The role of Syk/IB-[alpha]/NF-B pathway activation in the reversal effect of BAY 61-3606, a selective Syk inhibitor, on hypotension and inflammation in a rat model of zymosan-induced non-septic shock

Summary Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll-like receptor signalling to activate inflammatory responses following fungal infection but the ro...

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Veröffentlicht in:Clinical and experimental pharmacology & physiology 2018-02, Vol.45 (2), p.155
Hauptverfasser: Unsal, Demet, Kacan, Meltem, Temiz-Resitoglu, Meryem, Guden, Demet S, Korkmaz, Belma, Sari, Ayse N, Buharalioglu, Cuneyt K, Yildirim-Yaroglu, Hatice, Tamer-Gumus, Lulufer, Tunctan, Bahar, Malik, Kafait U, Sahan-Firat, Seyhan
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Sprache:eng
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Zusammenfassung:Summary Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll-like receptor signalling to activate inflammatory responses following fungal infection but the role of this enzyme in zymosan (ZYM)-induced non-septic shock and its impacts on hypotension and inflammation in rats is not well understood. This study was conducted to determine the effects of Syk inhibition on ZYM-induced alterations in the expression and/or activities of Syk, inhibitor B (IB)-[alpha], and nuclear factor-B (NF-B) p65. We also examined the effect of Syk inhibition on inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and tumour necrosis factor (TNF)-[alpha], and activity of myeloperoxidase (MPO) that contribute to hypotension and inflammation. Administration of ZYM (500 mg/kg, ip) to male Wistar rats decreased blood pressure and increased heart rate. These changes were associated with increased expression and/or activities of Syk, NF-[kappa]B p65, iNOS and COX-2 and decreased expression of I[kappa]B-[alpha] with enhanced levels of nitrite, nitrotyrosine, 6-keto-PGF1[alpha], and TNF-[alpha] and activity of MPO in renal, cardiac and vascular tissues. ZYM administration also elevated serum and tissue nitrite levels. The selective Syk inhibitor BAY 61-3606 (3 mg/kg, ip) given 1 hour after ZYM injection reversed all of these changes induced by ZYM. These results suggest that Syk/IB-[alpha]/NF-B pathway activation contributes to hypotension and inflammation caused by the production of vasodilator and proinflammatory mediators in the zymosan-induced non-septic shock model.
ISSN:0305-1870
1440-1681
DOI:10.1111/1440-1681.12864