4.6 Article

Direct Airway Instillation of Neutrophils Overcomes Chemotactic Deficits Induced by Injury

期刊

SHOCK
卷 56, 期 1, 页码 119-124

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0000000000001691

关键词

Chemoattractants; innate immunity; neutrophil transplantation; nosocomial pneumonia; trauma

资金

  1. NIAID/NIH [1R03AI135346-01]
  2. Department of Defense (DoD) [W81XWH-16-1-0464]

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Injury-induced mtFPs inhibit the migration of neutrophils to infected alveoli, but instillation of exogenous human neutrophils into the airway prevents the development of post-traumatic pneumonia in recipients.
Background: Trauma induces neutrophil migration toward injury sites, both initiating wound healing and protecting against local bacterial infection. We have previously shown that mitochondrial formyl peptides (mtFPs) released by injured tissues act as chemoattractants by ligating neutrophil (PMN) formyl peptide receptor 1 (FPR1). But this process can also internalize multiple neutrophil chemoattractant receptors and thus might limit neutrophil migration to the lung in response to bacteria. Our objective was to better understand susceptibility to pneumonia after injury and thus find ways to reverse it. Methods and Results: We modeled the alveolar chemotactic environment in pulmonary infections by incubating Staphylococcus aureus or Escherichia coli with peripheral blood mononuclear cells. Survey of the chemotactic mediators in the resultant conditioned media (CM) showed multiple potent chemoattractants. Pretreating PMN with mtFPs to mimic injury potently reduced net migration toward CM and this net effect was mostly reversed by an FPR1 antagonist. Using an established mouse model of injury-dependent lung infection, we then showed simple instillation of exogenous unstimulated human neutrophils into the airway resulted in bacterial clearance from the lung. Conclusion: Injury-derived mtFPs suppress global PMN localization into complex chemotactic environments like infected alveoli. Transplantation of naive exogenous human neutrophils into the airway circumvents that pathologic process and prevents development of post-traumatic pneumonia without injury noted to the recipients.

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