title: Targeting Inhibitor of Apoptosis Proteins Protects from Bleomycin-Induced Lung Fibrosis.
abstract: Accumulation of apoptosis-resistant fibroblasts is a hallmark of pulmonary fibrosis. We hypothesized that disruption of inhibitor of apoptosis protein (IAP) family proteins would limit lung fibrosis. We first show that transforming growth factor-β1 and bleomycin increase X-linked IAP (XIAP) and cellular IAP (cIAP)-1 and -2 in murine lungs and mesenchymal cells. Functional blockade of XIAP and the cIAPs with AT-406, an orally bioavailable second mitochondria-derived activator of caspases (Smac) mimetic, abrogated bleomycin-induced lung fibrosis when given both prophylactically and therapeutically. To determine whether the reduction in fibrosis was predominantly due to AT-406-mediated inhibition of XIAP, we compared the fibrotic response of XIAP-deficient mice (XIAP(-/y)) with littermate controls and found no difference. We found no alterations in total inflammatory cells of either wild-type mice treated with AT-406 or XIAP(-/y) mice. AT-406 treatment limited CCL12 and IFN-γ production, whereas XIAP(-/y) mice exhibited increased IL-1β expression. Surprisingly, XIAP(-/y) mesenchymal cells had increased resistance to Fas-mediated apoptosis. Functional blockade of cIAPs with AT-406 restored sensitivity to Fas-mediated apoptosis in XIAP(-/y) mesenchymal cells in vitro and increased apoptosis of mesenchymal cells in vivo, indicating that the increased apoptosis resistance in XIAP(-/y) mesenchymal cells was the result of increased cIAP expression. Collectively, these results indicate that: (1) IAPs have a role in the pathogenesis of lung fibrosis; (2) a congenital deficiency of XIAP may be overcome by compensatory mechanisms of other IAPs; and (3) broad functional inhibition of IAPs may be an effective strategy for the treatment of lung fibrosis by promoting mesenchymal cell apoptosis.
authors.affiliation: 1 Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Shanna L
authors.initials: SL
authors.lastname: Ashley
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Wheaton
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Iyabode O
authors.initials: IO
authors.lastname: Ajayi
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Natalya
authors.initials: N
authors.lastname: Subbotina
authors.affiliation: 3 Internal Medicine, Division of Hematology-Oncology.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: 4 Pathology.|5 Molecular Medicine and Genetics, and.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.|6 Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Departments of 2 Internal Medicine, Division of Pulmonary and Critical Care.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001392:Azocines / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage
chemical_list: D001392:Azocines; D001559:Benzhydryl Compounds; C107521:Birc4 protein, mouse; C491224:Ccl12 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D018945:Monocyte Chemoattractant Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D007371:Interferon-gamma
keywords: X-linked inhibitor of apoptosis protein; fibroblast; fibrocyte; mesenchymal; second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein–binding protein with low pI