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Emerging Concepts in the Pathogenesis of Lung Fibrosis

2009; Elsevier BV; Volume: 175; Issue: 1 Linguagem: Inglês

10.2353/ajpath.2009.081170

1525-2191

William D. Hardie, Stephan W. Glasser, James S. Hagood,

Medical Imaging and Pathology Studies

Fibrogenesis is an often-deadly process with increasing world-wide incidence and limited therapeutic options. Pulmonary fibrogenesis involves remodeling of the distal airspace and parenchyma of the lung, and is characterized by excessive extracellular matrix deposition and accumulation of apoptosis-resistant myofibroblasts. Recent studies have added significantly to our understanding of the complex mechanisms involved in lung fibrogenesis. Emerging concepts in this field include the critical role of the epithelium, particularly type II pneumocytes, in the initiation and perpetuation of fibrosis in response to either endogenous or exogenous stress; a growing awareness of alternative activation of macrophages in tissue remodeling; growing appreciation of the alternative origins and phenotypic plasticity of fibroblasts; the roles of epigenetic reprogramming and context-dependent signaling in profibrotic phenotype alterations; and recognition of the importance of cross talk and convergence of intracellular signaling pathways. In vitro, in vivo, and in silico approaches support a paradigm of "disordered re-development" of the lung. Designing effective antifibrotic interventions will require accurate understanding of the complex interactions among the genetic, environmental, epigenetic, biochemical, cellular, and contextual abnormalities that promote pulmonary fibrogenesis. Fibrogenesis is an often-deadly process with increasing world-wide incidence and limited therapeutic options. Pulmonary fibrogenesis involves remodeling of the distal airspace and parenchyma of the lung, and is characterized by excessive extracellular matrix deposition and accumulation of apoptosis-resistant myofibroblasts. Recent studies have added significantly to our understanding of the complex mechanisms involved in lung fibrogenesis. Emerging concepts in this field include the critical role of the epithelium, particularly type II pneumocytes, in the initiation and perpetuation of fibrosis in response to either endogenous or exogenous stress; a growing awareness of alternative activation of macrophages in tissue remodeling; growing appreciation of the alternative origins and phenotypic plasticity of fibroblasts; the roles of epigenetic reprogramming and context-dependent signaling in profibrotic phenotype alterations; and recognition of the importance of cross talk and convergence of intracellular signaling pathways. In vitro, in vivo, and in silico approaches support a paradigm of "disordered re-development" of the lung. Designing effective antifibrotic interventions will require accurate understanding of the complex interactions among the genetic, environmental, epigenetic, biochemical, cellular, and contextual abnormalities that promote pulmonary fibrogenesis. Lung fibrosis occurs in interstitial lung diseases (ILDs) and idiopathic interstitial pneumonias (IIPs), as part of several systemic connective tissue diseases and childhood interstitial lung disease syndrome, and in response to many types of lung injury, including radiation and some chemotherapeutic drugs. Idiopathic pulmonary fibrosis (IPF) is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis. IPF claims more lives annually in the United States than many types of cancer1Cancer Facts & Figures. American Cancer Society, Atlanta2008Google Scholar; however, effective therapy is lacking. Recent evidence indicates that both IPF prevalence and mortality are growing in the United States and elsewhere.2Olson AL Swigris JJ Lezotte DC Norris JM Wilson CG Brown KK Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003.Am J Respir Crit Care Med. 2007; 176: 277-284Crossref PubMed Scopus (118) Google Scholar The increasing burden of IPF is not simply reflective of an aging population, as age-adjusted mortality for IPF is increasing as well.2Olson AL Swigris JJ Lezotte DC Norris JM Wilson CG Brown KK Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003.Am J Respir Crit Care Med. 2007; 176: 277-284Crossref PubMed Scopus (118) Google Scholar In much of the latter half of the 20th century, perhaps as the result of successful use of anti-inflammatory therapies such as corticosteroids for some of the IIPs, fibrosis was believed to be initiated and propagated by persistent lung inflammation.3Crouch E Pathobiology of pulmonary fibrosis.Am J Physiol. 1990; 259: L159-L184PubMed Google Scholar, 4Crystal RG Ferrans VJ Basset F Biologic Basis of Pulmonary Fibrosis.in: Crystal RG Raven Press, New York1991: 2031-2057Google Scholar However, corticosteroids and other anti-inflammatory therapies have been uniformly unhelpful for IPF, and may in fact be harmful.5Mapel DW Samet JM Coultas DB Corticosteroids and the treatment of idiopathic pulmonary fibrosis. Past, present, and future.Chest. 1996; 110: 1058-1067Crossref PubMed Google Scholar This fact, combined with absence of classic inflammatory biomarkers in IPF, and evidence from animal models in which fibrosis proceeds in the absence of inflammation, led to reassessment of the inflammatory paradigm. The view that fibrotic remodeling, both of the lung parenchyma (eg, in IPF) and airways (eg, in asthma) instead represents a form of disordered wound healing, in which epithelial-mesenchymal interactions are predominant, has become canonical in the literature of the past two decades.6Clark RA The commonality of cutaneous wound repair and lung injury.Chest. 1991; 99: 57S-60SCrossref PubMed Google Scholar, 7Rennard SI Repair mechanisms in asthma.J Allergy Clin Immunol. 1996; 98: S278-S286Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 8Selman M King TE Pardo A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Google Scholar Selman et al accordingly proposed reconsideration of IPF as a disorder of epithelial-fibroblast interaction.8Selman M King TE Pardo A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Google Scholar Interactions between the epithelium and mesenchyme have been shown to be critical for developmental morphogenesis of the lung,9Shannon JM Nielsen LD Gebb SA Randell SH Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea.Dev Dyn. 1998; 212: 482-494Crossref PubMed Scopus (82) Google Scholar and are also prominent in lung fibrogenesis. Recent microarray data from IPF and experimental models of fibrosis demonstrated recapitulation of expression patterns and signaling pathways critical during lung development.10Selman M Pardo A Kaminski N Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs?.PLoS Med. 2008; 5: e62Crossref PubMed Scopus (108) Google Scholar, 11Tuder RM Yun JH Bhunia A Fijalkowska I Hypoxia and chronic lung disease.J Mol Med. 2007; 85: 1317-1324Crossref PubMed Scopus (47) Google Scholar Thus it appears that many of the cellular and molecular events critical to "modeling" of the lung during development are recapitulated during the "re-modeling" that occurs during fibrogenesis. Lung fibrosis may thus not only be conceptualized as a form of aberrant repair,6Clark RA The commonality of cutaneous wound repair and lung injury.Chest. 1991; 99: 57S-60SCrossref PubMed Google Scholar, 12Adamson IYR Hedgecock C Bowden DH Epithelial cell-fibroblast interactions in lung injury and repair.Am J Path. 1990; 137: 385-392PubMed Google Scholar, 13Demayo F Minoo P Plopper CG Schuger L Shannon J Torday JS Mesenchymal-epithelial interactions in lung development and repair: are modeling and remodeling the same process?.Am J Physiol Lung Cell Mol Physiol. 2002; 283: L510-L517PubMed Google Scholar, 14Torday JS Rehan VK The evolutionary continuum from lung development to homeostasis and repair.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L608-L611Crossref PubMed Scopus (36) Google Scholar but also as a "disordered re-development" of the lung. Because nearly 45% of all deaths in the developed world are attributed to some type of chronic fibroproliferative disease,15Wynn TA Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.J Clin Invest. 2007; 117: 524-529Crossref PubMed Scopus (378) Google Scholar it is important periodically to review new developments in the study of fibrogenesis. This review focuses on recent experimental findings with regard to the pulmonary epithelium and fibroblasts, which include novel observations regarding the role of the epithelium in the initiation and maintenance of pulmonary fibrogenesis, as well as support newer concepts regarding the origins and differentiation of fibroblasts in fibrotic processes. In addition, it will review the latest data on intracellular signaling pathways and cross talk within and between the fibroblasts and epithelial cells that mediate pulmonary fibrosis. Understanding the emerging concepts discussed in this review and their relative roles in lung fibrosis will facilitate development of novel therapeutic approaches to ameliorate the global burden of fibroproliferative disease. The pulmonary alveolar epithelium is the final barrier interface to inhaled substances. Together with sentinel macrophages, the epithelium controls pulmonary homeostasis by responding to environmental challenges through continuous reciprocal interactions with mesenchymal and vascular cells. Chronic epithelial cell stress, due to either intrinsic cellular defects or extrinsic insults such as infection, can promote epithelial cell death, impair normal re-epithelialization and alter epithelial–mesenchymal interactions, leading to fibroproliferation.16Selman M Pardo A Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers.Proc Am Thorac Soc. 2006; 3: 364-372Crossref PubMed Scopus (173) Google Scholar Defined etiologies for pulmonary fibrosis secondary to intrinsic cellular defects include genetic deficiency of the pulmonary surfactant protein C (SP-C) and ATP binding cassette protein (ABC)A3. Persistent infection by viruses (specifically Herpesviridae) targeting the respiratory epithelium have also been associated with a fibrotic response. These distinct origins of human fibrosis have related mouse models that share many features of human disease, thus better delineating epithelial-based mechanisms of lung fibrosis. Pulmonary SP-C is a highly hydrophobic protein that enhances surface activity and contributes to innate immune defense of the lung. SP-C is synthesized and secreted only by alveolar type II cells, which are the site of initial injury in SP-C dysfunction disease. A variety of mutations in the SFTPC gene have since been identified that strongly associate this gene with disease. SFTPC mutations include point mutations that alter single amino acid residues, frame shift mutations that change or terminate downstream translation, and splice site mutations that delete entire exons to produce a truncated proSP-C protein.17Nogee LM Alterations in SP-B and SP-C expression in neonatal lung disease.Annu Rev Physiol. 2004; 66: 601-623Crossref PubMed Scopus (102) Google Scholar, 18Beers MF Mulugeta S Surfactant protein C biosynthesis and its emerging role in conformational lung disease.Annu Rev Physiol. 2005; 67: 663-696Crossref PubMed Scopus (83) Google Scholar The natural history and severity of SP-C-associated lung disease is highly variable and may reflect the cellular response to the distinct mutations in the SFTPC gene coupled with the action of undefined modifier genes. Alterations of a proprotein structure due to mutations can potentially inhibit proper folding to achieve correct conformation and function (loss of function). Likewise, impaired processing can lead to accumulation of nonfunctional protein that the cell must now eliminate (toxic gain of function). Maturation of newly translated proteins occurs as a series of folding events as proteins transit the endoplasmic reticulum and Golgi for release into cellular compartments for secretion. Cells have adapted a series of endoplasmic reticulum-based responses to restore proper folding or guide elimination of terminally misfolded proteins to relieve further stress. The cascade of responses is termed the unfolded protein response (UPR). If the UPR does not ultimately relieve cellular stress, then caspase-dependent cellular apoptosis pathways can be activated to eliminate cells entirely. The presence of aberrant forms of the SP-C precursor protein is a particular threat to homeostasis due to the high levels of SP-C normally synthesized, processed, and stored for secretion by the type II epithelial cells. UPR marker immunostaining is increased in the lungs of individuals with both SP-C mutations and IPF.19Lawson WE Crossno PF Polosukhin VV Roldan J Cheng DS Lane KB Blackwell TR Xu C Markin C Ware LB Miller GG Loyd JE Blackwell TS Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection.Am J Physiol Lung Cell Mol Physiol. 2008; 294: L1119-L1126Crossref PubMed Scopus (111) Google Scholar These observations have been extended to non-SP-C-related sporadic IPF. Increased expression of UPR mediators and caspase 3 were demonstrated by immunoblotting in IPF but not in chronic obstructive pulmonary disease. Immunostaining co-localized markers of UPR and apoptosis to type II cells in regions of dense fibrosis.20Korfei M Ruppert C Mahavadi P Henneke I Markart P Koch M Lang G Fink L Bohle RM Seeger W Weaver TE Guenther A Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 178: 838-846Crossref PubMed Scopus (141) Google Scholar Collectively, these findings are consistent with a generalized endoplasmic reticulum stress response of epithelial cells in fibrotic tissue. In vitro expression of SP-C constructs encoding an SFTPC mutation found in patients resulted in SP-C aggregation, impaired epithelial cell growth, increased expression of an endoplasmic reticulum stress response and epithelial cell apoptosis.21Thomas AQ Lane K Phillips 3rd, J Prince M Markin C Speer M Schwartz DA Gaddipati R Marney A Johnson J Roberts R Haines J Stahlman M Loyd JE Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred.Am J Respir Crit Care Med. 2002; 165: 1322-1328Crossref PubMed Scopus (307) Google Scholar, 22Mulugeta S Nguyen V Russo SJ Muniswamy M Beers MF A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation.Am J Respir Cell Mol Biol. 2005; 32: 521-530Crossref PubMed Scopus (86) Google Scholar Co-chaperones precipitated with the truncated SP-C, indicating association of UPR pathway proteins with the truncated and potentially misfolded SP-C. Expression of the SFTPC exon-four deletion mutation in the lungs of transgenic mice was lethal at birth, and analysis of the lungs demonstrated severe hypoplasia, reduced branching morphogenesis, and epithelial cell death.23Bridges JP Wert SE Nogee LM Weaver TE Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice.J Biol Chem. 2003; 278: 52739-52746Crossref PubMed Scopus (71) Google Scholar These and additional studies are consistent with the overproduction of non-native proSP-C eliciting a misfolded protein stress response and epithelial cytotoxicity that contributes to the progressive lung disease in affected individuals. Usual interstitial pneumonia, the hallmark histopathological lesion in IPF, has also been described in two reports of SP-C deficiency without identified mutations in the SFTPC gene, in which no mature SP-C and greatly diminished proSP-C were detected.24Amin RS Wert SE Baughman RP Tomashefski Jr, JF Nogee LM Brody AS Hull WM Whitsett JA Surfactant protein deficiency in familial interstitial lung disease.J Pediatr. 2001; 139: 85-92Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 25Tredano M Griese M Brasch F Schumacher S de Blic J Marque S Houdayer C Elion J Couderc R Bahuau M Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease.Am J Med Genet A. 2004; 126A: 18-26Crossref PubMed Google Scholar Fibrotic disease in these affected individuals implies that the SP-C null condition may also produce altered type II cell or alveolar function that results in disease. When SP-C deficient mice were generated by gene targeting techniques, the mice developed a strain-specific ILD that progressed with age to irregular fibrosis.26Glasser SW Detmer EA Ikegami M Na CL Stahlman MT Whitsett JA Pneumonitis and emphysema in sp-C gene targeted mice.J Biol Chem. 2003; 278: 14291-14298Crossref PubMed Scopus (129) Google Scholar The severity of bleomycin-induced lung fibrosis was increased in the lungs of SP-C deficient mice, suggesting that the absence of SP-C predisposes the lung to fibrosis.27Lawson WE Polosukhin VV Stathopoulos GT Zoia O Han W Lane KB Li B Donnelly EF Holburn GE Lewis KG Collins RD Hull WM Glasser SW Whitsett JA Blackwell TS Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin.Am J Pathol. 2005; 167: 1267-1277Abstract Full Text Full Text PDF PubMed Google Scholar The SP-C deficient mice do not produce any proSP-C that could stimulate an UPR. Taken together, the origins of SP-C-related lung disease may be multifactorial, resulting from cumulative epithelial cell injury initiated by the lack of SP-C in the airspace, abnormality of cellular SP-C processing events, or the presence of aberrant forms of proSP-C and an UPR. The ABC transporter family is a diverse group of large transmembrane proteins that use ATP to translocate substrates. The ABCA subfamily facilitates the movement of cholesterol or specific phospholipids. ABCA3 is highly expressed in the lung relative to other organs. The localization of ABCA3 to the limiting membrane of lamellar bodies in type II cells implicated ABCA3 in the assembly of the intracellular storage form of pulmonary surfactant.28Yamano G Funahashi H Kawanami O Zhao LX Ban N Uchida Y Morohoshi T Ogawa J Shioda S Inagaki N ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells.FEBS Lett. 2001; 508: 221-225Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 29Mulugeta S Gray JM Notarfrancesco KL Gonzales LW Koval M Feinstein SI Ballard PL Fisher AB Shuman H Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3.J Biol Chem. 2002; 277: 22147-22155Crossref PubMed Scopus (118) Google Scholar ABCA3 mutations are recessive and associated with a highly variable disease phenotype. Infants homozygous for mutations in the ABCA3 gene generally develop severe and usually fatal neonatal respiratory distress; however, a subset has been described with ABCA3 mutations presenting as ILD in later childhood, some of whom had transient neonatal symptoms.30Bullard JE Wert SE Nogee LM ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease.Semin Perinatol. 2006; 30: 327-334Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 31Bullard JE Wert SE Whitsett JA Dean M Nogee LM ABCA3 mutations associated with pediatric interstitial lung disease.Am J Respir Crit Care Med. 2005; 172: 1026-1031Crossref PubMed Scopus (137) Google Scholar, 32Young LR Nogee LM Barnett B Panos RJ Colby TV Deutsch GH Usual interstitial pneumonia in an adolescent with ABCA3 mutations.Chest. 2008; 134: 192-195Crossref PubMed Scopus (42) Google Scholar Histopathology indicates alveolar proteinosis and interstitial thickening, with ultrastructural evidence of small lamellar bodies with dense eccentrically positioned membranes, consistent with a surfactant lipid transport function for ABCA3.30Bullard JE Wert SE Nogee LM ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease.Semin Perinatol. 2006; 30: 327-334Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Data are limited regarding disease progression in older individuals and the potential to develop clinical fibrosis. However, an adolescent heterozygous for three novel variants of ABCA3 was the first well-documented case of a child with usual interstitial pneumonia, which was not previously thought to occur in children.32Young LR Nogee LM Barnett B Panos RJ Colby TV Deutsch GH Usual interstitial pneumonia in an adolescent with ABCA3 mutations.Chest. 2008; 134: 192-195Crossref PubMed Scopus (42) Google Scholar A recent study identifies a modifier effect of ABCA3 mutation in individuals with a single specific SFTPC point mutation. The presence of the ABCA3 mutation with the SFTPC mutation increased the severity of clinical disease in comparison to individuals with only the SFTPC point mutation.33Bullard JE Nogee LM Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation.Pediatr Res. 2007; 62: 176-179Crossref PubMed Scopus (46) Google Scholar This study highlights the possibility that idiopathic lung disease may result either from single mutations altering epithelial cell integrity or multiple gene mutations that disrupt different components of a common process. Distinct mutations have been identified that alter ABCA3 structure, including nonsense mutations that prevent any ABCA3 production.34Shulenin S Nogee LM Annilo T Wert SE Whitsett JA Dean M ABCA3 gene mutations in newborns with fatal surfactant deficiency.N Engl J Med. 2004; 350: 1296-1303Crossref PubMed Scopus (315) Google ScholarAbca3−/− mice die of neonatal respiratory failure. Analysis of lungs of Abca3−/− mice demonstrates no detectable surfactant with impaired lamellar body formation, similar to lamellar body defects of patients.35Cheong N Zhang H Madesh M Zhao M Yu K Dodia C Fisher AB Savani RC Shuman H ABCA3 is critical for lamellar body biogenesis in vivo.J Biol Chem. 2007; 282: 23811-23817Crossref PubMed Scopus (52) Google ScholarABCA3 missense mutations have also been identified that likely generate a UPR.34Shulenin S Nogee LM Annilo T Wert SE Whitsett JA Dean M ABCA3 gene mutations in newborns with fatal surfactant deficiency.N Engl J Med. 2004; 350: 1296-1303Crossref PubMed Scopus (315) Google Scholar Thus the mechanisms of ABCA3-related ILD may also be multiple and complex, involving decreased surfactant production and cellular stress from UPR responses, similar to SFTPC-related ILD. Viral infection of the pulmonary epithelium is traditionally viewed as a transient injury. However, the capacity of some viruses to establish latent infection has been hypothesized to mediate a state of chronic or repetitive damage to the infected epithelium that eventually results in fibrosis. Herpesvirus family members can establish latency after acute infection, and various herpesviruses have been detected in tissue of patients with IPF. In one study, Epstein-Barr virus was found in lung tissue of almost half of patients with IPF, and a more recent study identified either Epstein-Barr virus, cytomegalovirus, human herpesvirus 7, human herpesvirus 8 (also known as Kaposi's sarcoma herpesvirus) or combinations of these herpesviruses in the lungs of IPF patients.36Egan JJ Stewart JP Hasleton PS Arrand JR Carroll KB Woodcock AA Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis.Thorax. 1995; 50: 1234-1239Crossref PubMed Google Scholar, 37Stewart JP Egan JJ Ross AJ Kelly BG Lok SS Hasleton PS Woodcock AA The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1999; 159: 1336-1341Crossref PubMed Google Scholar, 38Tang YW Johnson JE Browning PJ Cruz-Gervis RA Davis A Graham BS Brigham KL Oates Jr, JA Loyd JE Stecenko AA Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis.J Clin Microbiol. 2003; 41: 2633-2640Crossref PubMed Google Scholar Herpesviruses were detected in the lungs of non-IPF patients at a lower prevalence. Herpesvirus infection (Epstein-Barr virus, cytomegalovirus, or human herpesvirus 8/Kaposi's sarcoma herpesvirus) was detected by immunohistochemistry in the lungs of 15/23 individuals with IPF, with similar prevalence in sporadic, non-SFTPC-associated familial, and SFTPC-associated cases, but none was detected in controls. Notably, herpesvirus colocalized with cells expressing increased UPR markers. These results support the hypothesis that herpesvirus infections may be a modifier that exacerbates the severity of SP-C dysfunction disease, as well as an independent cause of disease. The concept of persistent herpesvirus infection-induced IPF is supported by reports of gamma herpesvirus in equine pulmonary fibrosis and murine gamma herpesvirus (MHV-68)-induced lung fibrosis in interferon γ-deficient mice.39Williams KJ Maes R Del Piero F Lim A Wise A Bolin DC Caswell J Jackson C Robinson NE Derksen F Scott MA Uhal BD Li X Youssef SA Bolin SR Equine multinodular pulmonary fibrosis: a newly recognized herpesvirus-associated fibrotic lung disease.Vet Pathol. 2007; 44: 849-862Crossref PubMed Scopus (54) Google Scholar, 40Mora AL Woods CR Garcia A Xu J Rojas M Speck SH Roman J Brigham KL Stecenko AA Lung infection with gamma-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice.Am J Physiol Lung Cell Mol Physiol. 2005; 289: L711-L721Crossref PubMed Scopus (54) Google Scholar Gamma herpesvirus infection also accentuates the severity of chemically-induced lung fibrosis in mice.41McMillan TR Moore BB Weinberg JB Vannella KM Fields WB Christensen PJ van Dyk LF Toews GB Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus.Am J Respir Crit Care Med. 2008; 177: 771-780Crossref PubMed Scopus (48) Google Scholar Fibrosis following chronic viral exposure may also result in part from altered function of alveolar macrophages. In murine MHV-68 infection models and human IPF lung tissue, macrophages found in fibrotic regions expressed markers of alternatively activated macrophages (AAMs).42Mora AL Torres-Gonzalez E Rojas M Corredor C Ritzenthaler J Xu J Roman J Brigham K Stecenko A Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis.Am J Respir Cell Mol Biol. 2006; 35: 466-473Crossref PubMed Scopus (75) Google Scholar, 43Gangadharan B Hoeve MA Allen JE Ebrahimi B Rhind SM Dutia BM Nash AA Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages.J Leukoc Biol. 2008; 84: 50-58Crossref PubMed Scopus (20) Google Scholar AAMs have reduced phagocytic and bactericidal activity and express genes consistent with a repair and remodeling phenotype. Markers associated with the AAM phenotype are better defined in mice, but both mouse and human AAMs express increased arginase 1 activity compared with classically activated macrophages.42Mora AL Torres-Gonzalez E Rojas M Corredor C Ritzenthaler J Xu J Roman J Brigham K Stecenko A Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis.Am J Respir Cell Mol Biol. 2006; 35: 466-473Crossref PubMed Scopus (75) Google Scholar, 43Gangadharan B Hoeve MA Allen JE Ebrahimi B Rhind SM Dutia BM Nash AA Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages.J Leukoc Biol. 2008; 84: 50-58Crossref PubMed Scopus (20) Google Scholar Arginine turnover by arginase 1 activity limits nitric oxide production and enhances production of collagen precursors used in wound healing processes. Arginase 1 activity is similarly induced in interstitial fibroblasts from the lungs of bleomycin-treated mice.42Mora AL Torres-Gonzalez E Rojas M Corredor C Ritzenthaler J Xu J Roman J Brigham K Stecenko A Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis.Am J Respir Cell Mol Biol. 2006; 35: 466-473Crossref PubMed Scopus (75) Google Scholar, 44Kitowska K Zakrzewicz D Konigshoff M Chrobak I Grimminger F Seeger W Bulau P Eickelberg O Functional role and species-specific contribution of arginases in pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol. 2008; 294: L34-L45Crossref PubMed Scopus (28) Google Scholar Both tissue arginase 1 and AAM arginase 1 activity are increased by chemically induced and herpesvirus-associated fibrosis and may contribute to the aberrant accumulation of matrix. The pathology of infants with SFPTC and ABCA3-related disease is frequently classified as desquamative interstitial pneumonia (DIP), indicative of a macrophage-dominated histopathology.34Shulenin S Nogee LM Annilo T Wert SE Whitsett JA Dean M ABCA3 gene mutations in newborns with fatal surfactant deficiency.N Engl J Med. 2004; 350: 1296-1303Crossref PubMed Scopus (315) Google Scholar, 45Nogee LM Dunbar 3rd, AE Wert SE Askin F Hamvas A Whitsett JA A mutation in the surfactant protein C gene associated with familial interstitial lung disease.N Engl J Med. 2001; 344: 573-579Crossref PubMed Scopus (404) Google Scholar, 46Bruder E Hofmeister J Aslanidis C Hammer J Bubendorf L Schmitz G Rufle A Buhrer C Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation.Mod Pathol. 2007; 20: 1009-1018Crossref PubMed Scopus (17) G