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

• Published in: Inflammation Vol. 42; no. 1; pp. 185 - 198
• Main Authors: Potera, Renee M., Cao, Mou, Jordan, Lin F., Hogg, Richard T., Hook, Jessica S., Moreland, Jessica G.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2019; Springer Nature B.V
• Subjects: Alveolar bone; Animal models; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bronchus; Chemokines; CYBB protein; Gene expression; Genotypes; Immunology; Inflammation; Internal Medicine; Leukocyte migration; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); Lungs; Macrophage inflammatory protein; Monocyte chemoattractant protein 1; Morbidity; NAD(P)H oxidase; Neutrophils; Original; Original Article; Pathology; Peritoneum; Pharmacology/Toxicology; Reactive oxygen species; Rheumatology; Rodents; Systemic inflammatory response syndrome; alveolar macrophage; acute lung injury; ARDS; Nox2; NADPH oxidase 2
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-018-0883-7

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 (gp91 phox-/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 gp91 phox-/y mice. Both genotypes demonstrated neutrophil sequestration in the lung during SIRS, but neutrophil migration into the alveolar space was only present in the gp91 phox-/y mice. Macrophage inflammatory protein (MIP)-1α gene expression and protein secretion were higher in whole-lung digest from uninjected gp91 phox-/y mice compared to the WT mice. Gene expression of MIP-1α, MCP-1, and MIP-2 was upregulated in alveolar macrophages obtained from gp91 phox-/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 gp91 phox-/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.