title: Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets.
abstract: Acidosis is one of the hallmarks of tissue injury such as trauma, infection, inflammation, and tumour growth. Although platelets participate in the pathophysiology of all these processes, the impact of acidosis on platelet biology has not been studied outside of the quality control of laboratory aggregation assays or platelet transfusion optimization. Herein, we evaluate the effect of physiologically relevant changes in extracellular acidosis on the biological function of platelets, placing particular emphasis on haemostatic and secretory functions. Platelet haemostatic responses such as adhesion, spreading, activation of αIIbβ3 integrin, ATP release, aggregation, thromboxane B2 generation, clot retraction and procoagulant activity including phosphatidilserine exposure and microparticle formation, showed a statistically significant inhibition of thrombin-induced changes at pH of 7.0 and 6.5 compared to the physiological pH (7.4). The release of alpha granule content was differentially regulated by acidosis. At low pH, thrombin or collagen-induced secretion of vascular endothelial growth factor and endostatin were dramatically reduced. The release of von Willebrand factor and stromal derived factor-1α followed a similar, albeit less dramatic pattern. In contrast, the induction of CD40L was not changed by low pH, and P-selectin exposure was significantly increased. While the generation of mixed platelet-leukocyte aggregates and the increased chemotaxis of neutrophils mediated by platelets were further augmented under acidic conditions in a P-selectin dependent manner, the increased neutrophil survival was independent of P-selectin expression. In conclusion, our results indicate that extracellular acidosis downregulates most of the haemostatic platelet functions, and promotes those involved in amplifying the neutrophil-mediated inflammatory response.
authors.affiliation: Thrombosis I Laboratory, National Academy of Medicine, CONICET, Buenos Aires, Argentina.
authors.forename: Julia
authors.initials: J
authors.lastname: Etulain
authors.forename: Soledad
authors.initials: S
authors.lastname: Negrotto
authors.forename: Agostina
authors.initials: A
authors.lastname: Carestia
authors.forename: Roberto Gabriel
authors.initials: RG
authors.lastname: Pozner
authors.forename: María Albertina
authors.initials: MA
authors.lastname: Romaniuk
authors.forename: Lina Paola
authors.initials: LP
authors.lastname: D'Atri
authors.forename: Giannoula Lakka
authors.initials: GL
authors.lastname: Klement
authors.forename: Mirta
authors.initials: M
authors.lastname: Schattner
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006487:Hemostasis; D006801:Humans; D007249:Inflammation; D008856:Microscopy, Fluorescence / Q000379:methods; D009504:Neutrophils / Q000166:cytology*; D010718:Phosphatidylserines / Q000737:chemistry; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D017713:Platelet Transfusion; D013929:Thromboxane B2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D043169:Endostatins; D010718:Phosphatidylserines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D013929:Thromboxane B2; D000255:Adenosine Triphosphate