# Macrophage Signaling Pathways in Acute Lung Injury and Resolution

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $589,544

## Abstract

ABSTRACT
We have been interested in understanding novel determinants of macrophage activation as therapeutics tools in
manipulating lung inflammation and its resolution. We identified MEK pathways as novel suppressors of
macrophage reparative function."By targeting both MEK1 and MEK2 (MEK1/2) using commercially available
inhibitors, we have been able to enhance the ability of macrophages to clear apoptotic PMNs and respond to IL-
4. Importantly, we showed a therapeutic benefit of MEK1/2 inhibition in 2 murine lung injury models: sterile acute
lung injury (ALI) using LPS, and bacterial pneumonia using Pseudomonas aeruginosa. In these ALI models,
mice treated with MEK inhibitors at 24 and 72 h post-LPS or bacteria exposure experienced improved activity,
faster recovery of body weight, reduced pulmonary neutrophilia, and greater M2 polarization."To address the
mechanism and cell source driving this improvement in outcome, we generated mice deficient in MEK1 in
myeloid cells (LysMCre+MEK1fl). These mice have no phenotype in naïve conditions, but experience 100%
mortality with LPS-induced ALI using a moderate LPS dose from which all wild-type mice recover. These mice
have a similar early inflammatory response to LPS, but fail to turn off inflammation at later time-points.
Interestingly, this phenotype can be completely rescued with MEK1/2 inhibitors given at days 1 and 3,
suggesting that MEK2 is an important contributor to non-resolving ALI."Importantly, we also identified a SNP in
MEK2 associated with death in ARDS patients, suggesting that MEK pathways may be clinically significant in
ARDS. These results highlight a potentially novel mechanism of inflammatory control in the macrophage with
striking consequences in murine lung injury models. The proposed aims below outline our approach to identify
how MEK1 and MEK2 work in concert to regulate macrophage responses to LPS to better define a novel
regulatory role of both MEK pathways and macrophages in ALI resolution. In aim 1, we will determine role and
cell source of MEK1 in controlling lung inflammation and test our hypothesis that loss of MEK1 in myeloid
cells leads to dysregulated inflammatory signals from the myeloid compartment in LPS-induced ALI and
contributes to enhanced inflammatory cell recruitment to the lung. In aim 2a, we will determine role of MEK2
in acute lung inflammation and its resolution and test our hypothesis that absence of MEK1 leads to
sustained MEK2 activity as the driver of prolonged inflammatory responses to LPS.!In aim 2b, we plan to
evaluate MEK1 and MEK2 interactions and mechanisms of MEK2 deactivation in macrophages. These
studies would advance our understanding of how the immune system stops inflammation, revealing new
therapeutic targets and approaches that could be brought to the bedside.

## Key facts

- **NIH application ID:** 9880312
- **Project number:** 5R01HL144656-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Anne M. Manicone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,544
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880312

## Citation

> US National Institutes of Health, RePORTER application 9880312, Macrophage Signaling Pathways in Acute Lung Injury and Resolution (5R01HL144656-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9880312. Licensed CC0.

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