# PAD2 and CitH3 in Pathogenesis of Sepsis-induced ALI

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $533,969

## Abstract

PROJECT SUMMARY ABSTRACT
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to
infection, and acute lung injury (ALI) is a leading cause of death associated with sepsis. An
emerging mechanism of sepsis induced-ALI (sepsis-ALI) involves neutrophils/macrophages
undergoing cell death, releasing nuclear histones and citrullinated histone H3 (CitH3) to cause
tissue damage and exacerbate pulmonary injury. CitH3 is catalyzed by peptidylarginine
deiminase 2 and 4 (PAD2 and PAD4). We found that CitH3 is elevated in serum of patients with
sepsis-ALI, but not in ALI patients due to non-infectious causes, suggesting that CitH3 could be
a biomarker, as well as a potential causative factor for sepsis-ALI. Significant elevations of
CitH3 and PAD2 in bronchoalveolar lavage fluid (BALF), not PAD4, are detected in septic
patients. While Pad4-/- mice do not show a clear septic phenotype compared with wild type
littermates, the Pad2-/- mice are strikingly more resistant to sepsis-ALI and other organ
dysfunctions. The improved survival of the Pad2-/- septic mice is linked to enhanced bacterial
clearance due to enhanced function of macrophages. We have data to show that chemical
inhibition of PAD2 and antibody sequestration of CitH3 have therapeutic benefits to treat sepsis-
ALI in mice. Combining our expertise in cell and molecular biology, animal models of and clinical
research in sepsis, and chemical biology, our team-based research aims to dissect the
physiological actions of PAD2 and CitH3 in modulating macrophage function associated with
sepsis (Aim 1), and to conduct proof-of-concept studies targeting PAD2 and CitH3 as novel
means to treat sepsis-ALI in mice (Aim 2). Circulating CitH3 could act as a signaling molecule
and bind to membrane receptor(s) to fulfill its biological function; or CitH3 can enter the host
cells via endocytosis to directly interfere with their survival or death pathways. Thus, knowledge
on the membrane delimited interaction between CitH3 and macrophages will add significant
insight into the pathogenesis and potential treatment of sepsis-ALI and other multi-organ
dysfunctions.

## Key facts

- **NIH application ID:** 10293158
- **Project number:** 1R01HL155116-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** HASAN B ALAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $533,969
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293158

## Citation

> US National Institutes of Health, RePORTER application 10293158, PAD2 and CitH3 in Pathogenesis of Sepsis-induced ALI (1R01HL155116-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10293158. Licensed CC0.

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