Teixeira M M, Doenhoff M J, McNeice C, Williams T J, Hellewell P G
Department of Applied Pharmacology, National Heart and Lung Institute, London, United Kingdom.
J Immunol. 1993 Nov 15;151(10):5525-34.
Penetration of skin by cercariae of Schistosoma mansoni is associated with a local inflammatory response characterised by leukocyte accumulation and tissue swelling. The significance of the inflammation and its relevance to infection of the host is unknown. In this study, we have investigated the mechanisms of the local inflammatory response induced by injecting extracts of Schistosoma mansoni cercariae into guinea pig skin. Intradermal injection of cercarial homogenate or cercarial transformation fluid induced a dose-dependent increase in local edema formation and accumulation of intravenously injected 111In-labeled eosinophils and neutrophils. The responses were rapid in onset and independent of new protein synthesis. The capacity of extracts to induce edema formation and leukocyte accumulation correlated significantly with their proteolytic activity. In addition, extract-induced inflammation was reduced by co-injection with Trasylol, soybean trypsin inhibitor, PMSF, or heparin. A combination of PMSF and heparin virtually abolished extract-induced inflammation. The known inhibitory effect of Trasylol on kallikrein prompted an investigation into the role of kinins in inducing local edema formation. The bradykinin antagonist HOE 140 substantially reduced extract-induced edema whereas bradykinin itself was weak at inducing leukocyte accumulation. The cyclooxygenase inhibitor ibuprofen, the platelet-activating factor antagonist WEB 2086, and the 5-lipoxygenase inhibitor PF5901 had no effect on edema formation. In contrast, extract-induced eosinophil accumulation was reduced by WEB 2086 and PF5901, suggesting that endogenous PAF and leukotriene B4 were involved in recruiting these cells to inflammatory sites. Thus, cercarial proteases induce a local inflammatory response in guinea pig skin that can be attributed, in part, to known mediators of inflammation. It remains to be established whether the response is protective for the host or whether it is beneficial for the parasite. Further understanding of the underlying mechanisms may provide a target for the pharmacologic control of infection in schistosomiasis.
曼氏血吸虫尾蚴穿透皮肤与以白细胞聚集和组织肿胀为特征的局部炎症反应相关。这种炎症的意义及其与宿主感染的相关性尚不清楚。在本研究中，我们调查了将曼氏血吸虫尾蚴提取物注射到豚鼠皮肤中诱导局部炎症反应的机制。皮内注射尾蚴匀浆或尾蚴转化液可导致局部水肿形成以及静脉注射的¹¹¹铟标记嗜酸性粒细胞和中性粒细胞聚集呈剂量依赖性增加。反应起效迅速且与新蛋白质合成无关。提取物诱导水肿形成和白细胞聚集的能力与其蛋白水解活性显著相关。此外，与抑肽酶、大豆胰蛋白酶抑制剂、苯甲基磺酰氟（PMSF）或肝素共同注射可减少提取物诱导的炎症。PMSF和肝素的组合几乎完全消除了提取物诱导的炎症。抑肽酶对激肽释放酶的已知抑制作用促使我们研究激肽在诱导局部水肿形成中的作用。缓激肽拮抗剂HOE 140可显著减少提取物诱导的水肿，而缓激肽本身在诱导白细胞聚集方面作用较弱。环氧化酶抑制剂布洛芬、血小板活化因子拮抗剂WEB 2086和5-脂氧合酶抑制剂PF5901对水肿形成无影响。相反，WEB 2086和PF5901可减少提取物诱导的嗜酸性粒细胞聚集，表明内源性血小板活化因子和白三烯B4参与将这些细胞募集到炎症部位。因此，尾蚴蛋白酶在豚鼠皮肤中诱导局部炎症反应，这在一定程度上可归因于已知的炎症介质。该反应对宿主是否具有保护作用或对寄生虫是否有益仍有待确定。对潜在机制的进一步了解可能为血吸虫病感染的药物控制提供靶点。
