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NF ‐κB activation mediates LPS ‐or zymosan‐induced hypotension and inflammation reversed by BAY 61‐3606, a selective Syk inhibitor, in rat models of septic and non‐septic shock
Author(s) -
SahanFirat Seyhan,
TemizResitoglu Meryem,
Guden Demet Sinem,
Senol Sefika Pinar,
Sari Ayse Nihal,
Cil Meltem,
Unsal Demet,
Korkmaz Belma,
Tunctan Bahar,
Malik Kafait U.,
Buharalioglu Cuneyt Kemal
Publication year - 2019
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 - 10.1111/1440-1681.13045
Subject(s) - syk , zymosan , septic shock , lipopolysaccharide , proinflammatory cytokine , pharmacology , tumor necrosis factor alpha , inflammation , chemistry , medicine , immunology , sepsis , tyrosine kinase , signal transduction , biochemistry , in vitro
Summary We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory‐κB (IκB)‐α/nuclear factor‐κB ( NF ‐κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan ( ZYM )‐induced non‐septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY 61‐3606 via NF ‐κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide ( LPS ) (septic)‐ and ZYM (non‐septic)‐induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor‐α, and interleukin‐8 levels, and NF ‐κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY 61‐3606 (3 mg/kg, ip), the selective Syk inhibitor, given 1 hour after LPS ‐ or ZYM injection reversed all the above‐mentioned effects. These results suggest that Syk contributes to the LPS ‐ or ZYM ‐induced hypotension and inflammation associated with transactivation of NF ‐κB in septic and non‐septic shock.