Targeting Inhibitor of Apoptosis Proteins Protects from Bleomycin-Induced Lung Fibrosis
| Autor: | Kevin K. Kim, Shaomeng Wang, Amanda K. Wheaton, Natalya Subbotina, Thomas H. Sisson, Carol A. Wilke, Iyabode O. Ajayi, Colin S. Duckett, Shanna L. Ashley, Bethany B. Moore, Jeffrey C. Horowitz |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Male Pulmonary Fibrosis Clinical Biochemistry Apoptosis Inhibitor of apoptosis Bleomycin Inhibitor of Apoptosis Proteins Transforming Growth Factor beta1 03 medical and health sciences chemistry.chemical_compound Interferon-gamma Mice Fibrosis Pulmonary fibrosis medicine Animals RNA Messenger Benzhydryl Compounds Molecular Biology Caspase Original Research Inhibitor of apoptosis domain biology Cell Biology medicine.disease Azocines XIAP Monocyte Chemoattractant Proteins Mice Inbred C57BL 030104 developmental biology chemistry biology.protein Cancer research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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