# Type II Alveolar Redox Control in Fibrogenesis and Resolution

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $491,857

## Abstract

Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic and highly lethal lung disease characterized by
excessive scarring of the lung and whose prevalence is increased in older individuals. The most accepted
theory in the pathogenesis of IPF is the injury and activation of alveolar epithelial type II cells (AECII) triggering
excessive and chronic wound-healing responses, mediated by growth factors such as TGF-b1. Oxidative
stress is recognized as key regulator of the tissue repair process, but the role of redox signaling pathways in
the mechanistic pathobiology of IPF remains largely unknown. One NADH-dependent redox enzyme that
contributes to stress protection and associates with healthspan and aging is Cyb5R3 (Cyb5R3). Cyb5R3
reduces heme iron (Fe3+→Fe2+), a major target of reactive oxygen species. Our preliminary data suggest that
IPF lungs have low expression of Cyb5R3. Using a novel mouse model of conditional deficiency of Cyb5R3 in
alveolar type II cells developed in our labs, we have found that 1) expression and activity of Cyb5R3 in AECII
are critical for protection against lung fibrosis, 2) Cyb5R3 negatively regulates the expression of TGF-b1-
dependent profibrotic and senescence genes, and 3) Cyb5R3 inhibition of expression of TGF-b1 target genes
is mediated by two pathways, one the heme reduction of sGC and downstream activation of cGMP-PKG
signaling pathway, and second, by control of mitochondrial function and activation of cAMP-PKA. These
observations have led to the hypothesis that Cyb5R3 deficiency promotes alteration of the AECII mitochondrial
function and redox state that enhances the TGF-b signaling via sGC-dependent and –independent pathways
decreasing the resilience against fibrosis: Aim 1. To test the hypothesis that Cyb5R3 in alveolar epithelial cells
confers protection against the development of lung fibrosis through suppression of TGF-b signaling. Aim 2.
Establish if loss of AECII Cyb5R3 expression confers efficacy to chronic sGC stimulator and/or sGC activator
therapy in mice with lung fibrosis. Completion of these aims will enhance our understanding of the role of
Cyb5R3 in the wound healing process and age-related mechanisms of resilience to disrepair and fibrosis.

## Key facts

- **NIH application ID:** 10307623
- **Project number:** 5R01HL149825-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ana Lucia Mora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $491,857
- **Award type:** 5
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307623

## Citation

> US National Institutes of Health, RePORTER application 10307623, Type II Alveolar Redox Control in Fibrogenesis and Resolution (5R01HL149825-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10307623. Licensed CC0.

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