Hellewell P G, Young S K, Henson P M, Worthen G S
Department of Medicine and Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado.
Am J Respir Crit Care Med. 1995 Apr;151(4):1218-27. doi: 10.1164/ajrccm/151.4.1218.
Evidence exists to suggest that the local accumulation of neutrophils in pulmonary inflammation occurs by a different mechanism than in other microvascular beds. In the present study, this suggestion was investigated using the nonsteroidal antiinflammatory drug ibuprofen. This drug was used because in addition to inhibiting cyclooxygenase, it prevents several aspects of neutrophil function, including adhesion. Local inflammation in the lung and skin of the same rabbits was induced by the administration of C5a, and the effect of intravenous injection of ibuprofen on the accumulation of neutrophils at these two sites was examined. In the skin, neutrophil accumulation was inhibited by ibuprofen, and this appeared to be independent of cyclooxygenase blockade. A possible mechanism was prevention of neutrophil adherence to endothelium in postcapillary venules, and in vitro experiments showed that ibuprofen could entirely prevent neutrophil adherence, in addition to suppressing azurophil granule secretion and superoxide anion generation. However, the effect on adherence appeared to be independent of expression of the CD11/CD18 adhesion complex on the neutrophil. By contrast, in the pulmonary circulation of the same rabbit, C5a-induced neutrophil accumulation was enhanced by ibuprofen treatment. This was suggested to result from the prevention of thromboxane production, which normally serves to decrease local pulmonary blood flow to diminish delivery of neutrophils to the inflammatory site. Ibuprofen had no effect on retention of neutrophils in filters (models of pulmonary capillaries), suggesting that the drug was not enhancing the retention of neutrophils in capillaries on the first pass through the lung. Thus, it was possible that enhancement in the lung was caused by an increase in neutrophil supply. Because the accumulation of neutrophils in the skin is known to be dependent on the adherence phenomena, the paradoxic effects of ibuprofen on inflammation suggest that mechanisms responsible for the accumulation of neutrophils in cutaneous and pulmonary microcirculations are different.
有证据表明，肺部炎症中嗜中性粒细胞的局部聚集是通过一种与其他微血管床不同的机制发生的。在本研究中，使用非甾体抗炎药布洛芬对这一观点进行了研究。使用这种药物是因为它除了抑制环氧化酶外，还能阻止嗜中性粒细胞功能的多个方面，包括黏附。通过给予C5a诱导同一只兔子的肺部和皮肤发生局部炎症，并检查静脉注射布洛芬对这两个部位嗜中性粒细胞聚集的影响。在皮肤中，布洛芬抑制了嗜中性粒细胞的聚集，这似乎与环氧化酶的阻断无关。一种可能的机制是阻止嗜中性粒细胞黏附于毛细血管后微静脉的内皮细胞，体外实验表明，布洛芬除了抑制嗜天青颗粒分泌和超氧阴离子生成外，还能完全阻止嗜中性粒细胞黏附。然而，对黏附的影响似乎与嗜中性粒细胞上CD11/CD18黏附复合物的表达无关。相比之下，在同一只兔子的肺循环中，布洛芬治疗增强了C5a诱导的嗜中性粒细胞聚集。这被认为是由于阻止了血栓素的产生，血栓素通常会减少局部肺血流量，从而减少嗜中性粒细胞向炎症部位的输送。布洛芬对嗜中性粒细胞在滤器（肺毛细血管模型）中的滞留没有影响，这表明该药物在首次通过肺部时并没有增强嗜中性粒细胞在毛细血管中的滞留。因此，肺部的增强可能是由于嗜中性粒细胞供应增加所致。由于已知皮肤中嗜中性粒细胞的聚集依赖于黏附现象，布洛芬对炎症的反常作用表明，皮肤和肺微循环中嗜中性粒细胞聚集的机制是不同的。
