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

Demet Unsal, Meltem Kacan, Meryem Temiz-Resitoglu, Demet S. Guden, Belma Korkmaz, Ayse N. Sari, Cuneyt K. Buharalioglu, Hatice Yildirim-Yaroglu, Lulufer Tamer-Gumus, Bahar Tunctan, Kafait Malik, Seyhan Sahan-Firat

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalClinical and Experimental Pharmacology and Physiology
Volume45
Issue number2
DOIs
StatePublished - Feb 1 2018

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Zymosan
Hypotension
Shock
Inflammation
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Nitrites
Peroxidase
Tumor Necrosis Factor-alpha
3'-(1-butylphosphoryl)adenosine
2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
Syk Kinase
Mycoses
Toll-Like Receptors
Vasodilator Agents
Protein-Tyrosine Kinases
Blood Vessels
Wistar Rats
Heart Rate
Blood Pressure

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

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. / 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; Sahan-Firat, Seyhan.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 45, No. 2, 01.02.2018, p. 155-165.

Research output: Contribution to journalArticle

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 ; Sahan-Firat, Seyhan. / 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. In: Clinical and Experimental Pharmacology and Physiology. 2018 ; Vol. 45, No. 2. pp. 155-165.
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abstract = "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-PGF1α, 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.",
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AU - Temiz-Resitoglu, Meryem

AU - Guden, Demet S.

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AU - Sari, Ayse N.

AU - Buharalioglu, Cuneyt K.

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