Platelet activation in cystic fibrosis

Abstract

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, neutrophilplatelet 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 ( IntroductionCystic fibrosis (CF) is the most common lethal genetic disease in whites, affecting approximately 1 in 2500 live births. 1 In 1989, Kerem et al 2 ; Riordan et al 3 ; and Rommens et al 4 identified the genetic mutation responsible for CF and cloned its protein product, which is called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of the adenosine triphosphate (ATP)-binding cassette family of transporters and acts chiefly as a chloride channel, although it has various other functions including regulation of alternate chloride channels and epithelial sodium channels, and transport of ATP. [5][6][7] Defects in CFTR cause reduced chloride secretion into airways and enhanced sodium reabsorption, thereby resulting in dehydrated airway secretions, poor mucociliary clearance, and airway obstruction. 1 Obstruction of the airways, along with poorly understood altered host defense mechanisms and an enhanced inflammatory response, leads to chronic airway infection and inflammation. This, in turn, causes an influx of polymorphonuclear cells that, when they become senescent and release their DNA into the airway mucous, contribute to thickening of airway secretions. 8 The self-perpetuating cycle of obstruction, infection, and inflammation eventually causes pulmonary parenchymal destruction and respiratory failure. The life expectancy for CF patients in the United States is currently approximately 33 years. 9 Previous studies have shown that CF patients have increased ex vivo platelet aggregability, increased release of thromboxane A 2 (TXA 2 ), 10-12 and a blunted response to prostaglandin E 1 (PGE 1 )-induced inhibition of platelet aggregation. 13,14 Platelets contain or generate many inf...

P2 receptors and platelet function

“…They are also responsible for the formation of pathogenic thrombi at sites of rupture or erosion of an atherosclerotic plaque, promoting atherothrombotic diseases including acute coronary syndromes, ischaemic stroke and peripheral artery disease [1]. Platelets also play an important role in inflammation and can influence the phenotype of other blood and vascular cells, thereby contributing to many other non-haemostatic disorders, from cystic fibrosis and arthritis to diabetes, atherosclerosis and cancer [2][3][4][5][6][7].…”

Platelet proinflammatory activity in clinically stable patients with CF starts in early childhood

“…However, there is evidence, that platelets, too, have an important role in the pathogenesis of inflammation. They release a variety of cytokines and also facilitate leukocyte recruitment to the sites of inflammation by direct interaction with leukocytes and endothelium [4][5][6][7]. P-selectin glycoprotein ligand 1 (PSGL-1) and integrin α M β 2 (CD11b/CD18) are the most important leukocyte proteins involved in binding to platelets and endothelium [4,8].…”

Selectins revisited: the emerging role of platelets in inflammatory lung disease

“…Zarbock and colleagues (12) have implemented this concept convincingly into the pathophysiology of ALI, but it may extend even further to other inflammatory respiratory diseases. Considerable numbers of circulating platelet-leukocyte aggregates can be found in patients with allergic asthma or cystic fibrosis (18,19), and a critical role for platelet P-selectin in the recruitment of eosinophils and lymphocytes was recently demonstrated in an experimental model of allergic lung disease (20). Whether platelets alone may…”