Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.
Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.
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DOI：
10.1186/1465-9921-7-137
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发表时间：
2006-11-21
影响因子：
5.8
通讯作者：
Vancheri C
中科院分区：
文献类型：
--
作者：
Failla M;Genovese T;Mazzon E;Gili E;Muià C;Sortino M;Crimi N;Caputi AP;Cuzzocrea S;Vancheri C
特发性肺纤维化中白三烯局部增高。此外，通过使用不同的基因敲除设置，这些花生四烯酸代谢物在动物博来霉素肺纤维化模型中的作用已经得到了彻底的表征。我们通过比较野生型小鼠与5-脂氧合酶抑制剂zileuton和cys-白三烯受体拮抗剂MK-571对白三烯活性的抑制作用，研究了白三烯活性在博莱霉素诱导的肺损伤中的作用。小鼠气管内给予博来霉素或生理盐水，每天给予1 mg/Kg剂量的MK-571或50 mg/Kg剂量的zileuton。博来霉素给药1周后，行BAL细胞计数、van Gieson胶原染色肺组织和骨髓过氧化物酶、IL-1和TNF-α免疫组化分析。与WT小鼠相比，给予博来霉素后，MK-571和zileuton处理小鼠的肺损伤和炎症程度均有所降低，这表明：(i)体重减轻，（ii）死亡率，（iii）中性粒细胞肺浸润（髓过氧化物酶活性、BAL总数和差异细胞计数），（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。这是第一个表明白三烯活性的药理抑制减轻博莱霉素诱导的小鼠肺损伤的研究。鉴于我们的研究结果以及来自基因研究的结果，将这类药物用于治疗肺纤维化可能被认为是有意义的，肺纤维化仍然是医学治疗的主要挑战。
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.
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影响因子：
9.6
作者：
Green, FHY
通讯作者：
Green, FHY
影响因子：
3.1
作者：
Mazzon, E;Sautebin, L;Cuzzocrea, S
通讯作者：
Cuzzocrea, S
影响因子：
6.5
作者：
MENSING, H;CZARNETZKI, BM
通讯作者：
CZARNETZKI, BM
影响因子：
2.9
作者：
PHAN, SH;MCGARRY, BM;KUNKEL, SL
通讯作者：
KUNKEL, SL
DOI：
10.1164/ajrccm.165.2.2104050
发表时间：
2002-01-15
影响因子：
24.7
作者：
Peters-Golden, M;Bailie, M;Moore, BB
通讯作者：
Moore, BB