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Inflammation

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Alveolar Macrophage Chemokine Secretion Mediates Neutrophilic Lung Injury in Nox2-Deficient Mice

  • Renee M. Potera
  • Mou Cao
  • Lin F. Jordan
  • Richard T. Hogg
  • Jessica S. Hook
  • Jessica G. Moreland
ORIGINAL ARTICLE
  • 131 Downloads

Abstract

Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen species (ROS), produced in part by the neutrophil NADPH oxidase 2 (Nox2), have been implicated in the pathogenesis of ALI. Previous studies in our laboratory demonstrated the development of pulmonary inflammation in Nox2-deficient (gp91phox-/y) mice that was absent in WT mice in a murine model of SIRS. Given this finding, we hypothesized that Nox2 in a resident cell in the lung, specifically the alveolar macrophage, has an essential anti-inflammatory role. Using a murine model of SIRS, we examined whole-lung digests and bronchoalveolar lavage fluid (BALf) from WT and gp91phox-/y mice. Both genotypes demonstrated neutrophil sequestration in the lung during SIRS, but neutrophil migration into the alveolar space was only present in the gp91phox-/y mice. Macrophage inflammatory protein (MIP)-1α gene expression and protein secretion were higher in whole-lung digest from uninjected gp91phox-/y mice compared to the WT mice. Gene expression of MIP-1α, MCP-1, and MIP-2 was upregulated in alveolar macrophages obtained from gp91phox-/y mice at baseline compared with WT mice. Further, ex vivo analysis of alveolar macrophages, but not bone marrow-derived macrophages or peritoneal macrophages, demonstrated higher gene expression of MIP-1α and MIP-2. Moreover, isolated lung polymorphonuclear neutrophils migrate to BALf obtained from gp91phox-/y mice, further providing evidence of a cell-specific anti-inflammatory role for Nox2 in alveolar macrophages. We speculate that Nox2 represses the development of inflammatory lung injury by modulating chemokine expression by the alveolar macrophage.

KEY WORDS

acute lung injury alveolar macrophage ARDS NADPH oxidase 2 Nox2 

Notes

Acknowledgements

The project described was supported by award number K12HD068369 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the offical views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

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Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of MicrobiologyUniversity of Texas Southwestern Medical CenterDallasUSA

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