P2X1 receptor blockers reduce the number of circulating thrombocytes and the overall survival of urosepsis with haemolysin-producing Escherichia coli

Abstract

Urosepsis is a severe condition often caused by Escherichia coli that spontaneously have ascended the urinary tract to the kidneys causing pyelonephritis and potentially bacteraemia. The number of sepsis cases has been steadily increasing over the last decades, and there are still no specific, molecular supportive therapies for sepsis to supplement antibiotic treatment. P2X 1 receptors are expressed by a number of immune cells including thrombocytes, which presently have been established as an important player in the acute immune response to bacterial infections. P2X 1 receptor-deficient mice have been shown to be relatively protected against urosepsis, with markedly reduced levels of circulating proinflammatory cytokines and intravascular coagulation. However, here we show that continuous intravenous infusion with P2X 1 receptor antagonist markedly accelerates development of a septic response to induced bacteraemia with uropathogenic E. coli. Mice exposed to the P2X 1 receptor antagonists die very early with haematuria, substantially elevated plasma levels of proinflammatory cytokines, massive intravascular coagulation and a concomitant reduction in circulating thrombocytes. Interestingly, infusion of P2X 1 receptor antagonists causes a marked acute reduction in circulating thrombocytes and a higher number of bacteria in the blood. These data support the notion that the number of functional thrombocytes is important for the acute defence against bacteria in the circulation and that the P2X 1 receptor potentially could be essential for this response.

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

“…In the case of P2Y 12 , the pattern was similar, with a less aggressive rise in the proinflammatory cytokines during sepsis. This is potentially important because mice lacking the P2X1 receptor, also show a very dampened cytokine response compared to control [37]. These findings support the notion that thrombocytes participate in the early immunological response to agents in the circulation [55].…”

“…Therefore, our group has established a model that mimics a fast-developing urosepsis, as it may be seen after instrumentation of the urinary tract [11,36], to examine the effect of P2 receptors upon HlyA-induced ATP release for the septic response. P2 receptor activation has a substantial impact on the course of sepsis, and generally, for all P2 receptors tested so far, lack of or inhibition accelerates the septic symptoms and increase the mortality [36,37]. Thus, P2Y 1 receptor inhibition is the first to show an increased survival of E. coli-induced sepsis, and, therefore, the effect of MRS2500 on survival is likely to result exclusively from P2Y 1 receptor inhibition.…”

“…Interestingly, mice lacking the P2X 1 receptor are protected against the sepsis-induced cytokine rush [36]. However, specific inhibition of P2X 1 receptors causes an acute reduction of circulating thrombocytes in itself and, thus, subsequently decreases the overall survival of urosepsis [37]. Therefore, the P2X 1 receptor is not immediately a promising target to reduce thrombocyte activation during sepsis.…”

“…Interestingly, infusion of a P2Y 12 receptor antagonist, cangrelor, showed a tendency towards improving survival, even though this was not statistically significant. Similar to inhibiting the P2X 1 receptor [37], cangrelor reduced the plasma levels of proinflammatory cytokines. Thus, we can conclude that inhibition of P2Y 1 receptors improves the survival of sepsis induced by HlyA-producing E. coli possibly by dampening the thrombocyte and cytokine response.…”

Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans

“…Interestingly, the activity of LtxA has been reported to be involved in induction of systemic autoantibodies to citrulline, which are risk markers for rheumatoid arthritis [17,44]. In addition, LtxA has a crucial role in sepsis induced by bacteremia in an animal model [45].…”