# Endoplasmic reticulum stress in MUC5B-driven lung fibrosis

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2023 · $640,622

## Abstract

ABSTRACT
The overall goal of the proposed research is to understand how enhanced expression of MUC5B
contributes to epithelial cell injury and lung fibrosis. Over the past decade, we have found that: 1) a gain-
of-function MUC5B promoter variant rs35705950 is the dominant risk factor for the development of IPF which
has been validated by multiple independent investigators; 2) among patients with IPF, MUC5B is misexpressed
in bronchioles and alveolar epithelial type 2 (AEC2) cells; 3) IPF epithelia from distal airways (<2 mm airway
caliber) have a unique migratory, pro-fibrotic phenotype in vitro that is replicated ex vivo in mice exposed to
bleomycin; and 4) MUC5B appears to be involved in the pathogenesis of IPF, and the concentration of Muc5b
is directly related to bleomycin-induced lung fibrosis in mice. Despite these findings, we don’t fully understand
how excess MUC5B in the distal lung is mechanistically linked to the development of pulmonary fibrosis. Our
preliminary findings combined with the established association between endoplasmic reticulum (ER) stress and
both IPF and experimental models of lung fibrosis, and the recent observation that XBP1(S) appears to be
necessary and sufficient for MUC5B expression induced by the MUC5B promoter variant, suggest that while
overexpression of MUC5B places individuals at risk of developing IPF by causing persistent homeostatic ER
stress of bronchiolar epithelia, fibroblast recruitment and pro-fibrotic programming requires second hits (such as
aging, tobacco smoke, and/or inflammation) resulting in detrimental ER stress of bronchiolar epithelia and
recruitment and activation of fibroblasts. Accordingly, we hypothesize that MUC5B overexpression in
bronchiolar epithelia causes homeostatic ER stress that primes responses to subsequent injury, thereby
leading to persistent activation of detrimental ER stress responses that cause epithelial dysfunction
during injury/repair and lead to fibroblast activation. In Aim 1, we will characterize the airway epithelial cell
populations most susceptible to variant-induced MUC5B overexpression and ER stress and map these
expression changes to the heterogeneity of lung fibrosis in IPF and the MUC5B promoter variant, examining the
relationship between ER stress, UPR, autophagy, cell senescence, and apoptosis. In Aim 2, we will use in vitro
experimental models to test the role of MUC5B and ER stress on the biophysical properties of airway epithelia
and epithelial-driven activation of fibroblasts. In Aim 3, we will use Muc5b and Xbp1(S) overexpression models,
and pharmacologic and genetic IRE1 pathway inhibition approaches at baseline (first hit) and in response to
aging and/or bleomycin (second hits) to investigate the relationship between Muc5b, ER stress, and lung fibrosis.
This research will address a crucial question about the pathobiology of IPF: How does enhanced expression of
MUC5B promote epithelial injury and lung fibrosis?

## Key facts

- **NIH application ID:** 10627599
- **Project number:** 1P01HL162607-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** David Albert Schwartz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $640,622
- **Award type:** 1
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10627599

## Citation

> US National Institutes of Health, RePORTER application 10627599, Endoplasmic reticulum stress in MUC5B-driven lung fibrosis (1P01HL162607-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10627599. Licensed CC0.

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