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Semin Respir Crit Care Med 2006; 27(6): 589-599
DOI: 10.1055/s-2006-957331
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Inflammation and Angiogenesis in Fibrotic Lung Disease

Michael P. Keane1 , Robert M. Strieter2 , Joseph P. Lynch1  III , John A. Belperio1
  • 1Division of Pulmonary and Critical Care Medicine, UCLA David Geffen School of Medicine at UCLA, Los Angeles, California
  • 2Department of Medicine, University of Virginia, Charlottesville, Virginia
Further Information

Publication History

Publication Date:
29 December 2006 (online)

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ABSTRACT

The pathogenesis of pulmonary fibrosis is poorly understood. Although inflammation has been presumed to have an important role in the development of fibrosis this has been questioned recently, particularly with regard to idiopathic pulmonary fibrosis (IPF). It is, however, increasingly recognized that the polarization of the inflammatory response toward a type 2 phenotype supports fibroproliferation. Increased attention has been on the role of noninflammatory structural cells such as the fibroblast, myofibroblast, epithelial cell, and endothelial cells. Furthermore, the origin of these cells appears to be multifactorial and includes resident cells, bone marrow-derived cells, and epithelial to mesenchymal transition. Increasing evidence supports the presence of vascular remodeling in fibrotic lung disease, although the precise role in the pathogenesis of fibrosis remains to be determined. Therefore, the pathogenesis of pulmonary fibrosis is complex and involves the interaction of multiple cell types and compartments within the lung.

KEYWORDS

Idiopathic pulmonary fibrosis - angiogenesis - fibrosis - fibroblasts - chemokines

REFERENCES

  • 1 Davidson J M. Wound repair. In: Gallin JI, Goldstein IM, Snyderman R Inflammation: Basic Principles and Clinical Correlates. New York; Raven 1992
    Google Scholar
  • 2 Vaillant P, Menard O, Vignaud J-M, Martinet N, Martinet Y. The role of cytokines in human lung fibrosis.  Monaldi Arch Chest Dis. 1996;  51 145-152
    PubMedGoogle Scholar
  • 3 Phan S H. New strategies for treatment of pulmonary fibrosis.  Thorax. 1995;  50 415-421
    PubMedGoogle Scholar
  • 4 Phan S H, Kunkel S L. Lung cytokine production in bleomycin-induced pulmonary fibrosis.  Exp Lung Res. 1992;  18 29-43
    PubMedGoogle Scholar
  • 5 Gauldie J, Jordana M, Cox G. Cytokines and pulmonary fibrosis.  Thorax. 1993;  48 931-935
    PubMedGoogle Scholar
  • 6 Kelly B G, Lok S S, Hasleton P S, Egan J J, Stewart J P. A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2002;  166 510-513
    CrossrefPubMedGoogle Scholar
  • 7 Mora A L, Torres-Gonzalez E, Rojas M et al.. Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis.  Am J Respir Cell Mol Biol  2006;  35 466-473
    PubMedGoogle Scholar
  • 8 Zamo A, Poletti V, Reghellin D et al.. HHV-8 and EBV are not commonly found in idiopathic pulmonary fibrosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 123-128
    PubMedGoogle Scholar
  • 9 Tang Y W, Johnson J E, Browning P J et al.. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis.  J Clin Microbiol. 2003;  41 2633-2640
    CrossrefPubMedGoogle Scholar
  • 10 Lok S S, Haider Y, Howell D, Stewart J P, Hasleton P S, Egan J J. Murine gammaherpes virus as a cofactor in the development of pulmonary fibrosis in bleomycin resistant mice.  Eur Respir J. 2002;  20 1228-1232
    CrossrefPubMedGoogle Scholar
  • 11 Hashimoto S, Gon Y, Takeshita I, Maruoka S, Horie T. IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway.  J Allergy Clin Immunol. 2001;  107 1001-1008
    CrossrefPubMedGoogle Scholar
  • 12 Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation.  Exp Cell Res. 1999;  250 273-283
    CrossrefPubMedGoogle Scholar
  • 13 Phan S H. Fibroblast phenotypes in pulmonary fibrosis.  Am J Respir Cell Mol Biol. 2003;  29(Suppl 3) S87-S92
    PubMedGoogle Scholar
  • 14 Bucala R, Spiegel L A, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.  Mol Med. 1994;  1 71-81
    PubMedGoogle Scholar
  • 15 Moore B B, Kolodsick J E, Thannickal V J et al.. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.  Am J Pathol. 2005;  166 675-684
    PubMedGoogle Scholar
  • 16 Abe R, Donnelly S C, Peng T, Bucala R, Metz C N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.  J Immunol. 2001;  166 7556-7562
    PubMedGoogle Scholar
  • 17 Chesney J, Metz C, Stavitsky A B, Bacher M, Bucala R. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.  J Immunol. 1998;  160 419-425
    PubMedGoogle Scholar
  • 18 Phillips R J, Burdick M D, Hong K et al.. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.  J Clin Invest. 2004;  114 438-446
    CrossrefPubMedGoogle Scholar
  • 19 Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis.  J Clin Invest. 2003;  112 1776-1784
    CrossrefPubMedGoogle Scholar
  • 20 Iwano M, Plieth D, Danoff T M, Xue C, Okada H, Neilson E G. Evidence that fibroblasts derive from epithelium during tissue fibrosis.  J Clin Invest. 2002;  110 341-350
    CrossrefPubMedGoogle Scholar
  • 21 Willis B C, Liebler J M, Luby-Phelps K et al.. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-{beta}1: potential role in idiopathic pulmonary fibrosis.  Am J Pathol. 2005;  166 1321-1332
    CrossrefPubMedGoogle Scholar
  • 22 Sheppard D. Pulmonary fibrosis: a cellular overreaction or a failure of communication?.  J Clin Invest. 2001;  107 1501-1502
    PubMedGoogle Scholar
  • 23 Kolb M, Margetts P J, Anthony D C, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis.  J Clin Invest. 2001;  107 1529-1536
    CrossrefPubMedGoogle Scholar
  • 24 King Jr T E, Schwarz M I, Brown K et al.. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.  Am J Respir Crit Care Med. 2001;  164 1025-1032
    CrossrefPubMedGoogle Scholar
  • 25 Collard H R, King Jr T E. Treatment of idiopathic pulmonary fibrosis: the rise and fall of corticosteroids.  Am J Med. 2001;  110 326-328
    CrossrefPubMedGoogle Scholar
  • 26 Selman M, King T E, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.  Ann Intern Med. 2001;  134 136-151
    CrossrefPubMedGoogle Scholar
  • 27 Chandler D B. Possible mechanisms of bleomycin-induced fibrosis.  Clin Chest Med. 1990;  11 21-30
    PubMedGoogle Scholar
  • 28 Christensen P J, Goodman R E, Pastoriza L, Moore B, Toews G B. Induction of lung fibrosis in the mouse by intratracheal instillation of fluorescein isothiocyanate is not T-cell-dependent.  Am J Pathol. 1999;  155 1773-1779
    CrossrefPubMedGoogle Scholar
  • 29 Sime P J, Xing Z, Graham F L, Csaky K G, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor- beta1 induces prolonged severe fibrosis in rat lung.  J Clin Invest. 1997;  100 768-776
    CrossrefPubMedGoogle Scholar
  • 30 Sime P J, Marr R A, Gauldie D et al.. Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts.  Am J Pathol. 1998;  153 825-832
    CrossrefPubMedGoogle Scholar
  • 31 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.  J Clin Invest. 1995;  96 250-259
    PubMedGoogle Scholar
  • 32 Leung D Y, de Castro M, Szefler S J, Chrousos G P. Mechanisms of glucocorticoid-resistant asthma.  Ann N Y Acad Sci. 1998;  840 735-746
    CrossrefPubMedGoogle Scholar
  • 33 Belperio J A, Keane M P, Burdick M D et al.. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome.  J Clin Invest. 2001;  108 547-556
    CrossrefPubMedGoogle Scholar
  • 34 Trulock E P. Lung transplantation.  Am J Respir Crit Care Med. 1997;  155 789-818
    CrossrefPubMedGoogle Scholar
  • 35 Flaherty K R, Travis W D, Colby T V et al.. Histopathologic variability in usual and nonspecific interstitial pneumonias.  Am J Respir Crit Care Med. 2001;  164 1722-1727
    CrossrefPubMedGoogle Scholar
  • 36 Belperio J A, Dy M, Murray L et al.. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis.  J Immunol. 2004;  173 4692-4698
    PubMedGoogle Scholar
  • 37 Zhang Y, McCormick L L, Desai S R, Wu C, Gilliam A C. Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation.  J Immunol. 2002;  168 3088-3098
    PubMedGoogle Scholar
  • 38 Luzina I G, Atamas S P, Wise R, Wigley F M, Xiao H Q, White B. Gene expression in bronchoalveolar lavage cells from scleroderma patients.  Am J Respir Cell Mol Biol. 2002;  26 549-557
    PubMedGoogle Scholar
  • 39 Antoniades H N, Neville-Golden J, Galanopoulos T, Kradin R L, Valente A J, Graves D T. Expression of monocyte chemoattractant protein-1 mRNA in human idiopathic pulmonary fibrosis.  Proc Natl Acad Sci USA. 1992;  89 5371-5375
    CrossrefPubMedGoogle Scholar
  • 40 Kodera M, Hasegawa M, Komura K, Yanaba K, Takehara K, Sato S. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis.  Arthritis Rheum. 2005;  52 2889-2896
    CrossrefPubMedGoogle Scholar
  • 41 Akira S. The role of IL-18 in innate immunity.  Curr Opin Immunol. 2000;  12 59-63
    CrossrefPubMedGoogle Scholar
  • 42 Belperio J A, Keane M P, Arenberg D A et al.. CXC chemokines in angiogenesis.  J Leukoc Biol. 2000;  68 1-8
    PubMedGoogle Scholar
  • 43 Giri S N, Hyde D M, Marafino B J. Ameliorating effect of murine interferon gamma on bleomycin-induced lung collagen fibrosis in mice.  Biochem Med Metab Biol. 1986;  36 194-197
    CrossrefPubMedGoogle Scholar
  • 44 Chizzolini C, Rezzonico R, Ribbens C, Burger D, Wollheim F A, Dayer J M. Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: different sensitivity to inhibition between systemic sclerosis and control fibroblasts.  Arthritis Rheum. 1998;  41 2039-2047
    CrossrefPubMedGoogle Scholar
  • 45 Cornelissen A M, Von den Hoff J W, Maltha J C, Kuijpers-Jagtman A M. Effects of interferons on proliferation and collagen synthesis of rat palatal wound fibroblasts.  Arch Oral Biol. 1999;  44 541-547
    PubMedGoogle Scholar
  • 46 Jaffe H A, Gao Z, Mori Y, Li L, Varga J. Selective inhibition of collagen gene expression in fibroblasts by an interferon-gamma transgene.  Exp Lung Res. 1999;  25 199-215
    PubMedGoogle Scholar
  • 47 Brody A R, Bonner J C, Badgett A. Recombinant interferon-gamma reduces PDGF-induced lung fibroblast growth but stimulates PDGF production by alveolar macrophages in vitro.  Chest. 1993;  103(Suppl 2) 121S-122S
    PubMedGoogle Scholar
  • 48 Dimitroff C J, Pera P, Dall'Olio F et al.. Cell surface n-acetylneuraminic acid alpha2,3-galactoside-dependent intercellular adhesion of human colon cancer cells.  Biochem Biophys Res Commun. 1999;  256 631-636
    CrossrefPubMedGoogle Scholar
  • 49 Keane M P, Belperio J A, Burdick M D, Strieter R M. IL-12 attenuates bleomycin-induced pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2001;  281 L92-L97
    PubMedGoogle Scholar
  • 50 Maeyama T, Kuwano K, Kawasaki M, Kunitake R, Hagimoto N, Hara N. Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12.  Am J Physiol Lung Cell Mol Physiol. 2001;  280 L1128-L1137
    PubMedGoogle Scholar
  • 51 Huaux F, Arras M, Tomasi D et al.. A profibrotic function of IL-12p40 in experimental pulmonary fibrosis.  J Immunol. 2002;  169 2653-2661
    PubMedGoogle Scholar
  • 52 Sakamoto H, Zhao L H, Jain F, Kradin R. IL-12p40( - / - ) mice treated with intratracheal bleomycin exhibit decreased pulmonary inflammation and increased fibrosis.  Exp Mol Pathol. 2002;  72 1-9
    CrossrefPubMedGoogle Scholar
  • 53 Segel M J, Cohen P Y, Izbicki G et al.. The role of interferon-{gamma} in the evolution of murine bleomycin lung fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2003;  285 L1255-L1262
    PubMedGoogle Scholar
  • 54 Chen E S, Greenlee B M, Wills-Karp M, Moller D R. Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin.  Am J Respir Cell Mol Biol. 2001;  24 545-555
    PubMedGoogle Scholar
  • 55 Stout A J, Gresser I, Thompson D. Inhibition of wound healing in mice by local interferon alpha/beta injection.  Int J Exp Pathol. 1993;  74 79-85
    PubMedGoogle Scholar
  • 56 Hyde D M, Henderson T S, Giri S N, Tyler N K, Stovall M Y. Effect of murine gamma interferon on the cellular responses to bleomycin in mice.  Exp Lung Res. 1988;  14 687-704
    PubMedGoogle Scholar
  • 57 Gurujeyalakshmi G, Giri S N. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression.  Exp Lung Res. 1995;  21 791-808
    PubMedGoogle Scholar
  • 58 Postlethwaite A E, Holness M A, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin-4.  J Clin Invest. 1992;  90 1479-1485
    PubMedGoogle Scholar
  • 59 Postlethwaite A E, Seyer J M. Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70-88 and 89-122.  J Clin Invest. 1991;  87 2147-2152
    PubMedGoogle Scholar
  • 60 Rankin J A, Picarella D E, Geba G P et al.. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity.  Proc Natl Acad Sci USA. 1996;  93 7821-7825
    CrossrefPubMedGoogle Scholar
  • 61 Chensue S W, Warmington K, Ruth J H, Lukacs N, Kunkel S L. Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-gamma and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks. [published erratum appears in J Immunol 1999 Mar 1;162(5):3106].  J Immunol. 1997;  159 3565-3573
    PubMedGoogle Scholar
  • 62 Wills-Karp M, Luyimbazi J, Xu X et al.. Interleukin-13: central mediator of allergic asthma. [see comments].  Science. 1998;  282 2258-2261
    CrossrefPubMedGoogle Scholar
  • 63 Hancock A, Armstrong L, Gama R, Millar A. Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung.  Am J Respir Cell Mol Biol. 1998;  18 60-65
    PubMedGoogle Scholar
  • 64 Hasegawa M, Fujimoto M, Kikuchi K, Takehara K. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis.  J Rheumatol. 1997;  24 328-332
    PubMedGoogle Scholar
  • 65 Ohshima K, Akaiwa M, Umeshita R, Suzumiya J, Izuhara K, Kikuchi M. Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis.  Histopathology. 2001;  38 368-375
    CrossrefPubMedGoogle Scholar
  • 66 Oriente A, Fedarko N S, Pacocha S E, Huang S K, Lichtenstein L M, Essayan D M. Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts.  J Pharmacol Exp Ther. 2000;  292 988-994
    PubMedGoogle Scholar
  • 67 Zhu Z, Homer R J, Wang Z et al.. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.  J Clin Invest. 1999;  103 779-788
    PubMedGoogle Scholar
  • 68 Lee C G, Homer R J, Zhu Z et al.. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).  J Exp Med. 2001;  194 809-821
    CrossrefPubMedGoogle Scholar
  • 69 Lanone S, Zheng T, Zhu Z et al.. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling.  J Clin Invest. 2002;  110 463-474
    CrossrefPubMedGoogle Scholar
  • 70 Kaviratne M, Hesse M, Leusink M et al.. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent.  J Immunol. 2004;  173 4020-4029
    PubMedGoogle Scholar
  • 71 Zhu Z, Ma B, Zheng T et al.. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling.  J Immunol. 2002;  168 2953-2962
    PubMedGoogle Scholar
  • 72 Ma B, Zhu Z, Homer R J, Gerard C, Strieter R, Elias J A. The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling.  J Immunol. 2004;  172 1872-1881
    PubMedGoogle Scholar
  • 73 Lee P J, Zhang X, Shan P et al.. ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo.  J Clin Invest. 2006;  116 163-173
    PubMedGoogle Scholar
  • 74 Gharaee-Kermani M, Denholm E M, Phan S H. Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors.  J Biol Chem. 1996;  271 17779-17784
    CrossrefPubMedGoogle Scholar
  • 75 Smith R E, Strieter R M, Phan S H et al.. Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury.  J Immunol. 1994;  153 4704-4712
    PubMedGoogle Scholar
  • 76 Smith R E, Strieter R M, Phan S H, Kunkel S L. CC chemokines: novel mediators of the profibrotic inflammatory response to bleomycin challenge.  Am J Respir Cell Mol Biol. 1996;  15 693-702
    PubMedGoogle Scholar
  • 77 Gu L, Tseng S, Horner R M, Tam C, Loda M, Rollins B J. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1.  Nature. 2000;  404 407-411
    PubMedGoogle Scholar
  • 78 Hogaboam C M, Lukacs N W, Chensue S W, Strieter R M, Kunkel S L. Monocyte chemoattractant protein-1 synthesis by murine lung fibroblasts modulates CD4 + T cell activation.  J Immunol. 1998;  160 4606-4614
    PubMedGoogle Scholar
  • 79 Belperio J A, Dy M, Burdick M D et al.. Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis.  Am J Respir Cell Mol Biol. 2002;  27 419-427
    PubMedGoogle Scholar
  • 80 Jakubzick C, Choi E S, Joshi B H et al.. Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells.  J Immunol. 2003;  171 2684-2693
    PubMedGoogle Scholar
  • 81 Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama T, Matsushima K. Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice.  J Immunol. 2000;  164 2745-2751
    PubMedGoogle Scholar
  • 82 Moore B B, Paine III R, Christensen P J et al.. Protection from pulmonary fibrosis in the absence of CCR2 signaling.  J Immunol. 2001;  167 4368-4377
    PubMedGoogle Scholar
  • 83 Moore B B, Peters-Golden M, Christensen P J et al.. Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2.  Am J Physiol Lung Cell Mol Physiol. 2003;  284 L342-L349
    PubMedGoogle Scholar
  • 84 Wallace W AH, Ramage E A, Lamb D, Howie E M. A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with crytogenic fibrosingalveolitis (CFA).  Clin Exp Immunol. 1995;  101 436-441
    PubMedGoogle Scholar
  • 85 Jakubzick C, Choi E S, Kunkel S L et al.. Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia.  J Clin Pathol. 2004;  57 477-486
    CrossrefPubMedGoogle Scholar
  • 86 Jakubzick C, Choi E S, Carpenter K J et al.. Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia.  Am J Pathol. 2004;  164 1989-2001
    PubMedGoogle Scholar
  • 87 Kuroki S, Ohta A, Sueoka N, Katoh O, Yamada H, Yamaguchi M. Determination of various cytokines and type III procollagen aminopeptide levels in bronchoalveolar lavage fluid of the patients with pulmonary fibrosis: inverse correlation between type III procollagen aminopeptide and interferon-γ in progressive fibrosis.  Br J Rheumatol. 1995;  34 31-36
    PubMedGoogle Scholar
  • 88 Raghu G, Brown K K, Bradford W Z et al.. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.  N Engl J Med. 2004;  350 125-133
    CrossrefPubMedGoogle Scholar
  • 89 Mulligan M S, Jones M L, Vaporciyan A A, Howard M C, Ward P A. Protective effects of IL-4 and IL-10 against immune complex-induced lung injury.  J Immunol. 1993;  151 5666-5674
    PubMedGoogle Scholar
  • 90 Standiford T J, Strieter R M, Lukacs N W, Kunkel S L. Neutralization of IL-10 increases lethality in endotoxemia: cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor.  J Immunol. 1995;  155 2222-2229
    PubMedGoogle Scholar
  • 91 Greenberger M J, Strieter R M, Kunkel S L, Danforth J M, Goodman R E, Standiford T J. Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia.  J Immunol. 1995;  155 722-729
    PubMedGoogle Scholar
  • 92 Lee C G, Homer R J, Cohn L et al.. Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways.  J Biol Chem. 2002;  277 35466-35474
    CrossrefPubMedGoogle Scholar
  • 93 Arai T, Abe K, Matsuoka H et al.. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 L914-L922
    PubMedGoogle Scholar
  • 94 Driscoll K E, Carter J M, Howard B W et al.. Interleukin-10 regulates quartz-induced pulmonary inflammation in rats.  Am J Physiol. 1998;  275(5 Pt 1) L887-L894
    PubMedGoogle Scholar
  • 95 Huaux F, Louahed J, Hudspith B et al.. Role of interleukin-10 in the lung response to silica in mice.  Am J Respir Cell Mol Biol. 1998;  18 51-59
    PubMedGoogle Scholar
  • 96 Arras M, Huaux F, Vink A et al.. Interleukin-9 reduces lung fibrosis and type 2 immune polarization induced by silica particles in a murine model.  Am J Respir Cell Mol Biol. 2001;  24 368-375
    PubMedGoogle Scholar
  • 97 Hoyle G W, Brody A R. IL-9 and lung fibrosis: a Th2 good guy?.  Am J Respir Cell Mol Biol. 2001;  24 365-367
    PubMedGoogle Scholar
  • 98 Rojas M, Xu J, Woods C R et al.. Bone marrow-derived mesenchymal stem cells in repair of the injured lung.  Am J Respir Cell Mol Biol. 2005;  33 145-152
    CrossrefPubMedGoogle Scholar
  • 99 Turner-Warwick M. Precapillary systemic-pulmonary anastomoses.  Thorax. 1963;  18 225-237
    CrossrefPubMedGoogle Scholar
  • 100 Peao M ND, Aguas A P, DeSa C M, Grande N R. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin.  Anat Rec. 1994;  238 57-67
    PubMedGoogle Scholar
  • 101 Mitzner W, Lee W, Georgakopoulos D, Wagner E. Angiogenesis in the mouse lung.  Am J Pathol. 2000;  157 93-101
    PubMedGoogle Scholar
  • 102 Srisuma S, Biswal S S, Mitzner W A, Gallagher S J, Mai K H, Wagner E M. Identification of genes promoting angiogenesis in mouse lung by transcriptional profiling.  Am J Respir Cell Mol Biol. 2003;  29 172-179
    CrossrefPubMedGoogle Scholar
  • 103 Keane M P, Arenberg D A, Lynch III J P et al.. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis.  J Immunol. 1997;  159 1437-1443
    PubMedGoogle Scholar
  • 104 Keane M P, Belperio J A, Arenberg D A et al.. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis.  J Immunol. 1999;  163 5686-5692
    PubMedGoogle Scholar
  • 105 Keane M P, Belperio J A, Burdick M, Lynch III J P, Fishbein M F, Strieter R M. ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2001;  164 2239-2242
    CrossrefPubMedGoogle Scholar
  • 106 Nakayama S, Mukae H, Ishii H et al.. Comparison of BALF concentrations of ENA-78 and IP10 in patients with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia.  Respir Med. 2005;  99 1145-1151
    PubMedGoogle Scholar
  • 107 Renzoni E A, Walsh D A, Salmon M et al.. Interstitial vascularity in fibrosing alveolitis.  Am J Respir Crit Care Med. 2003;  167 438-443
    CrossrefPubMedGoogle Scholar
  • 108 Simler N R, Brenchley P E, Horrocks A W, Greaves S M, Hasleton P S, Egan J J. Angiogenic cytokines in patients with idiopathic interstitial pneumonia.  Thorax. 2004;  59 581-585
    CrossrefPubMedGoogle Scholar
  • 109 Cosgrove G P, Brown K K, Schiemann W P et al.. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis.  Am J Respir Crit Care Med. 2004;  170 242-251
    CrossrefPubMedGoogle Scholar
  • 110 Strieter R M, Polverini P J, Kunkel S L et al.. The functional role of the “ELR” motif in CXC chemokine-mediated angiogenesis.  J Biol Chem. 1995;  270 27348-27357
    CrossrefPubMedGoogle Scholar
  • 111 Keane M P, Arenberg D A, Lynch J P et al.. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis.  J Immunol. 1997;  159 1437-1443
    PubMedGoogle Scholar
  • 112 Hyde D M, Henderson T S, Giri S N, Tyler N K, Stovall M Y. Effect of murine gamma interferon on the cellular responses to bleomycin in mice.  Exp Lung Res. 1988;  14 687-695
    PubMedGoogle Scholar
  • 113 Hein R, Behr J, Hundgen M et al.. Treatment of systemic sclerosis with gamma-interferon.  Br J Dermatol. 1992;  126 496-501
    CrossrefPubMedGoogle Scholar
  • 114 Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block L H. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. [see comments].  N Engl J Med. 1999;  341 1264-1269
    CrossrefPubMedGoogle Scholar
  • 115 Jordana M, Schulman J, McSharry C et al.. Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue.  Am Rev Respir Dis. 1988;  137 579-584
    PubMedGoogle Scholar
  • 116 Keane M P, Belperio J A, Moore T A et al.. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.  J Immunol. 1999;  162 5511-5518
    PubMedGoogle Scholar
  • 117 Strieter R M, Starko K M, Enelow R I, Noth I, Valentine V G. Effects of interferon gamma-1b on biomarker expression in idiopathic pulmonary fibrosis patients.  Am J Respir Crit Care Med. 2004;  170 133-140
    CrossrefPubMedGoogle Scholar
  • 118 Burdick M D, Murray L A, Keane M P et al.. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.  Am J Respir Crit Care Med. 2005;  171 261-268
    PubMedGoogle Scholar

Michael P KeaneM.D. 

UCLA, Department of Medicine, Division of Pulmonary and Critical Care Medicine

900 Veteran Ave., 14-154 Warren Hall, Los Angeles, CA 90095-1922

Email: mpkeane@mednet.ucla.edu

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