, Uhal BD, Selman M, et al. Fibroblastes from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am Respir Cell MolBiol 2001; 24: 591-8.
  55. Suga M, Lyonaga K, Okamoto T, Gushima Y, Miyakawa H, Akaike T, et al. Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias. Am J RespirCrit Care Med 2000; 162: 1949-56.
  56. Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, et al. Genes expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. ProcNatlAcadSci 2002; 99: 6292-7.
  57. Cosgrov GP, Brown KK, Henson PM, Shwarz MI, Worthen GS. Enhanced TGB-β1 activity by matrix metalloproteinase. Am J RespirCrit Care Med 2003; 167: A841.
  58. Gauldie J. Pro: Inflammatory mechanisms are a minor component of the pathogenesis of idiopathic pulmonary fibrosis. Am J RespirCrit Care Med 2002; 165: 1205-6.
  59. Strieter RM. Con: Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis. Am J RespirCrit Care Med 2002; 165: 1206-1207.
  60. Bringardner D,Baran P, Eubank D, Marsh B. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis.Antioxid Redox Signal. 2008; 10(2): 287-301.
  61. Gelrud LG, Arseneau JC, Milder MS, Kramer RJ, Swann SJ, Canellos GP, et al. The kinetics of 67gallium incorporation into inflammatory lesions: experimental and clinical studies. J Lab Clin Med 1974; 83: 489-95.
  62. Grijm K, Verberne HJ, Krouwels FH, Weller FR, Jansen HM, Bresser P. Semiquantitative 67Ga scintigraphy as an indicator of response to and prognosis after corticosteroid treatment in idiopathic interstitial pneumonia. J Nucl Med 2005; 46: 1421-6.
  63. Selman M, Carrillo G, Estrada A, Mejia M, Becerril C, Cisneros J, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern. Plos One 2007; 2: e482.
  64. Furuie H, Yamasaki H, Suga M, Ando M. Altered accessory cell function of alveolar macrophages: a possible mechanism for induction of Th2 secretory profile in idiopathic pulmonary fibrosis. EurRespir J 1997; 10: 787-94.
  65. Jakubzick C, Choi ES, Kunkel SL, Evanoff H, Martinez FJ, Puri RK, et al. Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia. J ClinPathol 2004; 57: 477-86.
  66. Standiford TJ, Rolfe MR, Kunkel SL, Lynch JP 3rd, Becker FS, Orringer MB, et al. Altered production and regulation of monocyte chemoattractant protein-1 from pulmonary fibroblasts isolated from patients with idiopathic pulmonary fibrosis. Chest 1993; 103: 121S.
  67. Standiford TJ, Rolfe MW, Kunkel SL, Lynch JP 3rd, Burdick MD, Gilbert AR, et al. Macrophage inflammatory protein-1 alpha expression in interstitial lung disease. J Immunol 1993; 151: 2852-63.
  68. Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A. Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J RespirCrit Care Med 1994; 149: 655-9.
  69. Ogushi F, Tani K, Maniwa K, Ichikawa W, Tada H, Kawano T, et al. Interleukin-8 in broncho-alveolar lavage fluid of patients with diffuse panbronchiolitis or idiopathic pulmonary fibrosis. J Med Invest 1997; 44: 53-8.
  70. Pechkovsky DV, Prasse A, Kollert F, Engel K, Dentler J, Luttmann W, et al. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. ClinImmunol 2010; 137: 89-101.
  71. Bargagli E, Oliveri C, Nikiforakis N, Cintorino M, Magi B, Prari MG, et al. Analysis of macrophage migration inhibitory factor (MIF) in patients with idiopathic pulmonary fibrosis. RespirphysiolNeurobiol 2009; 167: 261-67.
  72. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank MM, Crystal RG. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest 1977; 59: 165-75.
  73. Yasuoka S, Nakayama T, Kawano T, Ogushi F, Doi H, Hayashi H, et al. Comparison of cell profiles of bronchial and broncho-alveolar lavage fluids between normal subjects and patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med 1985; 146: 33-45.
  74. Hiwatari N, Shimura S, Sasaki T, Aikawa T, Ando Y, Ishihara H, et al. Prognosis of idiopathic pulmonary fibrosis in patients with mucous hypersecretion. AmRev Respir Dis 1991; 143: 182-5.
  75. Peterson MW, Monick M, Hunninghake GW. Prognostic role of eosinophilis in pulmonary fibrosis. Chest 1987; 92: 51-6.
  76. Hallgren R, Bjermer L, Lundgren R, Venge P. The eosinophil component of the alveolitis in idiopathic pulmonary fibrosis: signs of eosinophil activation in the lung are related to impaired lung function. Am Rev Respir Dis 1989; 139: 373-7.
  77. Shindoh Y, Shimura S, Tomioka M, Aikawa T, Sasaki H, Takishima T. Cellular analysis in broncho-alveolar lavage fluids in infiltrative and fibrotic stages of idiopathic pulmonary fibrosis. Tohoku J Exp Med 1986; 149: 47-60.
  78. Watters LC, Schwarz MI, Cherniack RM, Waldron JA, Dunn TL, Stanford RE, et al. Idiopathic pulmonary fibrosis: pre-treatment broncho-alveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy. Am Rev Respir Dis 1987; 135: 696-704.
  79. Obayashi Y, Yamadori I, Fujita J, Yoshinouchi T, Ueda N, Takahara J. The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis. Chest 1997; 112: 1338-43.
  80. Papiris SA, Kollintza A, Kitsanta P, Kapotsis G, Karatza M, Milic-Emili J, et al. Relationship of BAL and lung tissue CD4+ and CD8+ T lymphocytes, and their ratio in idiopathic pulmonary fibrosis. Chest 2005; 128: 2971-7.
  81. Parra ER, Kairalla RA, Ribeiro de Carvalho CR, Eher E, Capelozzi VL. Inflammatory cell phenotyping of the pulmonary interstitium in idiopathic interstitial pneumonia. Respiration 2007; 74: 159-69.
  82. Tabuena RP, Nagai S, Tsutsumi T, Handa T, Minoru T, Mikuniya T, et al. Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese patients. Respiration 2005; 72: 490-8.
  83. Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell MolPhysiol 2001; 280: L1327-34.
  84. Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6: 56.
  85. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, et al.Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. ProcNatlAcadSci USA 2006; 103: 13180-5.
  86. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96: 319-28.
  87. Vedham V, Phee H, Coggeshall KM. Vav activation and function as a rac guanine nucleotide exchange factor in macrophage colony-stimulating factor-induced macrophage chemotaxis. Mol Cell Biol 2005; 25: 4211-20.
  88. Baran CP, Opalek JM, McMaken S, Newland CA, O'Brien JM Jr, Hunter MG, et al. Important roles for MCSF, CCL2 and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J RespirCrit Care Med 2007; 176: 78-89.
  89. Giorgino F, Smith RJ. Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation: role of specific intracellular signaling pathways. J Clin Invest 1995; 96: 1473-83.
  90. Z89Liu JY, Brass DM, Hoyle GW, Brody AR. TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers. Am J Pathol 1998; 153: 1839-47.
  91. Chambers SK, Gilmore-Hebert M, Wang Y, Rodov S, Benz EJ Jr, Kacinski BM. Posttranscriptional regulation of colony-stimulating factor-1 (CSF-1) and CSF-1 receptor gene expression during inhibition of phorbol-ester-induced monocytic differentiation by dexamethasone and cyclosporin A: potential involvement of a destabilizing protein. ExpHematol 1993; 21: 1328-34.
  92. Wang Y, Zeigler MM, Lam GK, Hunter MG, Eubank TD, Khramtsov VV, et al. The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival. Am J Respir Cell MolBiol 2007; 36: 68-77.
  93. Inaba T, Yamada N, Gotoda T, Shimano H, Shimada M, Momomura K, et al. Expression of MCSF receptor encoded by c-fms on smooth muscle cells derived from arteriosclerotic lesion. J BiolChem 1992; 267: 5693-9.
  94. Sasmono RT, Ehrnsperger A, Cronau SL, Ravasi T, Kandane R, Hickey MJ, et al. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophagespecific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J LeukocBiol 2007; 82: 111-23.
  95. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128: 1475-82.
  96. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank MM, Crystal RG. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest 1977; 59: 165-75.
  97. Hunninghake GW, Gadek JE, Lawley TJ, Crystal RG. Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis. J Clin Invest 1981; 68: 259-69.
  98. Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, et al. Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. Hum Immunol 2006; 67: 284-97.
  99. Magro CM, Wusirika R, Frambach GE, Nuovo GJ, Ferri C, Ross P Jr. Autoimmune-like pulmonary disease in association with parvovirus B19: a clinical, morphologic, and molecular study of 12 cases. ApplImmunohistochemMolMorphol 2006; 14: 208-16.
  100. Beon M, Harley RA, Wessels A, Silver RM, Ludwicka-Bradley A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. ClinExpRheumatol 2004; 22: 733-42.
  101. Ihn H, Sato S, Fujimoto M, Igarashi A, Yazawa N, Kubo M et al. Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonary fibrosis. ClinExpImmunol 2000; 119: 203-9.
  102. Magro CM, Morrison C, Pope-Harman A, Rothrauff SK, Ross P Jr. Direct and indirect immunofluorescence as a diagnostic adjunct in the interpretation of nonneoplastic medical lung disease. Am J ClinPathol 2003; 119: 279-89.
  103. Wusirika R, Ferri C, Marin M, Knight DA, Waldman WJ, Ross P Jr, Magro CM. The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis: a study of indirect immunofluorescent and Western blot analysis in 49 patients with scleroderma. Am J ClinPathol 2003; 120: 596-606.
  104. Marsh CB, Gadek JE, Kindt GC, Moore SA, Wewers MD. Monocyte Fc gamma receptor cross-linking induces IL-8 production. J Immunol 1995; 155: 3161-7.
  105. Marsh CB, Pomerantz RP, Parker JM, Winnard AV, Mazzaferri ElJr, Moldovan N, et al. Regulation of monocyte survival in vitro by deposited IgG: role of macrophage colony-stimulating factor. J Immunol 1999; 162: 6217-25.
  106. Marsh CB, Wewers MD, Tan LC, Rovin BH. Fc (gamma) receptor cross-linking induces peripheral blood mononuclear cell monocyte chemoattractant protein-1 expression: role of lymphocyte Fc (gamma) RIII. J Immunol 1997; 18: 1078-84.
  107. Scotton CJ, Krupiczoc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, et al. increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest 2009; 119: 2550-63.
  108. Renzoni EA, Walsh DA, Salmen M, Wells AU, Sestini P, Nicholson AG, et al. Interstitial vascularity in fibrosingalveolitis. Am J RespirCrit Care Med 2003; 167: 438-43.
  109. Cosgrov GP, Brown KK, Cool CD, Geraci MW, Shwartz MI, Worthen GS. Aberrant angiogenesis in idiopathic pulmonary fibrosis. Am J RespirCrit Care Med 2003; 167: A300.
  110. Valeyre D, Dion G. Treatment of idiopathic pulmonary fibrosis. Bull AcadNatl Med 2010; 194(2):367-81.
  111. King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370(22):2083-92.
  112. Cottin V, Cordier JF. Fibrose pulmonaire idiopathique. Presse Med 2008; 37: 1581-90.
  113. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al.Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.Engl J Med 2011; 365(12):1079-87.
  114. Richeldi L, Du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. INPULSIS Trial Investigators.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med 2014;370(22):2071-82.
  115. Raghu G, Brown KK, Collard HR, Cottin V, Gibson KF, Kaner RJ, et al.Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial.Lancet Respir Med 2017;5(1):22-32.