1 Department of Anesthesiology, Union Hospital and 2 Department of Child and Adolescent Health and Maternal Care, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
*Corresponding author. Email: gaoju_003@163.com
Accepted for publication: September 24, 2003
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Abstract |
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Methods. Seventy-six male Wistar rats were randomly assigned to one of five groups: (i) saline control; (ii) endotoxin alone (receiving lipopolysaccharide (LPS) 8 mg kg1 i.v.); (iii) pretreatment with propofol 1 h before LPS; (iv) simultaneous treatment with propofol and LPS; (v) post-treatment with propofol 1 h after LPS. During the 5 h after LPS injection, survival rates were recorded. Lung tissue was sampled to measure values of nitrite/nitrates (NO2/NO3) and tumour necrosis factor (TNF)- in bronchoalveolar lavage (BAL) fluid, and wet-to-dry lung weight ratio, pulmonary permeability index, BAL protein and expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT).
Results. Compared with the endotoxaemic group, both the pre- and simultaneous treatment groups showed significantly improved 5 h survival rates, and attenuated endotoxin-induced increased BAL fluid NO2 /NO3 and TNF-, iNOS mRNA and NT expression in lung tissue, and decreased pulmonary microvascular permeability. These beneficial effects were blunted in the post-treatment group.
Conclusions. These findings indicate that early administration of propofol may provide protective effects against endotoxin-induced acute lung injury.
Br J Anaesth 2004; 92: 2779
Keywords: anaesthestics i.v., propofol; complications, acute lung injury; complications, endotoxaemia; pharmacology, nitric oxide; toxicity, peroxynitrite
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Introduction |
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Methods and results |
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After an i.p. injection of pentobarbital sodium 30 mg kg1, 76 adult pathogen-free male Wistar rats were randomly assigned to one of five groups: (i) control group (n=8), receiving saline only; (ii) endotoxaemic group (n=17), receiving an i.v. bolus injection of lipopolysaccharide (LPS, O55:B5, Sigma Chemical, St Louis, MO, USA) 8 mg kg1; (iii) pretreatment group; (iv) simultaneous treatment group and (v) post-treatment group (all n=17). Endotoxin was used as for the endotoxaemic group. Propofol 5 mg kg1 i.v. bolus followed by infusion at 10 mg kg1 h1 up to 5 h after LPS injection was given 1 h before, simultaneously with or 1 h after the injection of LPS in the pretreatment, simultaneous treatment and post-treatment groups, respectively. During the 5 h after LPS injection, survival rates were recorded. The rats were killed 5 h after LPS injection. Lung injury was evaluated by measuring the following parameters: (i) concentrations of nitrites/nitrates (NO2/NO3) and tumour necrosis factor (TNF)- concentrations in bronchoalveolar lavage fluid (BALF); (ii) protein concentration in BALF (BALFprot), wet-to-dry lung weight ratio (W/D), pulmonary permeability index (PPI) as indicators of high pulmonary vascular permeability; (iii) nitrotyrosine (NT) Western blot and iNOS mRNA expression in lung tissue.
Statistical analyses were performed by one-way ANOVA followed by Bonferroni post hoc test. Comparisons between survival rates were made with KaplanMeier analysis. A value of P<0.05 was considered significant.
Compared with the endotoxaemic group, both the pre- and simultaneous treatment groups showed significantly decreased BALF NO2/NO3 and TNF- and BALFprot concentrations, W:D and PPI values (P<0.05) (Table 1), and attenuated endotoxin-induced increased NT expression (Fig. 1) and iNOS mRNA (data not shown). These beneficial effects were blunted in the post-treatment group. In propofol-treated groups, especially the pretreatment group, there was an improvement in 5 h survival rates (P<0.05). Survival rates 5 h after LPS injection were 100%, 35.3%, 88.2%, 76.5% and 58.8% for the control, endotoxaemic, pretreatment, simultaneous treatment and post-treatment groups, respectively.
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Comment |
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Studies in vitro have reported that propofol protects endothelial cells against the toxicity of peroxynitrite and reduces NT in bronchial cells exposed to NO itself.8 9 Our present study demonstrates that, in an endotoxin model, early treatment (including both pre- and simultaneous treatment) with propofol significantly attenuates endotoxin-induced increased expression of lung peroxy nitrite and iNOS mRNA, as well as NO and TNF- production. Reduced NO production caused by down-regulation of mRNA expression for iNOS would contribute to a decrease in peroxynitrite generation in our current study. Values of W:D, PPI and BALFprot, which were used as indicators of pulmonary microvascular permeability, were decreased significantly in the pre- and simultaneous-treatment groups. Backman and colleagues10 showed that peroxynitrite infusion into a rabbit lung increased capillary permeability and lung weight, consistent with a pathogenic role for peroxynitrite in lung injury. Our findings suggest that the protective effects of early propofol treatment on endotoxin-induced endothelial barrier dysfuction and high microvascular permeability is caused, at least in part, by suppression of iNOS-NO-peroxynitrite dependent pathway. In contrast, the attenuation of endotoxin-induced ALI is reduced with propofol 1 h after LPS treatment. In addition, it has been reported that attenuation of TNF-
and NO production may improve the high mortality rate in septic shock. In this study, we present evidence that early treatment of LPS-exposed rats with propofol dramatically improved 5 h survival rates. These findings suggest that the improved mortality is associated with propofols suppression of TNF-
and NO production in animals with endotoxic shock.
Collectively, propofol can inhibit the production of pro-inflammatory cytokines, and appears to be an iNOS inhibitor and a peroxynitrite and free-radical scavenger. Through these mechanisms, propofol may attenuate endotoxin-induced ALI.
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References |
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