# REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $563,650

## Abstract

PROJECT SUMMARY
Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are neutrophilic inflammatory lung
diseases with unacceptably high rates of morbidity and mortality. Our supportive data indicate that genetic
ablation and pharmacologic inhibition of NFATc3 is beneficial in terms of tighter pulmonary barrier function,
decreased cytokine release and neutrophilic inflammation, improved arterial oxygenation, and better survival in
mouse models of ARDS/ALI. Based on these and other clinically relevant supportive data, we posit that
NFATc3 activation in macrophages induces inflammatory gene expression that mediates the initiation,
intensity and duration of ALI/ARDS. We propose three specific aims to address this hypothesis:
Specific Aim 1: To identify the mechanism(s) by which NFATc3 deletion protects against ALI/ARDS.
We will employ genetically defined mice that globally lack NFATc3 subjected to a well-defined murine model of
ALI/ARDS. We will also utilize established methods of NFATc3 KO/WT bone marrow chimera mice,
macrophage passive adoptive transfer of lung macrophages, and we will construct novel conditional
macrophage selective NFATc3-/- mice to identify the impact of macrophage NFATc3 deficiency on the
generation of pulmonary edema, arterial oxygen saturation, and mortality.
Specific Aim 2: To determine the mechanisms by which macrophage NFATc3 activation contributes to
the development of permeability pulmonary edema. In order to determine how macrophages contribute to
the pulmonary edema and severe hypoxemia in ALI/ARDS, we propose to examine the role of NFATc3
regulation of macrophage expression of TNF-related apoptosis-inducing ligand (TRAIL), which inhibits
alveolar fluid clearance (AFC), in addition to lung macrophage production of mediators that disrupt barrier
function of pulmonary microvascular endothelium.
Specific Aim 3: To determine the efficacy of a novel cell permeable peptide NFAT inhibitor in protecting
against ALI/ARDS-like pathophysiology in mouse models. Our group has developed a novel NFAT
inhibitor, CP9-ZIZIT, that has an impressively low Kd value of 2.6 nM, better cell permeability, higher binding
affinity, and improved stability against proteolysis than other available agents. We expect to show that
treatment with CP9-ZIZIT alone or in combination with a PARP1 inhibitor will attenuate pulmonary
inflammation and alveolar capillary barrier disruption.
We expect that this research will provide valuable preclinical data that blocking NFATc3 activation in
macrophages is an effective therapeutic agent for preventing ARDS in a high-risk patient population
and improving the clinical outcome of patients suffering from moderate and severe ARDS/ALI.

## Key facts

- **NIH application ID:** 10094230
- **Project number:** 5R01HL137224-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** John W Christman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $563,650
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094230

## Citation

> US National Institutes of Health, RePORTER application 10094230, REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS (5R01HL137224-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10094230. Licensed CC0.

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