Modulating Innate Immunity Improves Outcomes in Acute Lung Injury

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  • March 20, 2019
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  • Dunn, Julia
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Pulmonary inflammation following traumatic injury disrupts the lung architecture, leading to impaired oxygen exchange and rendering patients susceptible to life threatening bacterial infections. Innate immunity is central to the resolution of infection; however, excessive immune responses cause unresolved inflammation that exacerbate tissue damage. We hypothesize that partially attenuating recruitment of innate immune cells without impairing their function in situ will improve outcomes for patients diagnosed with acute lung injury (ALI) following burns and smoke inhalation by restoring homeostasis. Using mouse models of injury, we characterized the innate immune response in the lung following burns and smoke inhalation to establish mechanistic relationships that drive inflammation and to test therapeutic interventions. We show that significant neutrophil recruitment to the lung following burn injury is driven by damage associated molecular patterns (DAMPs); however, this recruitment does not result in improved bacterial clearance following pulmonary infection. To explore the factors that drive inflammation in a clinically relevant direct lung injury model, we developed and validated a novel murine model of acute smoke inhalation. This model mimics granulocyte recruitment, anti-inflammatory cytokine profile, DAMP release, and susceptibility to bacterial infection that are important drivers of outcome in patients. Using this model, we differentiate between correlative and causative inflammatory relationships in ALI. First, we demonstrate that inducible nitric oxide synthase is required for upregulation of interleukin-10 (IL-10), monocyte chemotactic protein 1, and hyaluronic acid (HA) following inhalational injury, but not for bacterial clearance. Thus, we propose that the relationship between elevated IL-10 and the onset of bacterial infection in patients may be correlative rather than causative. Furthermore, we demonstrate that neutrophil recruitment is driven by the chemokine CXCL1 as well as leukotriene B4, and we present data that granulocyte NADPH oxidase (NOX2) rapidly eliminates these signals and prevents excessive inflammation. Finally, we demonstrate that a 50% decrease in early neutrophil recruitment to the lung after smoke inhalation leads to decreased tissue damage and improved outcomes following bacterial challenge. Collectively, these data demonstrate the clinical relevance of our experimental model and suggest that downstream targets of NOX2 activity are promising candidates for accelerating resolution of inflammation in patients.
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  • In Copyright
Advisor
  • Kawula, Thomas
  • Maile, Robert
  • Miao, Edward
  • Cairns, Bruce
  • Arthur, Janelle
  • Doerschuk, Claire
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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