Role for intracellular platelet‐activating factor in the circulatory failure in a model of Gram‐positive shock

Abstract

This study investigates the effects of two structurally different antagonists of platelet‐activating factor (PAF), BN52021 and WEB2086, on the circulatory and renal failure elicited by lipoteichoic acid (LTA) from Staphylococcus aureus (an organism without endotoxin) in anaesthetized rats. Administration of LTA (10 mg kg−1, i.v.) caused hypotension and vascular hyporeactivity to noradrenaline (1 μg kg−1, i.v.). WEB2086 (5 mg kg−1, i.v., 20 min before and 150 min after LTA) inhibited the delayed fall in mean arterial blood pressure (at 300 min: 99 ±6 mmHg vs. 75 ±6 mmHg, P<0.01) and prevented the decrease in pressor response to noradrenaline (at 300 min: 36 ±5 mmHg min vs. 17±5 mmHg min, P<0.01). Surprisingly, BN52021 (20 mg kg−1, i.v., 20 min before and 150 min after LTA) neither prevented the hypotension (74±6 mmHg) nor the vascular hyporeactivity (21±5 mmHg min). However, BN52021 inhibited the hypotension to injections of PAF as well as the circulatory failure elicited by lipopolysaccharides (10 mg kg−1, i.v.). LTA caused an increase in plasma concentration of creatinine from 39±5 μm (sham‐operated) to 70±8 μm and urea from 4.7±0.1 to 13.1±1.6 mM. The renal failure elicited by LTA was significantly inhibited by WEB2086 (creatinine: 45±4 μm and urea: 5.7±0.7 mM), but not by BN52021. The induction of nitric oxide synthase activity in lungs by LTA was attenuated by WEB2086 from 98±17 to 40±15 pmol L‐citrulline 30 min−1 mg−1 protein (P<0.01), but not by BN52021 (148±21 pmol L‐citrulline 30 min−1 mg−1 protein). Similarly, WEB2086, but not BN52021, inhibited the increase in plasma nitrite concentration associated with the delayed circulatory failure caused by LTA. The release of tumour necrosis factor‐α (TNF‐α) after injection of LTA was not attenuated by WEB2086. The induction of nitrite release by cultured macrophages activated with LTA (10 μg ml−1 for 24 h) was inhibited by 74±4% by WEB2086 (3times10−4 m), but not by BN52021, indicating that only WEB2086 acts on intracellular PAF receptors. Thus, the intracellular release of PAF contributes to the circulatory and renal failure and induction of nitric oxide synthase elicited by LTA in anaesthetized rats. The difference between the two structurally different PAF antagonists in our septic shock models using either LTA or lipopolysaccharide (LPS), shows the importance of models for Gram‐positive sepsis in the elucidation of the pathophysiology of septic shock and for the evaluation of potential drugs.

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

“…The abscissa-time after introduction of LTA; the ordinate-changes in biochemical parameters Analysis of the biochemical parameters of blood after LTA addition, in contrast to LPS challenge, revealed less drastic deviations from the control values for the most parameters monitored. These results corroborate the conclusion of De Kimpe et al, who stated that LTA-induced sepsis is rarely accompanied by MODS, as opposed to sepsis induced by Gram-negative bacteria (LPS;De Kimpe et al 1995).…”

“…10c), which indicates acute kidney dysfunction, and was typical for bacterial infection (De Kimpe et al 1995). Prophylactic administration of rHsp70 turned out to be not effective in ameliorating subsequent creatinine increases induced by LTA induction (Fig.…”

“…Intravenous administration of bacterial cell wall components into animals is a widely used model of sepsis (De Kimpe et al 1995;Zanotti-Cavazzoni and Goldfarb 2009). This approach enables the investigation of both the early processes of sepsis development and the initial response of target cells to the pathogens used.…”

Suppression of lipopolysaccharide-induced nitric oxide synthase expression by platelet-activating factor receptor antagonists in the rat liver and cultured rat kupffer cells

“…16,17 PAF, when administered exogenously to animal models, mimics several pathophysiological responses observed after endotoxin exposure including hypotension, cardiac failure, and tissue necrosis. [17][18][19] Our laboratory has observed previously that infusion of LPS into a perfused rat liver for 2 minutes results in elevated tissue levels of PAF (Duffy-Krywicki R, Olson MS, unpublished data). Elevated levels of PAF in the liver cause marked changes in glycogenolysis and vasoconstriction.…”

Responses of microglia in vitro to the gram-positive bacterial component, lipoteichoic acid

“…In gram-positive sepsis, murine macrophages produce considerable amounts of nitric oxide (NO) through expression of inducible nitric oxide synthase (iNOS) when treated with lipoteichoic acid (LTA), a cell wall component of gram-positive organisms such as Staphylococcus aureus (Cunha et al, 1993). Large amounts of NO have been implicated in the genesis of septic and cytokine-induced circulatory shock (Thiemermann and Vane, 1990;Kilbourn and Griffith, 1992) that was also caused by the increase of LTA-induced NO formation (De Kimpe et al, 1995). In the central nervous system (CNS), NO was released from activated microglia after induction of iNOS (Chao et al, 1992;Murphy et al, 1993) in different modes of injury and diseases.…”