Dataset Information

P2X₁, P2X₄, and P2X₇ Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by ?-Haemolysin Producing Escherichia coli.

ABSTRACT: ?-haemolysin (HlyA)-producing Escherichia coli commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis. In vitro, the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X₁/P2X₇ receptor activation. This amplification of the lytic process is not unique to HlyA but is observed by many other pore-forming proteins including complement-induced haemolysis. Since free hemoglobin in the blood is known to be associated with a worse outcome in sepsis one could speculate that inhibition of P2X receptors would ameliorate the course of sepsis. Surprisingly, this study demonstrates that [Formula: see text] and [Formula: see text] mice are exceedingly sensitive to sepsis with uropathogenic E. coli. These mice have markedly lower survival, higher cytokine levels and activated intravascular coagulation. Quite the reverse is seen in [Formula: see text] mice, which had markedly lower cytokine levels and less coagulation activation compared to controls after exposure to uropathogenic E. coli. The high cytokine levels in the [Formula: see text] mouse are unexpected, since P2X₇ is implicated in caspase-1-dependent IL-1? production. Here, we demonstrate that IL-1? production during sepsis with uropathogenic E. coli is mediated by caspase-8, since caspase-8 and RIPK3 double knock out mice show substantially lower cytokine during sepsis and increased survival after injection of TNF?. These data support that P2X₇ and P2X₄ receptor activation has a protective effect during severe E. coli infection.

SUBMITTER: Greve AS

PROVIDER: S-EPMC5382212 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing Escherichia coli.

Greve Anne-Sofie AS Skals Marianne M Fagerberg Steen K SK Tonnus Wulf W Ellermann-Eriksen Svend S Evans Richard J RJ Linkermann Andreas A Praetorius Helle A HA

Frontiers in cellular and infection microbiology 20170406

α-haemolysin (HlyA)-producing Escherichia coli commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis. In vitro, the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X1/P2X7 receptor activation. This amplification of the lytic process is not unique to HlyA but is observed by many other pore-forming proteins including complement-induced haemolysis. ...[more]

PMID: 28428949

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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, P2X₄, and P2X₇ Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by ?-Haemolysin Producing Escherichia coli.

Publications

P2X<sub>1</sub>, P2X<sub>4</sub>, and P2X<sub>7</sub> Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing <i>Escherichia coli</i>.

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Dataset Information

P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by ?-Haemolysin Producing Escherichia coli.

Publications

P2X<sub>1</sub>, P2X<sub>4</sub>, and P2X<sub>7</sub> Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing <i>Escherichia coli</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

P2X₁, P2X₄, and P2X₇ Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by ?-Haemolysin Producing Escherichia coli.