Regulation of inflammation by Rac2 in immune complex-mediated acute lung injury.
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.
Dooley
James L
JL
Dept. of Medicine, Univ. of Alberta, Edmonton, Canada.
Abdel-Latif
Dalia
D
St Laurent
Chris D
CD
Puttagunta
Lakshmi
L
Befus
Dean
D
Lacy
Paige
P
D055371:Acute Lung Injury / Q000150:complications* / Q000201:enzymology / Q000276:immunology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement; D018925:Chemokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D007249:Inflammation / Q000150:complications* / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
D000936:Antigen-Antibody Complex; D018925:Chemokines; D018836:Inflammation Mediators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009195:Peroxidase; D013481:Superoxides; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse