# REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $568,802

## Abstract

Our published data show that genetic ablation and pharmacologic inhibition of NFATc3 in macrophages is
beneficial in maintaining alveolar-capillary barrier function, prevents inflammatory cytokine release and
neutrophilic inflammation, improved arterial oxygenation and survival in the LPS and cecal ligation puncture
mouse models of ARDS. Here, we propose to determine the granular details of the downstream molecular targets
of NFATc3 using a 2-hit mouse model, human lung macrophages, and BALF from patients with ARDS. Our team
has developed a novel non-toxic cell permeable calcineurin inhibitory (CNI) peptide (CNI103) that blocks
activation of NFATc3 in macrophages and mitigates ARDS in mice. We propose to determine the molecular
targets of NFATc3 using a pre-clinical 2-hit mouse model, human lung macrophages, and BALF from patients
meeting the Berlin criterion for ARDS. Our central hypothesis is that activation of calcineurin-dependent NFAT
in macrophages regulates the development of ALI/ARDS, and inhibition of NFAT activation by a novel
peptide calcineurin inhibitor (CNI) lessens disease severity. We propose two specific aims:
Specific Aim 1: To delineate the downstream molecular targets of NFATc3-Calcineurin activation pathway in
pulmonary macrophages during ALI/ARDS. Novel preliminary data show that the lipid content of extracellular
vesicles (EVs) in BALF are NFATc3 dependent and mediate disruption of barrier function in lung microvascular
endothelial cells (MVEC). In SA1, we will 1) determine the spectrum of NFAT regulated lipids mediators and
enzymes involved in lipid metabolism, 2) determine whether these mediators are packaged in extracellular
vesicles, 3) assess whether EVs mediate the the cell-to-cell communication that results in permeability
pulmonary edema and 4) determine whether blocking NFAT activation prevents lung injury and inflammation in
clinically relevant mouse and cellular models of ARDS.
Specific Aim 2: To determine the efficacy and safety of an optimized cell permeable calcineurin inhibitor,
which prevents NFAT activation, in clinically relevant infectious and non-infectious mouse models of
ALI/ARDS. We will test whether cell permeable calcineurin peptide inhibitors prevent and reverse lung injury
and inflammation in mouse models of ARDS. We will also assess the pharmacokinetic and pharmacodynamics
(PK/PD) properties, cellular selectivity, safety, efficacy, and potency in preventing and reversing lung injury in
preclinical mouse models of ARDS.
These studies will advance knowledge about the essential role of NFATc3 activation in macrophages
and other lung cell types in the pathogenesis of ALI/ARDS. We anticipate that knowledge gained from
these studies will establish NFATc3 as a novel therapeutic target that regulates EV-mediated cell-cell
interactions by governing the composition of biologically active lipid and protein mediators.

## Key facts

- **NIH application ID:** 10455872
- **Project number:** 2R01HL137224-05A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** John W Christman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $568,802
- **Award type:** 2
- **Project period:** 2018-01-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455872

## Citation

> US National Institutes of Health, RePORTER application 10455872, REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS (2R01HL137224-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10455872. Licensed CC0.

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