title: Aortic carboxypeptidase-like protein is expressed in fibrotic human lung and its absence protects against bleomycin-induced lung fibrosis.
abstract: The pathological hallmarks of idiopathic pulmonary fibrosis include proliferating fibroblasts and myofibroblasts, as well as excessive collagen matrix deposition. In addition, both myofibroblast contraction and remodeling of the collagen-rich matrix contribute to the abnormal structure and function of the fibrotic lung. Little is known, however, about collagen-associated proteins that promote fibroblast and myofibroblast retention, as well as the proliferation of these cells on the extracellular matrix. In this study, we demonstrate that aortic carboxypeptidase-like protein (ACLP), a collagen-associated protein with a discoidin-like domain, is expressed at high levels in human fibrotic lung tissue and human fibroblasts, and that its expression increases markedly in the lungs of bleomycin-injured mice. Importantly, ACLP-deficient mice accumulated significantly fewer myofibroblasts and less collagen in the lung after bleomycin injury, as compared with wild-type controls, despite equivalent levels of bleomycin-induced inflammation. ACLP that is secreted by lung fibroblasts was retained on fibrillar collagen, and ACLP-deficient lung fibroblasts that were cultured on collagen exhibited changes in cell spreading, proliferation, and contraction of the collagen matrix. Finally, the addition of recombinant discoidin-like domain of ACLP to cultured ACLP-deficient lung fibroblasts restored cell spreading and increased the contraction of collagen gels. Therefore, both ACLP and its discoidin-like domain may be novel targets for anti-myofibroblast-based therapies for the treatment of pulmonary fibrosis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Schissel
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dunsmore
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shine
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Layne
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology*; D001761:Bleomycin / Q000633:toxicity; D002268:Carboxypeptidases / Q000172:deficiency / Q000235:genetics*; D002448:Cell Adhesion; D003094:Collagen / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C484818:AEBP1 protein, human; C112918:Aebp1 protein, mouse; D012097:Repressor Proteins; D001761:Bleomycin; D003094:Collagen; D002268:Carboxypeptidases