Journal
PHARMACEUTICAL RESEARCH
Volume 30, Issue 7, Pages 1836-1847Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-013-1027-2
Keywords
acute lung injury; extracellular-regulated kinase; nanomedicine; permeability; thrombin
Funding
- American Thoracic Society/Sepsis Alliance Research Grant
- THORAX Research Center for Intensive and Emergency Thoracic Medicine, Athens, Greece
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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 16 mg/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 24 h 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.
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