# X-Linked Inhibitor of Apoptosis in Fibroblast Phenotypes and Lung Fibrosis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $586,657

## Abstract

Abstract/Project Summary
 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-β1, 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-β 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.

## Key facts

- **NIH application ID:** 10076125
- **Project number:** 7R01HL141195-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jeffrey C Horowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,657
- **Award type:** 7
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076125

## Citation

> US National Institutes of Health, RePORTER application 10076125, X-Linked Inhibitor of Apoptosis in Fibroblast Phenotypes and Lung Fibrosis (7R01HL141195-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076125. Licensed CC0.

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