title: Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury.
abstract: 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.
authors.affiliation: Rheumatology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Lapchak
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Kannan
authors.forename: Poonam
authors.initials: P
authors.lastname: Rani
authors.forename: Omer Nuri
authors.initials: ON
authors.lastname: Pamuk
authors.forename: Antonis
authors.initials: A
authors.lastname: Ioannou
authors.forename: Jurandir J
authors.initials: JJ
authors.lastname: Dalle Lucca
authors.forename: Polly
authors.initials: P
authors.lastname: Pine
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000631:Aminopyridines; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology*; D010976:Platelet Count; D017713:Platelet Transfusion; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D015427:Reperfusion Injury / Q000378:metabolism*; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib