Neutrophil caveolin-1 expression contributes to mechanism of lung inflammation and injury.
Caveolin-1 present in immune cells may be involved in regulation of the inflammatory response. Here, using caveolin-1-null (Cav-1(-/-)) mice, we addressed the role of caveolin-1 in polymorphonuclear neutrophils (PMNs) in regulating PMN activation-mediated lung injury. In lungs of wild-type (Cav-1(+/+)) mice perfused at constant flow with Krebs-Henseleit solution, addition of Cav-1(+/+) PMNs (4 x 10(6) cells) into the perfusate followed by their activation with formyl-Met-Leu-Phe (fMLP, 1.0 muM) plus platelet-activating factor (1.0 nM) increased pulmonary microvessel filtration coefficient by 150% and wet-to-dry lung weight ratio by 50% as well as PMN accumulation in lungs. These responses were markedly reduced in lungs perfused with Cav-1(-/-) PMNs followed by addition of the same activating agents. fMLP-stimulated adhesion of Cav-1(-/-) PMNs to pulmonary microvascular endothelial cells and migration of Cav-1(-/-) PMNs across endothelial monolayers were also impaired compared with Cav-1(+/+) PMNs. Cav-1(-/-) PMNs showed 50-80% reduction in PMA- or fMLP-stimulated superoxide production compared with Cav-1(+/+) PMNs. In addition, Cav-1(-/-) PMNs had decreased migratory activity (50%) and adhesion to fibrinogen (40%) in response to fMLP. Rac1 and Rac2 were activated in Cav-1(+/+) PMNs after stimulation of fMLP but not in Cav-1(-/-) PMNs. Exogenous expression of caveolin-1 in COS-phox cells augmented the fMLP-induced Rac1 activation and superoxide production, indicating a direct role of caveolin-1 in the mechanism of superoxide production. Thus caveolin-1 expression in PMNs plays a key role in mediating PMN activation, adhesion, and transendothelial migration and in PMN activation-induced lung inflammation and vascular injury.
Hu
Guochang
G
Department of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Ave., Chicago, IL 60612, USA. gchu@uic.edu
Ye
Richard D
RD
Dinauer
Mary C
MC
Malik
Asrar B
AB
Minshall
Richard D
RD
D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D011654:Pulmonary Edema / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
D051242:Caveolin 1; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D013481:Superoxides; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein