title: Mechanisms of alveolar epithelial injury, repair, and fibrosis.
abstract: The challenge facing many fibrotic lung diseases is that these conditions usually present late, often after several decades of repetitive alveolar epithelial injury, during which functional alveolar units are gradually obliterated and replaced with nonfunctional connective tissue. The resulting fibrosis is often progressive and, in the case of idiopathic pulmonary fibrosis (IPF), invariably leads to respiratory insufficiency and, ultimately, the premature death of affected individuals. Recent years have seen a greater appreciation of the relative importance of chronic inflammation as a driver of fibrotic responses. Current evidence suggests that IPF arises as a result of repetitive epithelial injury and a highly aberrant wound healing response in genetically susceptible and aged individuals. Nonspecific anti-inflammatory agents offer no clinical benefit, but the potential contribution of maladaptive immune responses in determining outcome is gaining increasing recognition. The importance of key differences in the tissue-regenerative potential in young versus aged individuals is also beginning to be more fully appreciated. Moreover, there is considerable overlap in the mechanisms underlying tissue repair and cancer, and patients with IPF are at heightened risk of developing lung cancer. Progressive fibrosis and cancer may therefore represent the extremes of a highly dysregulated tissue injury response. This brief review focuses on some of this evidence and on our current understanding of abnormal tissue repair responses after chronic epithelial injury in the specific context of IPF.
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.forename: Paul F
authors.initials: PF
authors.lastname: Mercer
mesh_terms: D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000503:physiopathology*; D055370:Lung Injury / Q000628:therapy; D058628:Myofibroblasts / Q000166:cytology; D011650:Pulmonary Alveoli / Q000503:physiopathology*; D015398:Signal Transduction
keywords: cancer; idiopathic pulmonary fibrosis; lung injury; myofibroblast; pulmonary fibrosis
references.citation: Curr Opin Pulm Med. 2012 Sep;18(5):517-23
references.pmid: 22854509
references.citation: Sci Transl Med. 2013 Oct 2;5(205):205ra136
references.pmid: 24089408
references.citation: J Exp Med. 2008 Jul 7;205(7):1659-72
references.pmid: 18541712
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):E1475-83
references.pmid: 22123957
references.citation: N Engl J Med. 2014 May 29;370(22):2071-82
references.pmid: 24836310
references.citation: Lancet Respir Med. 2014 May;2(5):416-28
references.pmid: 24815806
references.citation: J Biol Chem. 2000 Nov 10;275(45):35584-91
references.pmid: 10952976
references.citation: Am J Respir Crit Care Med. 2006 Sep 15;174(6):654-8
references.pmid: 16799077
references.citation: J Nucl Med. 2009 Apr;50(4):538-45
references.pmid: 19289428
references.citation: J Clin Invest. 2014 Apr;124(4):1622-35
references.pmid: 24590289
references.citation: J Aerosol Med Pulm Drug Deliv. 2010 Jun;23(3):161-72
references.pmid: 20109123
references.citation: J Clin Invest. 2006 Jun;116(6):1606-14
references.pmid: 16710477
references.citation: Am J Respir Crit Care Med. 2013 Oct 1;188(7):820-30
references.pmid: 23924232
references.citation: Int J Rheumatol. 2011;2011:208219
references.pmid: 22013449
references.citation: Eur Respir Rev. 2013 Sep 1;22(129):265-72
references.pmid: 23997054
references.citation: Biochem J. 1998 Jul 1;333 ( Pt 1):121-7
references.pmid: 9639571
references.citation: Am J Pathol. 2014 Jun;184(6):1643-51
references.pmid: 24726499
references.citation: Am J Respir Crit Care Med. 2009 Mar 1;179(5):414-25
references.pmid: 19060230
references.citation: Am J Respir Crit Care Med. 2006 Jan 1;173(1):112-21
references.pmid: 16179636
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Jul;64(7):731-9
references.pmid: 19359440
references.citation: Am J Pathol. 2005 May;166(5):1353-65
references.pmid: 15855637
references.citation: PLoS Med. 2008 Mar 4;5(3):e62
references.pmid: 18318599
references.citation: Am J Respir Crit Care Med. 2000 Jan;161(1):5-8
references.pmid: 10619790
references.citation: Nat Med. 2011 May;17(5):552-3
references.pmid: 21546973
references.citation: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references.pmid: 20379207
references.citation: Am J Respir Crit Care Med. 2014 May 15;189(10):1161-72
references.pmid: 24641682
references.citation: J Exp Med. 2011 Jul 4;208(7):1459-71
references.pmid: 21708929
references.citation: Chest. 2002 Mar;121(3 Suppl):31S-32S
references.pmid: 11893671
references.citation: Am J Respir Crit Care Med. 2014 Apr 15;189(8):966-74
references.pmid: 24628285
references.citation: PLoS One. 2012;7(4):e33770
references.pmid: 22506007
references.citation: J Clin Invest. 2009 Sep;119(9):2550-63
references.pmid: 19652365
references.citation: Exp Cell Res. 2005 Mar 10;304(1):16-27
references.pmid: 15707570
references.citation: Am J Respir Cell Mol Biol. 2013 Aug;49(2):260-8
references.pmid: 23526226
references.citation: Curr Opin Pulm Med. 2005 Sep;11(5):431-7
references.pmid: 16093818
references.citation: Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95
references.pmid: 22561965
references.citation: Biochim Biophys Acta. 2013 Jul;1832(7):1018-27
references.pmid: 23298546
references.citation: Br J Pharmacol. 2011 May;163(1):141-72
references.pmid: 21265830
references.citation: Am J Respir Crit Care Med. 2006 Jan 15;173(2):188-98
references.pmid: 16166619
references.citation: Transl Res. 2015 Jan;165(1):48-60
references.pmid: 24746870
references.citation: N Engl J Med. 2012 May 24;366(21):1968-77
references.pmid: 22607134
references.citation: Am J Respir Crit Care Med. 2008 Jan 1;177(1):56-65
references.pmid: 17916809
references.citation: J Proteomics. 2013 Jun 24;85:109-28
references.pmid: 23659799
references.citation: J Immunol. 2013 Sep 1;191(5):2089-95
references.pmid: 23872052
references.citation: Am J Pathol. 2007 Jan;170(1):110-25
references.pmid: 17200187