Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 294, Issue 2, Pages L178-L186Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00263.2007
Keywords
caveolae; permeability; edema; Rac
Categories
Funding
- NHLBI NIH HHS [P01 HL 60678, HL 71626] Funding Source: Medline
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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 106 cells) into the perfusate followed by their activation with formyl-Met-Leu-Phe ( fMLP, 1.0 mu M) 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.
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