The protective effect of alpha-lipoic acid on ventilator and lipopolysaccharide-induced lung injury in rats

Autor: Yu-Chien Kung, 龔育千
Rok vydání: 2010
Druh dokumentu: 學位論文 ; thesis
Popis: 98
Mechanical ventilation (MV) is an important therapeutic technique for patients with respiratory failure. However, an inappropriate or long time tidal volume used may cause lung injury, which may be the consequence of inflammatory response to mechanical ventilation, named ventilator-induced lung injury (VILI). Previous reports have demonstrated that MV alone with low and moderate tidal volume, may not cause lung injury. However, when ventilator combined with various pro-inflammatory compounds, including lipopolysaccharide (LPS), hydrochloric acid or oleic acid, the VILI may occur. Additionally, there were several studies indicate that increased free radical formation play a critical role in the pathogenesis of VILI. Therefore, reducing reactive oxygen species (ROS) may ameliorate the damage of the lung tissues. Alpha-lipoic acid (ALA), a naturally occurring antioxidant and a cofactor of mitochondrial respiratory enzyme, was reported to improve various diseases with high oxidative stress. The aim of this study was to investigate the effect of ALA on ventilator and LPS-induced lung injury, and further elucidated the mechanisms involved. In this study, the VILI model was established by using as intratracheal instillation of LPS (2 mg/kg) followed by VT=20 ml/kg at 60 breaths per min in rats. Rats were pretreated with ALA (25-100 mg/kg, i.p.) one hour before treatment with LPS and MV, and rat were sacrificed at 3 hours after LPS and MV treatment. ALA (100 mg/kg) significantly reduced protein concentration, total cell count, and TNF-α, IL-6, IL-1β, and MIP-2 levels in bronchoalveolar lavage fluid (BALF). Wet/dry ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA), and COX-2 protein expression in lung, accompanied by significantly improvement of the pathological changes of lung tissue. In addition, ALA (100 mg/kg) significantly diminished superoxide (O2·–) formation and inhibited iNOS, XBP1, ASK1, p38, CHOP, caspase-3 gene expression but upregulated HO-1, GRP78 expression in lung tissue, accompanied by reduced apoptosis. In conclusion, we demonstrate for the first time that treatment with ALA (100 mg/kg) exerts a beneficial effect in ventilator and LPS-induced lung injury through decrease of proinflammatory mediators formation, but enhancement of HO-1 and GRP78 gene expression, subsequently leading to attenuation of apoptosis.
Databáze: Networked Digital Library of Theses & Dissertations
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