Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas. (October 2016)
- Record Type:
- Journal Article
- Title:
- Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas. (October 2016)
- Main Title:
- Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas
- Authors:
- Long, Andrew J.
Sampson, Erik
McCarthy, Richard W.
Harris, Christopher M.
Barnard, Marc
Shi, Dan
Conlon, Donna
Caldwell, Robert
Honor, David
Wishart, Neil
Hoemann, Michael
Duggan, Lori
Fritz, Douglas
Stedman, Christopher
O'Connor, Elizabeth
Mikaelian, Igor
Schwartz, Annette - Abstract:
- Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusion. In addition, Syk inhibitor-induced lesions were prevented by the coadministration of prednisone. A relatively greater sensitivity of rat platelets to Syk inhibition was supported by functional analyses demonstrating rat-specific differences in response to convulxin, a glycoprotein VI agonist that signals through Syk. These data demonstrate that the Syk pathway is critical in platelet–endothelial cell homeostasis in the peri-islet pancreatic microvasculature in rats.
- Is Part Of:
- Toxicologic pathology. Volume 44:Number 7(2016)
- Journal:
- Toxicologic pathology
- Issue:
- Volume 44:Number 7(2016)
- Issue Display:
- Volume 44, Issue 7 (2016)
- Year:
- 2016
- Volume:
- 44
- Issue:
- 7
- Issue Sort Value:
- 2016-0044-0007-0000
- Page Start:
- 998
- Page End:
- 1012
- Publication Date:
- 2016-10
- Subjects:
- pancreas -- toxicity -- Syk -- platelet -- hemorrhage -- rat -- islet
Pathology -- Periodicals
Toxicology -- Periodicals
Pathology
Toxicology
615.9 - Journal URLs:
- http://tpx.sagepub.com/ ↗
http://online.sagepub.com/ ↗ - DOI:
- 10.1177/0192623316654015 ↗
- Languages:
- English
- ISSNs:
- 0192-6233
- Deposit Type:
- Legaldeposit
- View Content:
- Available online (eLD content is only available in our Reading Rooms) ↗
- Physical Locations:
- British Library DSC - 8873.015000
British Library DSC - BLDSS-3PM
British Library HMNTS - ELD Digital store - Ingest File:
- 7253.xml