Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice
Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice
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DOI：
10.1164/ajrccm.162.1.9903129
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发表时间：
2000-07-01
影响因子：
24.7
通讯作者：
Kitamura, S
中科院分区：
文献类型：
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作者：
Hagiwara, S;Ishii, Y;Kitamura, S
活性氧在肺纤维化的发病机制中起重要作用。我们以前证明，N-乙酰半胱氨酸（NAC），抗氧化剂，抑制粘附分子的表达和细胞因子的产生在肺细胞。当NAC被吸入肺泡腔时，预期其直接与炎性细胞相互作用并提高上皮衬里液中的谷胱甘肽水平。因此，我们研究了吸入NAC是否抑制博莱霉素（BLM）诱导的肺纤维化。雄性ICR小鼠单次静脉注射BLM（150 mg/kg）。用超声雾化器吸入NAC（70 mg/ml）或生理盐水30 ml，每日2次，共28 d。在炎症阶段（第7天），NAC给药减弱了支气管肺泡灌洗液（BALF）和肺泡组织中的细胞浸润。第28天，与仅BLM组相比，吸入NAC组中根据Aschroft标准估计的纤维化变化和羟脯氨酸含量显着降低（p < 0.05）。BALF中的CXC趋化因子、巨噬细胞炎性蛋白-2（MIP-2）、嘌呤诱导的中性粒细胞趋化因子（KC）和CC趋化因子、巨噬细胞炎性蛋白-1 α（MIP-1 α）在第7天仅BLM组中大多升高;然而，这些升高被NAC吸入显著抑制（p < 0.05）。还定量了BALF中的脂质过氧化氢（LPO）。在仅BLM组中，LPO在第3天显著增加，并且这种增加被NAC吸入显著降低（p < 0.05）。这些结果表明，雾化NAC通过抑制趋化因子和LPO的产生来改善由BLM注射诱导的急性肺部炎症，从而导致随后的肺纤维化的减弱。这些发现仅限于BLM诱导的肺纤维化动物模型。然而，NAC吸入有望成为其他间质性肺炎患者的潜在治疗方法，因为ROS参与了大多数间质性肺炎肺损伤的发病机制。
Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary fibrosis. We previously demonstrated that N-acetylcysteine (NAC), an antioxidant, inhibited adhesion molecule expression and cytokine production in lung cells. When NAC is inhaled into the alveolar space, it is expected to directly interact with inflammatory cells and to elevate glutathione levels in the epithelial lining fluids. We therefore examined whether inhaled NAC inhibits lung fibrosis induced by bleomycin (BLM). Male ICR mice were given a single intravenous injection of BLM (150 mg/kg). Thirty milliliters of NAC (70 mg/ml) or saline were inhaled twice a day for 28 d using an ultrasonic nebulizer. In the inflammatory phase (Day 7), NAC administration attenuated the cellular infiltration in both bronchoalveolar lavage fluid (BALF) and alveolar tissues. At Day 28, the fibrotic changes estimated by Aschroft's criteria and hydroxyproline content in the NAC inhalation group were significantly decreased compared with the BLM-only group (p < 0.05). CXC chemokines, macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant (KC), and CC chemokines, macrophage inflammatory protein-1 alpha (MIP-1 alpha), in BALF were mostly elevated on Day 7 in the BLM-only group; however, these elevations were significantly repressed by NAC inhalation (p < 0.05). Lipid hydroperoxide (LPO) was also quantified in BALF. LPO was markedly increased on Day 3 in the BLM-only group, and this increase was significantly decreased by NAC inhalation (p < 0.05). These results revealed that aerosolized NAC ameliorated acute pulmonary inflammation induced by BLM injection via the repression of chemokines and LPO production, resulting in the attenuation of subsequent lung fibrosis. These findings are limited to the BLM-induced lung fibrosis animal model. However, NAC inhalation will be expected to be a potential therapy for patients with other interstitial pneumonias because ROS are involved in the pathogenesis of lung injury in most interstitial pneumonia.