Advertisement

Usual interstitial pneumonia: a review of the pathogenesis and discussion of elastin fibres, type II pneumocytes and proposed roles in the pathogenesis

  • Edwina E. Duhig
    Correspondence
    Address for correspondence: Dr Edwina Duhig, Sullivan Nicolaides Pathology, The John Flynn Hospital, Inland Drive, Tugun, Qld 4224, Australia.
    Affiliations
    Sullivan Nicolaides Pathology, The John Flynn Hospital, Tugun, Qld, Australia

    UQ Thoracic Research Centre, The Prince Charles Hospital, Chermside, Qld, Australia

    Faculty of Medicine, The University of Queensland, Herston, Qld, Australia
    Search for articles by this author

      Summary

      The pathogenesis of idiopathic pulmonary fibrosis (IPF) and its histological counterpart, usual interstitial pneumonia (UIP) remains debated. IPF/UIP is a disease characterised by respiratory restriction, and while there have been recent advances in treatment, mortality remains high. Genetic and environmental factors predispose to its development and aberrant alveolar repair is thought to be central. Following alveolar injury, the type II pneumocyte (AEC2) replaces the damaged thin type I pneumocytes. Despite the interstitial fibroblast being considered instrumental in formation of the fibrosis, there has been little consideration for a role for AEC2 in the repair of the septal interstitium. Elastin is a complex protein that conveys flexibility and recoil to the lung. The fibroblast is presumed to produce elastin but there is evidence that the AEC2 may have a role in production or deposition. While the lung is an elastic organ, the role of elastin in repair of lung injury and its possible role in UIP has not been explored in depth. In this paper, pathogenetic mechanisms of UIP involving AEC2 and elastin are reviewed and the possible role of AEC2 in elastin generation is proposed.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barratt S.L.
        • Creamer A.
        • Hayton C.
        • Chaudhuri N.
        Idiopathic pulmonary fibrosis (IPF): an overview.
        J Clin Med. 2018; 7: 201
        • Lederer D.J.
        • Martinez F.J.
        Idiopathic pulmonary fibrosis.
        N Engl J Med. 2018; 378: 1811-1823
        • Katzenstein A.-L.A.
        Diagnostic Atlas of Non-Neoplastic Lung Disease: A Practical Guide for Surgical Pathologists.
        Demos Medical, New York2016: 55-65
        • Yanagihara T.
        • Sato S.
        • Upagupta C.
        • Kolb M.
        What have we learned from basic science studies on idiopathic pulmonary fibrosis?.
        Eur Respir Rev. 2019; 28190029
        • Tatler A.L.
        • Jenkins G.
        TGF-β activation and lung fibrosis.
        Proc Am Thorac Soc. 2012; 9: 130-136
        • Annes J.P.
        • Chen Y.
        • Munger J.S.
        • Rifkin D.B.
        Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1.
        J Cell Biol. 2004; 165: 723-734
        • Munger J.S.
        • Huang X.
        • Kawakatsu H.
        • 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: 319-328
        • Munger J.S.
        • Sheppard D.
        Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix.
        Cold Spring Harb Perspect Biol. 2011; 3: a005017
        • Tatler A.L.
        • Jenkins G.
        Reducing affinity of αvβ8 interactions with latent TGFβ: dialling down fibrosis.
        Ann Transl Med. 2015; 3: S31
        • Leslie K.O.
        Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis.
        Arch Pathol Lab Med. 2012; 136: 591-600
        • Wu H.
        • Yu Y.
        • Huang H.
        • et al.
        Progressive pulmonary fibrosis is caused by elevated mechanical tension on alveolar stem cells.
        Cell. 2020; 180: 107-121
        • Sainz de Aja J.
        • Kim C.F.
        May the (mechanical) force be with AT2.
        Cell. 2020; 180: 20-22
        • Ismail A.
        • Beckum K.
        • McKay K.
        Transepithelial elimination in sarcoidosis: a frequent finding.
        J Cutan Pathol. 2014; 41: 22-27
        • Myers J.L.
        • Katzenstein A.L.
        Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia.
        Am J Pathol. 1988; 132: 102-109
        • Fukuda Y.
        • Ishizaki M.
        • Masuda Y.
        • Kimura G.
        • Kawanami O.
        • Masugi Y.
        The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage.
        Am J Pathol. 1987; 126: 171-182
        • Chilosi M.
        • Zamò A.
        • Doglioni C.
        • et al.
        Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis.
        Respir Res. 2006; 7: 95
        • Desai T.J.
        • Brownfield D.G.
        • Krasnow M.A.
        Alveolar progenitor and stem cells in lung development, renewal and cancer.
        Nature. 2014; 507: 190-194
        • Treutlein B.
        • Brownfield D.G.
        • Wu A.R.
        • et al.
        Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq.
        Nature. 2014; 509: 371-375
        • Mariani T.J.
        • Dunsmore S.E.
        • Li Q.
        • Ye X.
        • Pierce R.A.
        Regulation of lung fibroblast tropoelastin expression by alveolar epithelial cells.
        Am J Physiol. 1998; 274: L47-L57
        • Blaauboer M.E.
        • Boeijen F.R.
        • Emson C.L.
        • et al.
        Extracellular matrix proteins: a positive feedback loop in lung fibrosis?.
        Matrix Biol. 2014; 34: 170-178
        • Hansen N.U.
        • Karsdal M.A.
        • Brockbank S.
        • Cruwys S.
        • Rønnow S.
        • Leeming D.J.
        Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor.
        Respir Res. 2016; 17: 76
        • McCullough B.
        • Collins J.F.
        • Johanson Jr., W.G.
        • Grover F.L.
        Bleomycin-induced diffuse interstitial pulmonary fibrosis in baboons.
        J Clin Invest. 1978; 61: 79-88
        • Raghow R.
        • Lurie S.
        • Seyer J.M.
        • Kang A.H.
        Profiles of steady state levels of messenger RNAs coding for type I procollagen, elastin, and fibronectin in hamster lungs undergoing bleomycin-induced interstitial pulmonary fibrosis.
        J Clin Invest. 1985; 76: 1733-1739
        • Fukuda Y.
        • Ferrans V.J.
        • Schoenberger C.I.
        • Rennard S.I.
        • Crystal R.G.
        Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis.
        Am J Pathol. 1985; 118: 452-475
        • Kielty C.M.
        • Sherratt M.J.
        • Shuttleworth C.A.
        Elastic fibres.
        J Cell Sci. 2002; 115: 2817-2828
        • Chrzanowski P.
        • Keller S.
        • Cerreta J.
        • Mandl I.
        • Turino G.M.
        Elastin content of normal and emphysematous lung parenchyma.
        Am J Med. 1980; 69: 351-359
        • Shapiro S.D.
        • Endicott S.K.
        • Province M.A.
        • Pierce J.A.
        • Campbell E.J.
        Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.
        J Clin Invest. 1991; 87: 1828-1834
        • Mecham R.P.
        Elastin in lung development and disease pathogenesis.
        Matrix Biol. 2018; 73: 6-20
        • Shifren A.
        • Durmowicz A.G.
        • Knutsen R.H.
        • Hirano E.
        • Mecham R.P.
        Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema.
        Am J Physiol Lung Cell Mol Physiol. 2007; 292: L778-L787
        • Shifren A.
        • Mecham R.P.
        The stumbling block in lung repair of emphysema: elastic fiber assembly.
        Proc Am Thorac Soc. 2006; 3: 428-433
        • Muiznieks L.D.
        • Keeley F.W.
        Molecular assembly and mechanical properties of the extracellular matrix: a fibrous protein perspective.
        Biochim Biophys Acta. 2013; 1832: 866-875
        • Benjamin J.T.
        • van der Meer R.
        • Im A.M.
        • et al.
        Epithelial-derived inflammation disrupts elastin assembly and alters saccular stage lung development.
        Am J Pathol. 2016; 186: 1786-1800
        • Mariani T.J.
        • Crouch E.
        • Roby J.D.
        • Starcher B.
        • Pierce R.A.
        Increased elastin production in experimental granulomatous lung disease.
        Am J Pathol. 1995; 147: 988-1000
        • Mariani T.J.
        • Arikan M.C.
        • Pierce R.A.
        Fibroblast tropoelastin and alpha-smooth-muscle actin expression are repressed by particulate-activated macrophage-derived tumor necrosis factor-alpha in experimental silicosis.
        Am J Respir Cell Mol Biol. 1999; 21: 185-192
        • Dabovic B.
        • Chen Y.
        • Choi J.
        • et al.
        Control of lung development by latent TGF-β binding proteins.
        J Cell Physiol. 2011; 226: 1499-1509
        • Wu L.
        • Zhang J.
        • Qu J.M.
        • Bai C.X.
        • Merrilees M.J.
        Deposition of insoluble elastin by pulmonary fibroblasts from patients with COPD is increased by treatment with versican siRNA.
        Int J Chron Obstruct Pulmon Dis. 2017; 12: 267-273
        • Deslee G.
        • Woods J.C.
        • Moore C.M.
        • et al.
        Elastin expression in very severe human COPD.
        Eur Respir J. 2009; 34: 324-331
        • Fletcher C.D.M.
        • Bridge J.A.
        • Hogendoorn P.C.W.
        • Bridge J.A.
        • Hogendoorn P.
        WHO Classification of Tumours of Soft Tissue and Bone.
        IARC, Lyon2013
        • Fukushima M.
        • Fukuda Y.
        • Kawamoto M.
        • Yamanaka N.
        Elastosis in lung carcinoma: immunohistochemical, ultrastructural and clinical studies.
        Pathol Int. 2000; 50: 626-635
        • Griffin M.
        • Bhandari R.
        • Hamilton G.
        • Chan Y.C.
        • Powell J.T.
        Alveolar type II cell-fibroblast interactions, synthesis and secretion of surfactant and type I collagen.
        J Cell Sci. 1993; 105: 423-432
        • Marinkovich M.P.
        • Keene D.R.
        • Rimberg C.S.
        • Burgeson R.E.
        Cellular origin of the dermal-epidermal basement membrane.
        Dev Dyn. 1993; 197: 255-267
        • Furuyama A.
        • Kimata K.
        • Mochitate K.
        Assembly of basement membrane in vitro by cooperation between alveolar epithelial cells and pulmonary fibroblasts.
        Cell Struct Funct. 1997; 22: 603-614
        • Busch S.M.
        • Lorenzana Z.
        • Ryan A.L.
        Implications for extracellular matrix interactions with human lung basal stem cells in lung development, disease, and airway modeling.
        Front Pharmacol. 2021; 12645858
        • Vaccaro C.
        • Brody J.S.
        Ultrastructure of developing alveoli. I. The role of the interstitial fibroblast.
        Anat Rec. 1978; 192: 467-479
        • Noguchi A.
        • Reddy R.
        • Kursar J.D.
        • Parks W.C.
        • Mecham R.P.
        Smooth muscle isoactin and elastin in fetal bovine lung.
        Exp Lung Res. 1989; 15: 537-552
        • Papke C.L.
        • Yanagisawa H.
        Fibulin-4 and fibulin-5 in elastogenesis and beyond: insights from mouse and human studies.
        Matrix Biol. 2014; 37: 142-149
        • Yanagisawa H.
        • Davis E.C.
        Unraveling the mechanism of elastic fiber assembly: the roles of short fibulins.
        Int J Biochem Cell Biol. 2010; 42: 1084-1093
        • Belknap J.K.
        • Weiser-Evans M.C.
        • Grieshaber S.S.
        • Majack R.A.
        • Stenmark K.R.
        Relationship between perlecan and tropoelastin gene expression and cell replication in the developing rat pulmonary vasculature.
        Am J Respir Cell Mol Biol. 1999; 20: 24-34
        • Noguchi A.
        • Samaha H.
        Developmental changes in tropoelastin gene expression in the rat lung studied by in situ hybridization.
        Am J Respir Cell Mol Biol. 1991; 5: 571-578
        • Shi M.
        • Zhu J.
        • Wang R.
        • et al.
        Latent TGF-β structure and activation.
        Nature. 2011; 474: 343-349
        • Haynes S.L.
        • Shuttleworth C.A.
        • Kielty C.M.
        Keratinocytes express fibrillin and assemble microfibrils: implications for dermal matrix organization.
        Br J Dermatol. 1997; 137: 17-23
        • Dzamba B.J.
        • Keene D.R.
        • Isogai Z.
        • et al.
        Assembly of epithelial cell fibrillins.
        J Invest Dermatol. 2001; 117: 1612-1620
        • Kumarasamy A.
        • Schmitt I.
        • Nave A.H.
        • et al.
        Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs.
        Am J Respir Crit Care Med. 2009; 180: 1239-1252
        • Srisuma S.
        • Bhattacharya S.
        • Simon D.M.
        • et al.
        Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis.
        Am J Respir Crit Care Med. 2010; 181: 838-850
        • Wang J.
        • Bao L.
        • Yu B.
        • et al.
        Interleukin-1β promotes epithelial-derived alveolar elastogenesis via αvβ6 integrin-dependent TGF-β activation.
        Cell Physiol Biochem. 2015; 36: 2198-2216
        • Enomoto N.
        • Suda T.
        • Kono M.
        • et al.
        Amount of elastic fibers predicts prognosis of idiopathic pulmonary fibrosis.
        Respir Med. 2013; 107: 1608-1616
        • Burgess J.K.
        • Mauad T.
        • Tjin G.
        • Karlsson J.C.
        • Westergren-Thorsson G.
        The extracellular matrix - the under-recognized element in lung disease?.
        J Pathol. 2016; 240: 397-409
        • Hashisako M.
        • Fukuoka J.
        Pathology of idiopathic interstitial pneumonias.
        Clin Med Insights Circ Respir Pulm Med. 2015; 9: 123-133
        • Negri E.M.
        • Montes G.S.
        • Saldiva P.H.
        • Capelozzi V.L.
        Architectural remodelling in acute and chronic interstitial lung disease: fibrosis or fibroelastosis?.
        Histopathology. 2000; 37: 393-401
        • Rozin G.F.
        • Gomes M.M.
        • Parra E.R.
        • Kairalla R.A.
        • de Carvalho C.R.
        • Capelozzi V.L.
        Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP).
        Histopathology. 2005; 46: 413-421
        • Parra E.R.
        • Kairalla R.A.
        • de Carvalho C.R.
        • Capelozzi V.L.
        Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias.
        Thorax. 2007; 62: 428-437
        • Smith M.L.
        • Hariri L.P.
        • Mino-Kenudson M.
        • et al.
        Histopathologic assessment of suspected idiopathic pulmonary fibrosis: where we are and where we need to go.
        Arch Pathol Lab Med. 2020; 144: 1477-1489
        • Chilosi M.
        • Poletti V.
        • Murer B.
        • et al.
        Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63.
        Lab Invest. 2002; 82: 1335-1345
        • Jonsdottir H.R.
        • Arason A.J.
        • Palsson R.
        • et al.
        Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture.
        Lab Invest. 2015; 95: 1418-1428
        • Raghu G.
        • Remy-Jardin M.
        • Myers J.L.
        • et al.
        Diagnosis of idiopathic pulmonary fibrosis. an official ATS/ERS/JRS/ALAT clinical practice guideline.
        Am J Respir Crit Care Med. 2018; 198: e44-e68
        • Adams T.S.
        • Schupp J.C.
        • Poli S.
        • et al.
        Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis.
        Sci Adv. 2020; 6eaba1983
        • Katzenstein A.L.
        Smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases.
        J Clin Pathol. 2013; 66: 882-887
        • Wick M.R.
        Pathologic features of smoking-related lung diseases, with emphasis on smoking-related interstitial fibrosis and a consideration of differential diagnoses.
        Semin Diagn Pathol. 2018; 35: 315-323
        • Becker C.D.
        • Gil J.
        • Padilla M.L.
        Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity?.
        Mod Pathol. 2008; 21: 784-787
        • Reddy T.L.
        • Tominaga M.
        • Hansell D.M.
        • et al.
        Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes.
        Eur Respir J. 2012; 40: 377-385
        • von der Thüsen J.H.
        Pleuroparenchymal fibroelastosis: its pathological characteristics.
        Curr Respir Med Rev. 2013; 9: 238-247
        • Hirota T.
        • Yoshida Y.
        • Kitasato Y.
        • et al.
        Histological evolution of pleuroparenchymal fibroelastosis.
        Histopathology. 2015; 66: 545-554
        • Strock S.B.
        • Alder J.K.
        • Kass D.J.
        From bad to worse: when lung cancer complicates idiopathic pulmonary fibrosis.
        J Pathol. 2018; 244: 383-385
        • Aubry M.C.
        • Myers J.L.
        • Douglas W.W.
        • et al.
        Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis.
        Mayo Clin Proc. 2002; 77: 763-770
        • Lee T.
        • Park J.Y.
        • Lee H.Y.
        • et al.
        Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival.
        Respir Med. 2014; 108: 1549-1555
        • Park J.
        • Kim D.S.
        • Shim T.S.
        • et al.
        Lung cancer in patients with idiopathic pulmonary fibrosis.
        Eur Respir J. 2001; 17: 1216-1219