# BM alterations in exacerbation of pulmonary fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $570,539

## Abstract

ABSTRACT
Distal organ insult can cause alterations in the bone marrow (BM) that may impact on the response of the
distal organ to a subsequent insult. Transfer of CD11c+ cells from BM of bleomycin-treated mice exacerbates
pulmonary fibrosis in recipient mice compared to those receiving cells from saline treated controls. Similarly
transfer of a subpopulation of BM derived lung myeloid cells caused exacerbation of fibrosis in recipient mice.
However, the nature of these alterations and the mechanism of enhancement are poorly understood. Acute
exacerbation in idiopathic pulmonary fibrosis (IPF) is poorly understood with respect to pathogenic mechanism,
but its resemblance to acute respiratory distress syndrome suggests involvement of the innate immune
system. Based on animal model studies and the implication of innate immune system involvement in acute
exacerbation in IPF, the evidence suggests that lung injury/fibrosis causes alterations in the BM that then
influences the innate immune response to cause exacerbation of the response in the lung to subsequent insult.
Previous and preliminary studies revealed elevated expression of the co-regulatory molecule, B7-H3 in IPF
lung and detection of soluble B7-H3 in bronchoalveolar lavage fluid of IPF patients with acute exacerbation.
Increased B7H3+ cells, an enhanced Th2 response and epigenetic changes in BM cells are associated with
exacerbation in the bleomycin model. Thus the project's hypothesis is that initial insult to the lung caused
stable alterations in BM cells that result in exacerbation of pulmonary fibrosis in response to a second insult in
the same animal, or in recipients when transplanted with this altered BM. This effect is mediated by BM
monocytic cells in a B7-H3 dependent manner and in part due to enhancement of lung innate immune cell
recruitment and Th2 immune response. To test this hypothesis the following specific aims are proposed, 1) To
analyze the effects of lung injury/fibrosis on BM cells with respect to their ability to exacerbate pulmonary
fibrosis, 2) To identify the signals from the injured/fibrotic lung causing the BM alterations, 3) To elucidate the
role of B7-H3 and the Th2 response in exacerbation of pulmonary fibrosis by the altered BM, and 4) To assess
changes in B7-H3 expression in peripheral blood mononuclear cells and plasma from IPF patients with/without
acute exacerbation. The studies will use BM chimeric and transgenic mice to evaluate BM alterations and
assess their clinical relevance to exacerbation of pulmonary fibrosis by examination of human lung and blood
samples from IPF patients with or without acute exacerbation.

## Key facts

- **NIH application ID:** 9898440
- **Project number:** 5R01HL138417-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SEM H PHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $570,539
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898440

## Citation

> US National Institutes of Health, RePORTER application 9898440, BM alterations in exacerbation of pulmonary fibrosis (5R01HL138417-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898440. Licensed CC0.

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