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The role of Syk/IĸB‐α/ NF ‐ ĸB 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
Author(s) -
Unsal Demet,
Kacan Meltem,
TemizResitoglu Meryem,
Guden Demet S,
Korkmaz Belma,
Sari Ayse N,
Buharalioglu Cuneyt K,
YildirimYaroglu Hatice,
TamerGumus Lulufer,
Tunctan Bahar,
Malik Kafait U,
SahanFirat Seyhan
Publication year - 2018
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12864
Subject(s) - syk , inflammation , pharmacology , chemistry , proinflammatory cytokine , tumor necrosis factor alpha , peroxynitrite , tyrosine kinase , receptor , medicine , immunology , biochemistry , enzyme , superoxide
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 ĸB (IĸB)‐α, and nuclear factor‐ ĸB ( NF ‐ ĸB ) p65. We also examined the effect of Syk inhibition on inducible nitric oxide synthase ( iNOS ), cyclooxygenase ( COX )‐2, and tumour necrosis factor ( TNF )‐α, 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 ‐κB p65, iNOS and COX ‐2 and decreased expression of IκB‐α with enhanced levels of nitrite, nitrotyrosine, 6‐keto‐ PGF 1α , and TNF ‐α 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/IĸB‐α/ NF ‐ ĸB pathway activation contributes to hypotension and inflammation caused by the production of vasodilator and proinflammatory mediators in the zymosan‐induced non‐septic shock model.