Activation of mTOR/I-κB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats

Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-kappa B (NF-kappa B) p65, inhibitor kappa B (I kappa B)-alpha, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-alpha and activity of myeloperoxidase (MPO), which results in hypotension and inflammation. Injection of LPS (10 mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF(1a), and TNF-alpha levels and MPO activity, and increased expressions and/or activities of rpS6, NF-kappa B p65, iNOS, and COX -2 and decreased expression of I kappa B-alpha in renal, cardiac, and vascular tissues. LPS also increased serum and tissue nitrite levels. Rapamycin (1 mg/kg, i.p.) given one h after injection of LPS reversed these effects of LPS. These data suggest that the activation of mTOR/I kappa B-alpha/NF-kappa B pathway associated with vasodilator and proinflammatory mediator formation contributes to LPS-induced hypotension and inflammation.