Platelet activation in cystic fibrosis.
Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E(1) (PGE(1)). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF.
O'Sullivan
Brian P
BP
Department of Pediatrics, UMass Memorial Health Care and University of Massachusetts Medical School, Worcester, MA 01655, USA. osullivb@ummhc.org <osullivb@ummhc.org>
Linden
Matthew D
MD
Frelinger
Andrew L
AL
Barnard
Marc R
MR
Spencer-Manzon
Michele
M
Morris
James E
JE
Salem
Raneem O
RO
Laposata
Michael
M
Michelson
Alan D
AD
D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000527:Alprostadil / Q000037:antagonists & inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000097:blood* / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013928:Thromboxane A2 / Q000378:metabolism; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C505032:CFTR protein, human; D005227:Fatty Acids; D019007:P-Selectin; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014810:Vitamin E; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000527:Alprostadil; D007052:Ibuprofen