Dataset Information

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. P2X₁ 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. P2X₁ 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 P2X₁ receptor antagonist markedly accelerates development of a septic response to induced bacteraemia with uropathogenic E. coli. Mice exposed to the P2X₁ 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 P2X₁ 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 P2X₁ receptor potentially could be essential for this response.

SUBMITTER: Skals M

PROVIDER: S-EPMC6635539 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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P2X<sub>1</sub> receptor blockers reduce the number of circulating thrombocytes and the overall survival of urosepsis with haemolysin-producing Escherichia coli.

Skals Marianne M Greve Anne-Sofie AS Fagerberg Steen K SK Johnsen Nanna N Christensen Mette G MG Praetorius Helle A HA

Purinergic signalling 20190526 2

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<sub>1</sub> receptors are expressed by a number of immune cells including thrombocytes, which presently have been establish ...[more]

PMID: 31129780

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Project description:Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham-operated animals, septic animals had significant increases in heart rate (-1(-4 to 8)% vs. 21(12-26)%; P = 0.003), fever (37.4(37.2-37.6)°C vs. 38.6(38.2-39.0)°C; P = 0.0009), and falls in serum albumin (29(27-30)g/L vs. 26(24-28); P = 0.0242). Serum IL-1β (0(0-10)(pg/mL) vs. 1671(1445-33778)(pg/mL); P < 0.001) and renal IL-1β (86(50-102)pg/mg protein vs. 200 (147-248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham-operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham-operated animals at 24 h (23(22-25) μmol/L vs. 28 (25-30)μmol/L; P = 0.0321). Renal IL-1β levels were significantly lower in A-438079-treated animals compared with untreated animals at 6 h (70(55-128)pg/mg protein vs. 200(147-248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A-438079-treated animals had more rapid resolution of tachycardia (22(13-36)% vs. -1(-6 to 7)%; P = 0.019) and fever (39.0(38.6-39.1)°C vs. 38.2(37.6-38.7)°C; P < 0.024), higher serum albumin (23(21-25)g/L vs. (27(25-28)g/L); P = 0.006), lower arterial lactate (3.2(2.5-4.3)mmol/L vs. 1.4(0.9-1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25-30)μmol/L vs. 22(17-27)μmol/L; P = 0.019). P2X7 A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis-related AKI.

Dataset Information

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

Publications

P2X<sub>1</sub> receptor blockers reduce the number of circulating thrombocytes and the overall survival of urosepsis with haemolysin-producing Escherichia coli.

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Dataset Information

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

Publications

P2X<sub>1</sub> receptor blockers reduce the number of circulating thrombocytes and the overall survival of urosepsis with haemolysin-producing Escherichia coli.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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