Résumé
Pulmonary fibrosis is the end stage of a heterogeneous group of disorders of known and unknown etiology. One of the clinically important causative agents in pulmonary fibrosis is bleomycin [BLM]. Silymarin is an old herbal remedy known to protect a cell membrane against xenobiotic injury principally due to its antioxidant potential. Melatonin, which is the chief secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. The antioxidant, N-acetylcysteine [NAC], has shown beneficial effects in diseases in which reactive oxygen species appear to be involved. The aim of the present study was to assess and compare the protective effect of orally administered silymarin, melatonin, or N-acetylcysteine on lung injury induced in rat model by endotracheal instillation of BLM. Fifty six animals were divided into: group I [control group] [n=24] which were equally subdivided into IA [vehicle and intratracheal saline]; IB [silymarin and intratracheal saline]; IC [melatonin and intratracheal saline]; ID [NAC and intratracheal saline]. Group II [treatment group] [n=32]: which were equally subdivided into IIA [vehicle and intratracheal BLM]; IIB [silymarin and intratracheal BLM]; IIC [melatonin and intratracheal BLM]; IID [NAC and intratracheal BLM]. silymarin was taken in a dose of 50 mg/kg/day suspended in 2% gum acacia mucilage. Melatonin was administered in a dose of 10 mg/kg/day. NAC was given in a dose of 486.6 mg/kg/ day. Treatments were administered orally for 14 days after the day of BLM or saline instillation. Animals received endotracheally a single dose of BLM hydrochloride [5 mg/kg body weight] to produce pulmonary fibrosis. Bronchoalveolar lavage fluid [BALF] was used to measure total protein concentration, lactate dehydrogenase [LDH] activity, and total glutathione levels. Lung tissue homogenates were used to measure myeloperoxidase [MPO] activity, lipid peroxide [LPO] content, and total lung collagen. The body weight of rats not exposed to BLM increased with time. Rats in group IIA failed to gain weight during the first week; thereafter weight gain paralleled that observed in rats not exposed to BLM. A similar but less marked trend was noticed for treated rats. Bleomycin produced a significant increase in lung weight. Treatment with silymarin, melatonin, or NAC decreased lung weight but statistical significance was not reached. The lung hydroxyproline levels were increased in BLM-instilled rats [group IIA] but significantly deceased on treatment with silymarin, melatonin, or NAC. The total cell count and neutrophil cell count in BALF were significantly increased in BLM-exposed rat group. On the contrary of melatonin and NAC, treatment with silymarin significantly decreased these elevated cell counts. The elevated protein concentration in BALF due to the effect of BLM instillation was not reduced by treatment with any of the drugs used. Treatment with silymarin, melatonin, or NAC significantly attenuated the increased LDH activity following BLM instillation. Bleomycin was shown to reduce glutathione levels in the lung. Treatment with silymarin, melatonin, or NAC resulted in a significant increase of glutathione in BALF. Silymarin, but not melatonin or NAC significantly attenuated the increase in lung MPO activity following BLM instillation. The lipid peroxide content in the lung was significantly increased in BLM instilled rats. Treatment with silymarin, melatonin, or NAC attenuated this elevated peroxidation. We conclude that treatment with silymarin inhibit lung fibrotic progression induced by BLM. The decreased neutrophil recruitment to the lung, attenuation of cell damage and the antioxidant properties of silymarin may be involved in its protective mechanism against pulmonary fibrosis. Melatonin also exerts protection against BLM- induced pulmonary fibrosis, probably by suppressing oxidative stress. Treatment with oral NAC is partially effective against lung fibrosis which may be due to replenishment of lung glutathione or reduction of damage to lung structure in the early stage of the disease