Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis

摘要: Vascular leakage in multiple organs is a characteristic pathological change sepsis. Our recent study revealed that ascorbate protects endothelial barrier function microvascular cell monolayers through inhibiting serine/threonine protein phosphatase 2A (PP2A) activation (Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Free Radic Biol Med 48: 128–135, 2010). The present addressed the mechanism of protection by against vascular cecal ligation and puncture (CLP)-induced septic peritonitis mice. CLP caused NADPH oxidase nitric oxide synthase (eNOS) uncoupling to produce superoxide, increased NO production inducible NOS (iNOS) neuronal (nNOS) activity, elevated 3-nitrotyrosine (a product peroxynitrite) formation PP2A activity hindlimb skeletal muscles at 12 h after CLP. increase was associated with decreased levels phosphorylated serine threonine occludin, which immunoprecipitated from freshly harvested cells muscles. Moreover, permeability fluorescent dextran Evans blue dye An intravenous bolus injection (200 mg/kg body wt), given 30 min prior CLP, prevented eNOS uncoupling, attenuated increases iNOS nNOS preserved phosphorylation state completely inhibited blue. A delayed injection, 3 also increase. We conclude sepsis sequentially excessive peroxynitrite, activation, occludin dephosphorylation. provides scientific basis for as an adjunct treatment