Submitted on September 4, 2008
Revised on September 28, 2009
Accepted on September 29, 2009
Regulation of inflammation by Rac2 in immune complex-mediated acute lung injury
James L. Dooley1, Dalia Abdel Latif1, Chris D. St. Laurent1, Lakshmi Puttagunta1, Dean Befus1, and Paige Lacy1*
1 University of Alberta
* To whom correspondence should be addressed. E-mail: Paige.Lacy{at}ualberta.ca.
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 WT mice undergoing ALI, with significant decreases in alveolar leukocyte numbers, vascular leakage, and the inflammatory mediators, myeloperoxidase (MPO) and matrix metalloproteases (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 to sham-treated mice (no ALI). BAL levels of MMP-2 and 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 wild type 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.
