Neutrophil caveolin-1 expression contributes to mechanism of lung inflammation and injury

Guochang Hu, Richard D. Ye, Mary C. Dinauer, Asrar B. Malik, Richard D. Minshall

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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 μM) 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.

Original languageEnglish
Pages (from-to)L178-L186
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Caveolae
  • Edema
  • Permeability
  • Rac

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