MONOCROTALINE PNEUMOTOXICITY IN MICE
MONOCROTALINE PNEUMOTOXICITY IN MICE
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DOI：
10.1007/bf02899076
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发表时间：
1989-01-01
期刊：
影响因子：
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通讯作者：
SOLLIDAY, NH
中科院分区：
文献类型：
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作者：
MOLTENI, A;WARD, WF;SOLLIDAY, NH
吡咯里西丁生物碱野百合碱诱导的大鼠肺损伤是一种公认的肺高压模型。然而，据我们所知，野百合碱引起的心肺损伤很少被描述，也从未在小鼠身上进行过量化。在本研究中，成年雄性小鼠每天饮用2.4、4.8或24.0 mg野百合碱/公斤体重，连续6周。这些剂量相当于大鼠严重肺部中毒方案的1倍、2倍和10倍。通过右肺血管紧张素转换酶(ACE)活性、纤溶酶原激活物(PLA)活性以及前列环素(PGI2)和血栓素A2(TXA2)的产生来监测肺内皮细胞功能。取左肺进行光镜和电子显微镜检查。右室/左室加室间隔重量比(RV/LV+S)评价心脏右室肥厚。野百合碱治疗的小鼠肺血管紧张素转换酶和聚乳酸活性呈剂量依赖性下降，PGI2和TXA2产生增加，表明内皮功能障碍。然而，这些反应只有在最高剂量的野百合碱之后才显著。光镜和电子显微镜显示剂量依赖的肺部炎症和渗出反应。然而，与之前在大鼠身上进行的研究不同，野百合碱治疗的小鼠出现相对较少的肺纤维化、心脏增大或右室肥大，而且即使在最高剂量水平，也没有出现阻塞性的肺动脉中层增厚。这些和以前的数据表明，就野百合碱的肺毒性而言，小鼠和大鼠之间存在定量、生化和定性的形态差异。此外，在野百合碱治疗的小鼠(而不是大鼠)中，一方面肺内皮细胞功能障碍和炎症之间似乎存在分离，另一方面在肺高压和纤维化之间似乎存在分离。
Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.