Wallace J L, McKnight W, Miyasaka M, Tamatani T, Paulson J, Anderson D C, Granger D N, Kubes P
Gastrointestinal Research Group, University of Calgary, Alberta, Canada.
Am J Physiol. 1993 Nov;265(5 Pt 1):G993-8. doi: 10.1152/ajpgi.1993.265.5.G993.
A number of recent studies have demonstrated that neutrophil adherence to the vascular endothelium is a critical early event in the pathogenesis of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Although a role in this process for the leukocyte adhesion molecule, CD11/CD18, has been demonstrated, the involvement of endothelial adhesion molecules has not previously been examined. Therefore, using monoclonal antibodies directed against a number of endothelial adhesion molecules (ICAM-1, P-selectin, E-selectin), we studied the role of these molecules in the production of mucosal injury after indomethacin administration and in indomethacin-induced leukocyte adherence. As previously shown in the rabbit, anti-CD18 markedly reduced (by 75%) the severity of damage induced by indomethacin in the rat. Moreover, this antibody completely prevented indomethacin-induced leukocyte adherence. Similarly, anti-ICAM-1 significantly attenuated (by 74%) the severity of indomethacin-induced gastric injury while also markedly reducing leukocyte adherence (by 83%). Anti-P-selectin and anti-E-selectin produced only small (approximately 35%), but statistically significant, reductions of mucosal injury, but only anti-P-selectin significantly affected indomethacin-induced leukocyte adherence (by approximately 50%). These results demonstrate that indomethacin-induced leukocyte adherence and mucosal injury are dependent on the expression of CD18 and ICAM-1. P-selectin also appears to play a small, but important, role in these processes, whereas the role of E-selectin remains equivocal. These studies support the hypothesis that interactions at the leukocyte-endothelium interface are critical in the pathogenesis of NSAID-induced mucosal injury, and this interface may represent a rational target for therapies aimed at preventing this form of injury.
最近的一些研究表明，中性粒细胞与血管内皮的黏附是非甾体抗炎药（NSAIDs）诱导的胃黏膜损伤发病机制中的一个关键早期事件。尽管已证明白细胞黏附分子CD11/CD18在此过程中发挥作用，但内皮黏附分子的参与情况此前尚未得到研究。因此，我们使用针对多种内皮黏附分子（ICAM-1、P-选择素、E-选择素）的单克隆抗体，研究了这些分子在吲哚美辛给药后黏膜损伤产生以及吲哚美辛诱导的白细胞黏附中的作用。如先前在兔子中所示，抗CD18可显著降低（75%）吲哚美辛在大鼠中诱导的损伤严重程度。此外，该抗体完全阻止了吲哚美辛诱导的白细胞黏附。同样，抗ICAM-1可显著减轻（74%）吲哚美辛诱导的胃损伤严重程度，同时也显著减少白细胞黏附（83%）。抗P-选择素和抗E-选择素仅使黏膜损伤有小幅（约35%）但具有统计学意义的降低，但只有抗P-选择素显著影响吲哚美辛诱导的白细胞黏附（约50%）。这些结果表明，吲哚美辛诱导的白细胞黏附和黏膜损伤依赖于CD18和ICAM-1的表达。P-选择素在这些过程中似乎也发挥着较小但重要的作用，而E-选择素的作用仍不明确。这些研究支持了这样一种假说，即白细胞-内皮界面的相互作用在NSAIDs诱导的黏膜损伤发病机制中至关重要，并且该界面可能是旨在预防这种损伤形式的治疗的合理靶点。
