p38 mitogen-activated protein kinase activation during platelet storage: consequences for platelet recovery and hemostatic function in vivo.
Platelets undergo several modifications during storage that reduce their posttransfusion survival and functionality. One important feature of these changes, which are known as platelet storage lesion, is the shedding of the surface glycoproteins GPIb-alpha and GPV. We recently demonstrated that tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) mediates mitochondrial injury-induced shedding of adhesion receptors and that TACE activity correlates with reduced posttransfusion survival of these cells. We now confirm that TACE mediates receptor shedding and clearance of platelets stored for 16 hours at 37 degrees C or 22 degrees C. We further demonstrate that both storage and mitochondrial injury lead to the phosphorylation of p38 mitogen-activated kinase (MAPK) in platelets and that TACE-mediated receptor shedding from mouse and human platelets requires p38 MAP kinase signaling. Protein kinase C, extracellular regulated-signal kinase MAPK, and caspases were not involved in TACE activation. Both inhibition of p38 MAPK and inactivation of TACE during platelet storage led to a markedly improved posttransfusion recovery and hemostatic function of platelets in mice. p38 MAPK inhibitors had only minor effects on the aggregation of fresh platelets under static or flow conditions in vitro. In summary, our data suggest that inhibition of p38 MAPK or TACE during storage may significantly improve the quality of stored platelets.
Canault
Matthias
M
Immune Disease Institute, Boston, MA, USA.
Duerschmied
Daniel
D
Brill
Alexander
A
Stefanini
Lucia
L
Schatzberg
Daphne
D
Cifuni
Stephen M
SM
Bergmeier
Wolfgang
W
Wagner
Denisa D
DD
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency / Q000235:genetics; D000072198:ADAM17 Protein; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000502:physiology; D001793:Blood Preservation; D004789:Enzyme Activation; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017713:Platelet Transfusion; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000097:blood*
D019038:Platelet Glycoprotein GPIb-IX Complex; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse