N‐ACETYLCYSTEINE ABROGATES ACUTE LUNG INJURY INDUCED BY ENDOTOXIN

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Abstract
1 Acute lung injury (ALI) or acute respiratory distress syndrome is a serious clinical problem with high mortality. N‐Acetylcysteine (NAC) is an anti‐oxidant and a free radical scavenger. It has been reporeted recently that NAC ameliorates organ damage induced by endotoxin (lipopolysaccharide; LPS) in conscious rats. The present study was designed to evaluate the effects of NAC on LPS‐induced ALI and other changes in anaesthetized rats. 2 Sprague‐Dawley rats were anaesthetized with pentobarbital (40 mg/kg, i.p.). Endotracheal intubation was performed to provide artificial ventilation. Arterial pressure and heart rate were monitored. The extent of ALI was evaluated with the lung weight (LW)/bodyweight ratio, LW gain, exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). Haematocrit, white blood cells, plasma nitrate/nitrite, methyl guanidine (MG), tumour necrosis factor (TNF)‐a and interleukin (IL)‐1b were measured. Pathological changes in the lung were examined and evaluated. 3 Endotoxaemia was produced by injection of 10 mg/kg, i.v., LPS (Escherichia coli). Animals were randomly divided into three groups. In the vehicle group, rats received an i.v. drip of physiological saline solution (PSS) at a rate of 0.3 mL/h. The LPS group received an i.v. drip of PSS for 1 h, followed by LPS (10 mg/kg by slow blous injection, i.v., over 1–2 min). Rats in the LPS + NAC group received NAC by i.v. drip at a rate of 150 mg/kg per h (0.3 mL/h) for 60 min starting 10 min before LPS administration (10 mg/kg by slow blous injection, i.v., over 1–2 min). Each group was observed for a period of 6 h. 4 N‐Acetylcysteine treatment improved the LPS‐induced hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in LW changes, exhaled NO, PCBAL and lung pathology. In addition, NAC diminished the LPS‐induced increases in nitrate/nitrite, MG, TNF‐a and IL‐1b. 5 In another series of experiments, LPS increased the mortality rate compared with the vehicle group (i.v. drip of PSS at a rate of 0.3 mL/h) during a 6 h observation period. N‐Acetylcysteine, given 10 min prior to LPS, significantly increased the survival rate. 6 The results of the present study suggest that NAC exerts a protective effect on the LPS‐induced ALI. The mechanisms of action may be mediated through the reduction of the production of NO, free radicals and pro‐inflammatory cytokines.