# Targeting the myeloid lineage to inhibit exacerbation of pulmonary fibrosis due to chronic stress

> **NIH VA IK2** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

Pulmonary fibrosis (PF) is a devastating disease characterized by dyspnea, cough, fatigue and poor survival.
Veterans who served in desert regions overseas have an increased risk of developing respiratory diseases
including PF as a result of exposures in theater. The incidence of respiratory disease in Veterans is ~4-16-fold
greater than those exposed to inhaled occupational hazards alone (based on Work-Related Lung Disease
Surveillance Report 2007, NIOS and Health Analysis of VA Health Care Utilization among OEF/OIF/OND
Veterans Report, VHA), suggesting an additional factor contributes to Veterans’ risk. Chronic psychological
stress-associated mental health diseases disproportionately affect Veterans, are associated with increased
inflammation, and may be one contributing factor to respiratory disease among Veterans. Current therapeutics
provide limited effectiveness and do not address the multifactorial nature of PF, indicating the critical need to
understand risk factors for PF and develop improved therapeutics for our nation’s Veterans.
 Our preliminary data demonstrated that chronic stress exacerbated PF. Our laboratory has identified a novel
myeloid circulating fibroblast precursor (CFP) population that is elevated in a silica-induced model of PF and in
chronic stress. CFPs exhibited an activated phenotype defined by increased co-stimulatory molecule expression,
and promoted a pro-inflammatory pulmonary microenvironment in PF. Therefore, we hypothesize that chronic
stress exacerbates silica exposure-induced PF through myeloid lineage dependent mechanisms. Toward this, a
chronic unpredictable stress (CUS) model in conjunction with a highly relevant silica exposure-induced model of
PF will be employed in three specific aims: Aim 1 will determine the impact of CUS on exacerbation of PF
through clinically relevant parameters in vivo and examine the temporal participation and activated phenotype
of myeloid cells in disease. Aim 2 will determine the role of glucocorticoid (GC) signaling in myeloid
proinflammatory cytokine production and in disease promotion. Aim 3 will examine the role of DDR2/collagen
I signaling in the immune functions of CFPs in PF exacerbated by CUS. Adoptive transfer gain-of-function
studies and transplantation-based loss-of-function studies will be employed to directly test the causal role of
CFPs in PF. These studies will provide critical insight into immune response to combat exposures and an
understanding of the pathological impact of chronic stress.
 These studies are innovative in the use of highly relevant models of CUS and exposure-induced PF with
direct applicability to Veterans’ health. Short-term, these studies will provide increased understanding of the
myeloid-dependent, CFP-driven mechanisms, and molecular (glucocorticoid signaling) mechanisms leading to
CUS exacerbation of PF. These studies will also identify unexplored mechanisms of immune function through
activation of the novel CFP and will determine the ca...

## Key facts

- **NIH application ID:** 9914824
- **Project number:** 5IK2BX004072-02
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Lindsay Theresa McDonald
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914824

## Citation

> US National Institutes of Health, RePORTER application 9914824, Targeting the myeloid lineage to inhibit exacerbation of pulmonary fibrosis due to chronic stress (5IK2BX004072-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914824. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*