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
Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
Department of Pharmacology, Faculty of Pharmacy International, Cyprus University, Nicosia, Cyprus.
Clin Exp Pharmacol Physiol. 2018 Feb;45(2):155-165. doi: 10.1111/1440-1681.12864. Epub 2017 Nov 28.
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 , 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.
脾酪氨酸激酶（Syk）是一种非受体酪氨酸激酶，在过敏性疾病和炎症中发挥重要作用。Syk触发多种细胞内信号级联反应，包括Toll样受体信号传导，以在真菌感染后激活炎症反应，但该酶在酵母聚糖（ZYM）诱导的非感染性休克中所起的作用及其对大鼠低血压和炎症的影响尚不清楚。本研究旨在确定抑制Syk对ZYM诱导的Syk、抑制蛋白κB（IκB）-α和核因子κB（NF-κB）p65表达和/或活性变化的影响。我们还研究了抑制Syk对诱导型一氧化氮合酶（iNOS）、环氧化酶（COX）-2和肿瘤坏死因子（TNF）-α以及髓过氧化物酶（MPO）活性的影响，这些因素会导致低血压和炎症。给雄性Wistar大鼠腹腔注射ZYM（500 mg/kg）可降低血压并增加心率。这些变化与肾、心脏和血管组织中Syk、NF-κB p65、iNOS和COX-2的表达和/或活性增加以及IκB-α表达降低有关，同时亚硝酸盐、硝基酪氨酸、6-酮-前列腺素F1α和TNF-α水平升高以及MPO活性增强。ZYM给药还会提高血清和组织中亚硝酸盐水平。在注射ZYM 1小时后腹腔注射选择性Syk抑制剂BAY 61-3606（3 mg/kg）可逆转ZYM诱导的所有这些变化。这些结果表明，在酵母聚糖诱导的非感染性休克模型中，Syk/IκB-α/NF-κB途径的激活通过产生血管舒张剂和促炎介质导致低血压和炎症。
