Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury

Abstract

<jats:p>Tissue injury following ischemia-reperfusion (I/R) occurs as a consequence of actions of soluble factors and immune cells. Growing evidence supports a role for platelets in the manifestation of tissue damage following I/R. Spleen tyrosine kinase has been well documented to be important in lymphocyte activation and more recently in platelet activation. We performed experiments to evaluate whether inhibition of platelet activation through inhibition of spleen tyrosine kinase prevents tissue damage after mesenteric I/R injury. Platelets isolated from C57BL/6J mice fed with R788 for 10 days were transfused into C57BL/6J mice depleted of platelets 2 days before mesenteric I/R injury. Platelet-depleted mice transfused with platelets from R788-treated mice before mesenteric I/R displayed a significant reduction in the degree of remote lung damage, but with little change in the degree of local intestinal damage compared with control I/R mice. Transfusion of R788-treated platelets also decreased platelet sequestration, C3 deposition, and immunoglobulin deposition in lung, but not in the intestine, compared with control groups. These findings demonstrate that platelet activation is a requisite for sequestration in the pulmonary vasculature to mediate remote tissue injury after mesenteric I/R. The use of small-molecule inhibitors may be valuable to prevent tissue damage in remote organs following I/R injury.</jats:p>

Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

“…Hematopoietic cells are involved in the expression of ischemia reperfusion injury, implying that targeting Syk could be applied to the treatment of ischemia reperfusion injury [113]. R788 has been reported to suppress the symptoms of ischemia reperfusion injury in an animal model [113, 114]. Syk is also involved in the pathogenesis of SLE.…”

Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice

“…Spleen tyrosine kinase is a cellular non-receptor tyrosine kinase, which has been shown by numerous studies to modulate disease conditions characterized significant inflammation, steatosis and cell which are major hall marks of ALD (Mocsai et al, 2010, Dennehy et al, 2008, Lee et al, 2015, Miller et al, 2012, Sanderson et al, 2009, Yi et al, 2014). Functional inhibition of SYK in these conditions has been shown to alleviate inflammation and cell death (Bajpai, 2009, Genovese et al, 2011, Lapchak et al, 2012, Lin et al, 2010, Scott, 2011, Thorarensen and Kaila, 2014). The role of SYK in the pathomechanism of or use of SYK inhibitors in binge drinking induced ALD has not been studied.…”

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases

“…Several oral SYK inhibitors, including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070) and TAK-659, are being evaluated in clinical trials [ 143 ]. Among them, fostamatinib is also used in the treatment of ischemia-reperfusion injury, particularly for improving coronary flow after myocardial infarction [ 144 , 145 ].…”

“… reduces the incidence of early atherosclerosis, but could not effectively affect established atherosclerosis. improving coronary flow after myocardial infarction [ [132] , [133] , [134] , 136 , 144 , 145 ] Entospletinib (GS-9973) inhibits platelet aggregation and has no adverse bleeding events. [ 116 , 135 ] PRT060318 inhibits arterial thrombus formation.…”