Summary
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.
Keywords
Acidosis - platelets - inflammation - P-selectin - neutrophils
