RESUMO
Disruption of pulmonary endothelial permeability and associated barrier integrity increase the severity of acute respiratory distress syndrome (ARDS). This study investigated the potential ability of the human immunodeficiency virus-1 (HIV-1) integrase inhibitor raltegravir to protect against acute lung injury (ALI) and the underlying mechanisms. Accordingly, the impact of raltegravir treatment on an in vitro lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMEC) model of ALI and an in vivo LPS-induced two-hit ALI rat model was examined. In the rat model system, raltegravir treatment alleviated ALI-associated histopathological changes, reduced microvascular permeability, decreased Evans blue dye extravasation, suppressed the expression of inflammatory proteins including HMGB1, TLR4, p-NF-κB, NLRP3, and MPO, and promoted the upregulation of protective proteins including claudin 18.1, VE-cadherin, and aquaporin 5 as measured via western blotting. Immunohistochemical staining further confirmed the ability of raltegravir treatment to reverse LPS-induced pulmonary changes in NLRP3, claudin 18.1, and aquaporin 5 expression. Furthermore, in vitro analyses of HPMECs reaffirmed the ability of raltegravir to attenuate LPS-induced declines in VE-cadherin and claudin 18.1 expression while simultaneously inhibiting NLRP3 activation and reducing the expression of HMGB1, TLR4, and NF-kB, thus decreasing overall vascular permeability. Overall, our findings suggested that raltegravir may represent a viable approach to treating experimental ALI that functions by maintaining pulmonary microvascular integrity.
RESUMO
Nitric oxide (NO) is a key factor in inflammation as it regulates microvascular permeability, leukocyte adhesion and wound healing. This mini-review addresses mainly spatial and temporal requirements of NO regulatory mechanisms, with special emphasis on S-nitrosation. Endothelial nitric oxide synthase (eNOS)-derived NO induces S-nitrosation of p120 and ß-catenin, particularly in response to platelet-activating factor (PAF), and through traffic and interactions at the adherens junction promotes endothelial hyperpermeability. S-nitrosation is a determinant in vascular processes such as vasodilation and leukocyte-endothelium interactions. Interestingly, NO decreases leukocytes adhesion to endothelium, but the mechanisms are unknown. Advances in NO molecular biology and regulation may serve as a basis for the development of new therapeutic strategies in the treatment of diseases characterized by inflammation such as ischemia-reperfusion injury, stroke, cancer and atherosclerosis.