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Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury

机译:在博来霉素诱导的急性肺损伤动物模型中白三烯的药理抑制作用

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摘要

Leukotrienes are increased locally in idiopathic pulmonary fibrosis. Furthermore, a role for these arachidonic acid metabolites has been thoroughly characterized in the animal bleomycin model of lung fibrosis by using different gene knock-out settings.We investigated the efficacy of pharmacological inhibition of leukotrienes activity in the development of bleomycin-induced lung injury by comparing the responses in wild-type mice with mice treated with zileuton, a 5-lipoxygenase inhibitor and MK-571, a cys-leukotrienes receptor antagonist.Mice were subjected to intra-tracheal administration of bleomycin or saline and were assigned to receive either MK-571 at 1 mg/Kg or zileuton at 50 mg/Kg daily. One week after bleomycin administration, BAL cell counts, lung histology with van Gieson for collagen staining and immunohistochemical analysis for myeloperoxidase, IL-1 and TNF-α were performed.Following bleomycin administration both MK-571 and zileuton treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i) loss of body weight, (ii) mortality rate, (iii) lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts), (iv) lung edema, (v) histological evidence of lung injury and collagen deposition, (vi) lung myeloperoxidase, IL-1 and TNF-α staining.This is the first study showing that the pharmacological inhibition of leukotrienes activity attenuates bleomycin-induced lung injury in mice. Given our results as well as those coming from genetic studies, it might be considered meaningful to trial this drug class in the treatment of pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.
机译:白三烯在特发性肺纤维化中局部增加。此外,通过使用不同的基因敲除设置,已在动物博来霉素肺纤维化模型中彻底表征了这些花生四烯酸代谢物的作用。我们研究了药理学抑制白三烯活性在由博来霉素诱导的肺损伤发展中的功效。比较野生型小鼠与接受5-leuoxygenase抑制剂齐留通和cys-leukotrienes受体拮抗剂MK-571治疗的小鼠的反应。对小鼠进行气管内施用博来霉素或生理盐水,并指定接受MK -571(每天1 mg / Kg)或齐留通(每天50 mg / Kg)。博来霉素给药后一周,进行BAL细胞计数,van Gieson肺组织学检查,胶原染色以及髓过氧化物酶,IL-1和TNF-α的免疫组织化学分析。博来霉素给药后,MK-571和齐留通治疗的小鼠表现出降低的程度。与WT小鼠相比,肺损伤和炎症表现为:(i)体重减轻;(ii)死亡率;(iii)中性粒细胞的肺浸润(髓过氧化物酶活性,BAL总细胞和分化细胞数),( iv)肺水肿,(v)肺损伤和胶原沉积的组织学证据,(vi)肺髓过氧化物酶,IL-1和TNF-α染色。这是第一个研究表明白三烯活性的药理学抑制作用减弱了博来霉素诱导的肺小鼠受伤。考虑到我们的研究结果以及来自遗传学研究的结果,在肺纤维化治疗中尝试此类药物可能被认为是有意义的,该疾病仍然是药物治疗的主要挑战。

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