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A Model of Self-limited Acute Lung Injury by Unilateral Intra-bronchial Acid Instillation
Published on: August 30, 2019
Specialized Pro-Resolving Mediators MaR1 and LXA4 Resolve Inflammation During Acute Chemical Lung Injury in the
Maureen E Haynes1, Vivienne Fang1, Meital Gewirtz1
1Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Abstract:
Gastric aspiration pneumonia involves chemical injury to the alveoli of the lungs with inflammation, tissue damage, and recruitment of polymorphonuclear leukocytes (PMNs). PMNs are also known to be involved in the production of specialized pro-resolving mediators (SPMs), small lipid molecules that contribute to the resolution of inflammation. This study aimed to identify target PMN-produced SPMs and interrogate their actions and potential use for therapeutic treatment after chemical injury. The data revealed that maresin 1 (MaR1), lipoxin A4, and 18-HEPE are produced after chemical injury in the lungs, and that exogenous treatment with these SPMs reduces the acute influx of PMNs into the airspace. In a chemical lung injury model in which neutropenic mice all die within 48 hours, treatment with MaR1 or LXA4 rescued survival of neutropenic mice to the levels of immunologically intact mice, and reduced CD11b expression, a proinflammatory marker, on recruited PMNs. Exogenous treatment with MaR1 or LXA4 reduced the concentration of proinflammatory cytokines TNF⍺, IL6, and MCP-1 in the airspace at 24 hours after injury. These data show that exogenous treatment with MaR1 or LXA4 ameliorates acute inflammation after chemical lung injury and contributes to survival of severe murine aspiration pneumonia in neutropenic animals. These data have implications for treatment of sterile lung injury in immunocompromised patients.
Insights
Specialized pro-resolving mediators like maresin 1 (MaR1) and lipoxin A4 (LXA4) reduce inflammation and improve survival in lung injury models. These findings suggest potential new treatments for aspiration pneumonia in immunocompromised patients.
Area of Science:
- Pulmonary Medicine
- Immunology
- Biochemistry
Background:
- Gastric aspiration pneumonia causes lung inflammation and tissue damage.
- Polymorphonuclear leukocytes (PMNs) drive inflammation but also produce pro-resolving mediators (SPMs).
Purpose of the Study:
- Identify PMN-produced SPMs involved in chemical lung injury.
- Investigate the therapeutic potential of SPMs for treating lung injury.
Main Methods:
- Identified SPMs (MaR1, LXA4, 18-HEPE) produced after chemical lung injury.
- Administered exogenous SPMs to a murine model of chemical lung injury.
- Assessed PMN influx, survival rates, CD11b expression, and cytokine levels (TNFα, IL6, MCP-1).
Main Results:
- Exogenous SPMs reduced PMN influx and CD11b expression.
- MaR1 and LXA4 treatment significantly improved survival in neutropenic mice with lung injury.
- SPM treatment decreased pro-inflammatory cytokine concentrations in the lungs.
Conclusions:
- Maresin 1 and lipoxin A4 ameliorate acute inflammation and improve survival in aspiration pneumonia models.
- These SPMs hold therapeutic promise for sterile lung injury in immunocompromised individuals.
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