Caveolar Uptake and Endothelial-Protective Effects of Nanostructured Lipid Carriers in Acid Aspiration Murine Acute Lung Injury

Abstract

Nanostructured lipid carriers (NLC), nanosized phospholipids/triglyceride particles developed for drug delivery, are considered biologically inactive. We assessed the efficacy of unloaded NLC as experimental treatment for acute lung injury (ALI). To induce ALI, C57Black/6 male mice received intratracheal injections of HCl or saline; A single dose of 16mg/Kg NLC or saline was injected intravenously concomitantly with HCl challenge. NLC uptake mechanisms and effects on endothelial permeability and signaling were studied in cultured endothelial cells and neutrophils. NLC pre-treatment attenuated pulmonary microvascular protein leak, airspace inflammatory cells, thrombin proteolytic activity and histologic lung injury score 24h post insult. Using fluorescence measurements and flow cytometry in mouse lung microvascular endothelial cell culture homogenates, we determined that NLC rendered fluorescent by curcumin labeling are taken up by endothelial cells from mice expressing caveolin-1, the coat protein of caveolar endocytic vesicles, but not from caveolin-1 gene-disrupted mice, which lack caveolae. In contrast, conventional emulsions (CE), consisting of larger particles, were not incorporated. In addition, NLC pre-treatment of cultured human lung microvascular endothelial cells abrogated thrombin-induced activation of p44/42, albumin permeability response, actin cytoskeletal remodeling and interleukin-6 production. Finally, NLC but not CE abrogated lipopolysaccharide-triggered interleukin-8 release. NLC are engulfed by endothelial caveolae and possess endothelial-protective effects. These novel properties may be of potential utility in ALI.