Lung fibrosis is an aberrant wound-repair response in which soluble and biomechanical stimuli promote the activation and survival of myofibroblasts which deposit excessive amounts of extracellular matrix (ECM). This leads to the destruction of normal lung architecture and function, with progressive respiratory failure and death. Myofibroblast apoptosis heralds the resolution of wound repair, but we have shown that fibrotic lung myofibroblasts circumvent apoptosis through increased expression of X- linked Inhibitor of Apoptosis Protein (XIAP), the prototypical member of the IAP family of proteins. Broad pharmacologic inhibition of IAPs promotes myofibroblast apoptosis and the resolution of lung fibrosis in vivo, and our preliminary data demonstrate that the specific deletion of XIAP is sufficient to attenuate lung fibrosis. XIAP is expressed within the myofibroblasts that comprise fibroblastic foci of patients with idiopathic pulmonary fibrosis (IPF), explanted IPF lung fibroblasts have increased levels of XIAP, XIAP is induced by TGF-?1, and the loss or inhibition of XIAP function enhances the fibroblast susceptibility to apoptosis. However, it remains unclear whether enhanced myofibroblast apoptosis is sufficient to resolve fibrotic lung injury or whether inhibition of additional non-canonical functions of XIAP contribute to the anti-fibrotic effects observed. Emerging studies have linked lung fibrosis with suppression of homeostatic autophagy/mitophagy and with mitochondrial damage and dysfunction. Our preliminary data demonstrate that XIAP mediates TGF-? induced myofibroblast differentiation and suppression of autophagy while promoting mitochondrial damage. Collectively, these findings motivate our novel hypothesis that XIAP integrates soluble and matrix-mediated stimuli to promote a program of pro-fibrotic fibroblast phenotypes including autophagy/mitophagy suppression, mitochondrial DNA damage, and myofibroblast differentiation in addition to apoptosis resistance. The goals of this proposal are to: 1) determine the role of XIAP in the regulation of fibroblast autophagy/mitophagy and myofibroblast differentiation, 2) examine XIAP in the regulation of metabolic activity and mitochondrial function in lung fibroblasts, and 3) define the role of XIAP during the initiation, progression, and resolution of lung injury and fibrotic repair. Completion of these studies will define the mechanisms by which XIAP has a central role in myofibroblast biology and lung fibrosis, providing pre-clinical support for targeting this IAP in the treatment of IPF.
Public Health Relevance Statement Lung fibrosis is a common endpoint of lung injury due to known and unknown etiologies that causes progressive respiratory failure and, in the case of idiopathic pulmonary fibrosis (IPF), death within 3-5 years of the diagnosis. Illustrating an urgent and ongoing need for novel targets for therapeutic intervention, no current therapy for IPF has been shown to improve symptoms, quality of life or mortality. The proposed studies will enhance our fundamental understanding of the mechanisms regulating the maintenance and propagation of lung fibrosis and assess the potential of targeting a novel protein, XIAP, as a therapeutic strategy with the potential to not only halt, but also to reverse lung fibrosis.
|Sisson, Thomas H; Christensen, Paul J; Muraki, Yo et al. (2018) Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury. Physiol Rep 6:e13753|
|Dodi, Amos E; Ajayi, Iyabode O; Chang, Christine et al. (2018) Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli. Respir Res 19:91|
|Bai, Le; Bernard, Karen; Tang, Xuebo et al. (2018) Glutaminolysis Epigenetically Regulates Anti-Apoptotic Gene Expression in IPF Fibroblasts. Am J Respir Cell Mol Biol :|
|Jia, Shijing; Agarwal, Manisha; Yang, Jibing et al. (2018) Discoidin Domain Receptor 2 Signaling Regulates Fibroblast Apoptosis through PDK1/Akt. Am J Respir Cell Mol Biol 59:295-305|