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This Article Full Text Full Text (PDF) Corrigendum All Versions of this Article: 297/6/L1091    most recent 90471.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dooley, J. L. Articles by Lacy, P. PubMed PubMed Citation Articles by Dooley, J. L. Articles by Lacy, P.

Regulation of inflammation by Rac2 in immune complex-mediated acute lung injury

¹Department of Medicine, and ; ²Department of Laboratory Medicine and Pathology, Pulmonary Research Group, University of Alberta, Edmonton, Alberta, Canada

Submitted 4 September 2008 ; accepted in final form 29 September 2009

Acute lung injury (ALI) is an inflammatory disorder associated with recruitment and activation of neutrophils in lungs. Rac2, a member of the Rho GTPase subfamily, is an essential regulator of neutrophil degranulation, superoxide release, and chemotaxis. Here, we hypothesized that Rac2 is important in mediating lung injury. Using a model of IgG immune complex-mediated ALI, we showed that injury was attenuated in rac2^–/– mice compared with wild-type (WT) mice undergoing ALI, with significant decreases in alveolar leukocyte numbers, vascular leakage, and the inflammatory mediators, myeloperoxidase (MPO) and matrix metalloproteinases (MMPs). Reduced injury in rac2^–/– mice was not associated with diminished cytokine and chemokine production, since bronchoalveolar lavage (BAL) levels of IL-17, TNF, CCL3, CXCL1, and CXCL2 were similarly increased in WT and rac2^–/– mice with ALI compared with sham-treated mice (no ALI). BAL levels of MMP-2 and MMP-9 were significantly decreased in the airways of rac2^–/– mice with ALI. Immunohistochemical analysis revealed that MMP-2 and MMP-9 expression was evident in alveolar macrophages and interstitial neutrophils in WT ALI. In contrast, MMP-positive cells were less prominent in rac2^–/– mice with ALI. Chimeric mice showed that Rac2-mediated lung injury was dependent on hematopoietic cells derived from bone marrow. We propose that lung injury in response to immune complex deposition is dependent on Rac2 in alveolar macrophages and neutrophils.

neutrophils; macrophages; bronchoalveolar lavage; cytokines; bone marrow chimeras; matrix metalloproteinases