# The role of PUMA in the progression of cigarette smoking-induced COPD

> **NIH NIH R56** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $413,958

## Abstract

Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of mortality worldwide. The causes
of COPD are usually determined by multiple factors, among which exposure to cigarette smoke (CS) is the most
common cause of COPD. CS exposure has been reported to induce epithelial cell death by apoptosis and
necroptosis, and trigger lung inflammation. Most previous studies on cell death focus on the mechanism of
apoptosis. Necroptosis, a new form of cell death, has emerged as another important mechanism for COPD
pathogenesis. Therefore, revealing a novel target for both apoptosis and necroptosis will help the development
of new treatments for COPD. Our preliminary data show that p53 up-regulated modulator of apoptosis (PUMA),
a pro-apoptotic BH3-only Bcl-2 family member, is markedly induced in the lung tissues of COPD patients and
mice exposed to CS treatment, as well as in lung epithelial cells treated with air-liquid interface (ALI) CS exposure
or cigarette smoking extract (CSE). PUMA deficiency protected against CSE-induced apoptosis and necroptosis
in the lung epithelial cells, and mouse alveolar organoids. Depletion of PUMA in the lung epithelial cells also
attenuated the macrophage inflammatory profile. Moreover, knockdown of PUMA has higher suppressive effect
on pro-inflammatory cytokines induction by CSE exposure than inhibition of cell death, indicating that PUMA
might have a new function in triggering inflammation besides cell death. PUMA knock-out mice showed
decreased lung inflammation, apoptosis, and necroptosis after 2 months of CS exposure, and rescued lung
function loss after 6 months of CS exposure. Based on these preliminary findings, we hypothesize that PUMA
mediates CS-induced apoptosis and necroptosis, and contributes to lung inflammation in the pathogenesis of
COPD. We further hypothesize that PUMA can be pharmacologically targeted as a novel therapy against COPD.
Specifically, we will investigate the functional role of PUMA in CS-induced lung epithelial cell death, as well as
inflammatory macrophage activation, and test whether PUMA deletion or inhibition by a first-in-class small
molecule inhibitor can protect the lung from CS-induced emphysema. In the proposed studies, we will pursue
these three specific aims: (1) Test the hypothesis that PUMA orchestrates CS-induced apoptosis and
necroptosis. (2) Test the hypothesis that PUMA induction in lung epithelial cells triggers pro-inflammatory
cytokines expression and causes cell death independent lung inflammation. (3) Test the hypothesis that inhibition
of PUMA by small molecular weight inhibitors prevents the development of cigarette smoke-induced emphysema
in mice.
This project is expected to reveal a new function of PUMA in the pathogenesis of COPD, especially its novel
function in the induction of inflammatory cytokines. The completion of the proposed studies will provide proof-of-
principle evidence for targeting PUMA as a novel therapeutic approach for C...

## Key facts

- **NIH application ID:** 10930186
- **Project number:** 1R56HL162749-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Dongshi Chen
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $413,958
- **Award type:** 1
- **Project period:** 2023-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930186

## Citation

> US National Institutes of Health, RePORTER application 10930186, The role of PUMA in the progression of cigarette smoking-induced COPD (1R56HL162749-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10930186. Licensed CC0.

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