Journal article
Blocking CXCL1-dependent neutrophil recruitment prevents immune damage and reduces pulmonary bacterial infection after inhalation injury
American journal of physiology. Lung cellular and molecular physiology, Vol.314(5), pp.L822-L834
05/01/2018
DOI: 10.1152/ajplung.00272.2017
PMCID: PMC6008131
PMID: 29368547
Abstract
Smoke inhalation associated with structural fires, wildfires, or explosions leads to lung injury, for which innovative and clinically relevant animal models are needed to develop effective therapeutics. We have previously reported that damage-associated molecular patterns (DAMPs) and anti-inflammatory cytokines correlate with infectious complications in patients diagnosed with inhalational injury. In this study, we describe a novel and translational murine model of acute inhalational injury characterized by an accumulation of protein and neutrophils in the bronchoalveolar space, as well as histological evidence of tissue damage. Mice were anesthetized, and a cannula was placed in the trachea and exposed to smoldering plywood smoke three times for 2-min intervals in a smoke chamber. Here we demonstrate that this model recapitulates clinically relevant phenotypes, including early release of double-stranded DNA (dsDNA), IL-10, monocyte chemoattractant protein (MCP)-1, and CXCL1 along with neutrophilia early after injury, accompanied by subsequent susceptibility to opportunistic infection with Pseudomonas aeruginosa. Further investigation of the model, and in turn a reanalysis of patient samples, revealed a late release of the DAMP hyaluronic acid (HA) from the lung. Using nitric oxide synthase-deficient mice, we found that Nos2 was required for increases in IL-10, MCP-1, and HA following injury but not release of dsDNA, CXCL1 expression, early neutrophilia, or susceptibility to opportunistic infection. Depletion of CXCL1 attenuated early neutrophil recruitment, leading to decreased histopathology scores and improved bacterial clearance in this model of smoke inhalation. Together, these data highlight the potential therapeutic benefit of attenuating neutrophil recruitment in the first 24 h after injury in patients.
Details
- Title: Subtitle
- Blocking CXCL1-dependent neutrophil recruitment prevents immune damage and reduces pulmonary bacterial infection after inhalation injury
- Creators
- Julia L. M. Dunn - University of North Carolina at Chapel HillLaurel B. Kartchner - University of North Carolina at Chapel HillWesley H. Stepp - University of North Carolina at Chapel HillLindsey I. Glenn - University of North Carolina at Chapel HillMadison M. Malfitano - University of North Carolina at Chapel HillSamuel W. Jones - University of North Carolina at Chapel HillClaire M. Doerschuk - University of North Carolina at Chapel HillRobert Maile - University of North Carolina at Chapel HillBruce A. Cairns - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Lung cellular and molecular physiology, Vol.314(5), pp.L822-L834
- DOI
- 10.1152/ajplung.00272.2017
- PMID
- 29368547
- PMCID
- PMC6008131
- NLM abbreviation
- Am J Physiol Lung Cell Mol Physiol
- ISSN
- 1040-0605
- eISSN
- 1522-1504
- Publisher
- Amer Physiological Soc
- Number of pages
- 13
- Grant note
- R01GM076250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30-CA-016086; K08-GM-109106-02 / National Institutes of Health Grants; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30-CA-016086-40 / National Cancer Institute Center Core Support Grant American Association of Immunologists P30CA016086 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30-CA-016086 / University of North Carolina (UNC) Flow Cytometry Core Facility - Cancer Center Core Support Grant
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Surgery
- Record Identifier
- 9984755391602771
Metrics
17 Record Views