fostamatinib and Reperfusion-Injury

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.

Topics: Aminopyridines; Animals; Blood Platelets; Intestinal Mucosa; Intestines; Intracellular Signaling Peptides and Proteins; Lung; Male; Mice; Morpholines; Oxazines; Platelet Count; Platelet Transfusion; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Reperfusion Injury; Syk Kinase

Topics: Aminopyridines; Autoimmune Diseases; Diabetes Mellitus, Type 2; Glomerulonephritis; Humans; Intracellular Signaling Peptides and Proteins; Morpholines; Oxazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Reperfusion Injury; Signal Transduction; Spleen; Syk Kinase

Reperfusion injury to tissue following an ischemic event occurs as a consequence of an acute inflammatory response that can cause significant morbidity and mortality. Components of both the innate (complement, immunoglobulin, monocytes, and neutrophils) and adaptive (B and T lymphocytes) immune systems have been demonstrated to mediate tissue injury. Spleen tyrosine kinase (Syk) is responsible for membrane-mediated signaling in various cell types including B lymphocytes, macrophages, and T cells. We investigated the ability of a small drug Syk inhibitor, R788, to protect mice against mesenteric ischemia-reperfusion (I/R)-induced local (intestine) and remote lung injury. Mice were fed with chow containing a Syk inhibitor for 6 days before the performance of intestinal I/R, which resulted in silencing of the expression of the active phosphorylated Syk. Syk inhibition significantly suppressed both local and remote lung injury. The beneficial effect was associated with reduced IgM and complement 3 deposition in the tissues and significant reduction of polymorphonuclear cell infiltration. Our data place Syk upstream of events leading to the binding of natural antibodies to the ischemia-conditioned tissues and urge the consideration of the use of Syk inhibitors in the prevention or improvement of tissue injury of organs exposed to ischemia or hypoperfusion.

Topics: Aminopyridines; Animals; Complement C3; Enzyme Activation; Enzyme Inhibitors; Immunoglobulin G; Immunoglobulin M; Intestines; Intracellular Signaling Peptides and Proteins; Lung; Mice; Mice, Inbred C57BL; Morpholines; Neutrophil Infiltration; Oxazines; Protein-Tyrosine Kinases; Pulmonary Circulation; Pyridines; Pyrimidines; Receptors, Cell Surface; Reperfusion Injury; Splanchnic Circulation; Syk Kinase