We used a CLP model of sepsis for the following reasons: it is reproducible and more comparable with human surgical sepsis; apoptosis of selected cell types and host immune responses seem to mimic the course of human sepsis [28]; and it is considered a good model for abdominal sepsis therapy research selleck chem SB203580 [28-30].In our study, a single 0.75 g/kg dose of iv Gln was used as it resulted in a plasma Gln level of 3 to 7 mM/L in a model of endotoxemia [4]. This dose of Gln was found to markedly enhance HSP expression in lung attenuate proinflammatory cytokine release [4,11], and improve survival after endotoxemia [4,12,17].In the present study, Gln led to a reduction in neutrophil infiltration, interstitial oedema, and alveolar collapse (Table (Table1),1), as well as a repair in alveolar capillary membrane (Figure (Figure22 and Table Table2)2) yielding an improvement in oxygenation, lung Est, ��P1, and ��P2 (Figure (Figure1).
1). The beneficial effects of iv Gln on pulmonary inflammation in experimental models of sepsis have been previously reported [11-13,17], but not directly related to gas-exchange and lung mechanics. Furthermore, no prior study has analysed the impact of Gln on the repair of the alveolar capillary membrane through electron or confocal microscopy. Therefore, the beneficial effects of Gln on lung parenchymal structure result in the improvement in clinical parameters (lung mechanics and gas exchange) which may lead to a less injurious setting of mechanical ventilation.We also observed that Gln reduced in vivo epithelial cell apoptosis in lung, small intestine villi, kidney, and liver (Table (Table3).
3). Emerging in vitro evidence showed that Gln deprivation may influence cell survival and gene expression [15,31-33]. Additionally, the effects of Gln on epithelial cell apoptosis have been studied mainly in intestinal [32-34] but not in lung cells. A recent in vitro study demonstrated that in intestinal cells, the role of extracellular signal-regulated kinase pathway in Gln-mediated prevention of cellular apoptosis following stress or injury [33]. The phosphoinositide-3 kinase/Akt pathway appears to be activated during periods of Gln starvation, which may serve as a protective mechanism to limit apoptosis associated with cell stress [34]. Additionally, other factors have been variably implicated in Gln-dependent survival signalling [15].
To date, no other studies have shown in vivo distal organ apoptosis after iv Gln therapy in sepsis.Pro-inflammatory Anacetrapib cytokines are primarily responsible for initiating an effect against exogenous pathogens. However, excessive production of these mediators may significantly contribute to shock and multiple organ failure [21]. In contrast, anti-inflammatory cytokines are crucial for down regulating the incremented inflammatory process and maintaining homeostasis for the correct function of vital organs.