Bassett D J, Elbon C L, Ishii Y, Yang H, Otterbein L, Boswell G A, Kerr J S
Wayne State University, Detroit, Michigan 48202.
Toxicol Appl Pharmacol. 1994 Jul;127(1):76-82. doi: 10.1006/taap.1994.1141.
Pretreatment with the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has previously been shown to reduce polymorphonuclear leukocyte (PMN) infiltration into the airways of ozone-exposed rats. The present study further examined the effects of 1 and 2 days EDU pretreatment on rat lung inflammatory responses by determining PMN infiltration in response to intratracheal instillation with the chemoattractant formyl-norleucine-leucine-phenylalanine (fNLP). Maximal recovery of PMNs by bronchoalveolar lavage was observed 4 hr after fNLP instillation with no alteration in the numbers of recoverable macrophages and lymphocytes. Although 1-day pretreatment with EDU did not affect PMN recovery from fNLP-instilled rat lungs, 2 days of EDU pretreatment prevented PMN infiltration as indicated by PMN recoveries that were similar to those obtained from saline-instilled lungs. Measurements of lung-marginated and interstitial pools of inflammatory cells using collagenase tissue digestion demonstrated no effect of 2 days EDU pretreatment. Although 2 days EDU pretreatment alone did not alter blood PMN content, lung permeability, and the lavage recoveries of inflammatory cells, blood PMN responses to chemotactic stimuli in vitro were impaired. In addition, EDU was shown to directly inhibit PMN chemotaxis and superoxide anion generation in vitro. These data demonstrated that EDU acts by interfering with PMN activation and migration rather than by decreasing PMN availability. EDU, by modulating the inflammatory response, represents a useful compound for preventing PMN-associated amplification of acute lung injuries.
先前的研究表明，用杂环化合物EDU（N-[2-(2-氧代-1-咪唑啉基)乙基]-N'-苯基脲）进行预处理可减少多形核白细胞（PMN）向暴露于臭氧的大鼠气道内浸润。本研究通过测定气管内滴注趋化剂甲酰基-正亮氨酸-亮氨酸-苯丙氨酸（fNLP）后PMN的浸润情况，进一步研究了EDU预处理1天和2天对大鼠肺部炎症反应的影响。在滴注fNLP后4小时观察到支气管肺泡灌洗法回收的PMN达到最大值，可回收的巨噬细胞和淋巴细胞数量没有变化。虽然用EDU预处理1天不影响从滴注fNLP的大鼠肺中回收PMN，但EDU预处理2天可防止PMN浸润，这可通过与从滴注生理盐水的肺中获得的PMN回收率相似来表明。使用胶原酶组织消化法测量肺边缘和间质炎症细胞池表明，EDU预处理2天没有影响。虽然单独用EDU预处理2天不会改变血液中PMN含量、肺通透性以及炎症细胞的灌洗回收率，但体外血液中PMN对趋化刺激的反应受损。此外，EDU在体外可直接抑制PMN趋化和超氧阴离子生成。这些数据表明，EDU的作用是干扰PMN的激活和迁移，而不是减少PMN的数量。通过调节炎症反应，EDU是一种预防PMN相关急性肺损伤放大的有用化合物。
