Hydroxyethyl starch (130 kD) inhibits Toll-like receptor 4 signaling pathways in rat lungs challenged with lipopolysaccharide.

BACKGROUND

A number of studies have shown that hydroxyethyl starch (HES) solutions are able to down-regulate the expression of inflammatory mediators and inhibit neutrophil-mediated tissue injuries when they are used in patients with sepsis or other diseases with severe inflammatory responses. However, our knowledge about the underlying mechanisms is limited. Toll-like receptor 4 (TLR4) signaling has a pivotal role in inflammatory processes. In this study, we examined the possible involvement of TLR4 signaling in the antiinflammatory effects of HES.

METHODS

Male Sprague-Dawley rats were exposed to lipopolysaccharide (LPS) (10 mg/kg, IV) and received IV saline (30 mL/kg) or HES 130/0.4 (15 or 30 mL/kg). Six hours after LPS challenge, rats were killed and their lungs harvested. Lung injury was examined by hematoxylin and eosin staining. TLR4 mRNA expression, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 MAPK activation, and activator protein 1 (AP-1) activity in the lungs were detected with quantitative polymerase chain reaction, Western blotting, and electrophoretic mobility shift assay, respectively.

RESULTS

Compared with saline, HES profoundly attenuated the histological changes induced by LPS in the lungs at both dose levels. Molecular analysis showed that both 15 and 30 mL/kg HES significantly decreased TLR4 mRNA levels and inhibited activation of p38 MAPK and AP-1 in rats challenged with LPS, whereas activation of extracellular signal-regulated kinases 1/2 MAPK was not affected by either dose of HES.

CONCLUSIONS

These findings indicate that the beneficial effects of HES 130/0.4 on inflammation are mediated at least in part by inhibiting the TLR4/p38 MAPK/AP-1 pathway in lungs from rats challenged with LPS.