Robinson C E, Kottapalli V, D'Astice M, Fields J Z, Winship D, Keshavarzian A
Department of Medicine, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.
J Lab Clin Med. 1997 Dec;130(6):590-602. doi: 10.1016/s0022-2143(97)90109-8.
The mucosal injury of active ulcerative colitis (UC) could involve enhanced migration and activation of neutrophils (PMNs). Because, in vitro, PMNs from patients with UC appear normal and are not therefore a likely cause for the enhancements, we hypothesized an abnormal colonic milieu. We previously found that factors in the UC colonic milieu markedly increase production of reactive oxygen species (ROS) by control PMNs. We now hypothesize that these factors also regulate PMN surface integrins, that regulation of UC PMNs is different than that of control PMNs, and that the integrin regulation is consistent with the ROS regulation. Using rectal dialysis, we sampled the colonic milieu in patients with active UC, in patients with inactive UC, and in control subjects. We monitored a key PMN adhesion molecule, CD11b. When control PMNs were tested, active UC rectal dialysate was almost as effective (+115%) as N-formyl-methionyl-leucyl-phenylalanine (+132%) in up-regulating CD11b. When inactive UC PMNs were tested, baseline CD11b was 50% higher than that for control PMNs. In contrast, rectal dialysates failed to up-regulate CD11b of inactive UC PMNs and in fact down-regulated CD11b. Preincubating control PMNs with UC rectal dialysates converted their CD11b response to PMN activators from up-regulation to down-regulation, mimicking inactive UC PMNs. Changes in intracellular calcium levels paralleled these changes in CD11b. Rectal dialysate-induced changes in both CD11b and calcium paralleled our previous findings on rectal dialysate-induced changes in ROS production. Thus the net overall effect of factors in the colonic milieu is a consistent and predictable regulation of PMN function--proinflammatory in UC, anti-inflammatory in control subjects. These factors may be a critical part of the pathophysiology of UC.
活动性溃疡性结肠炎（UC）的黏膜损伤可能涉及中性粒细胞（PMN）迁移和活化增强。由于在体外，UC患者的PMN看似正常，因此不太可能是这种增强的原因，我们推测结肠内环境异常。我们之前发现，UC结肠内环境中的因子可显著增加对照PMN产生活性氧（ROS）。我们现在推测，这些因子还可调节PMN表面整合素，UC患者PMN的调节方式与对照PMN不同，且整合素调节与ROS调节一致。我们通过直肠透析，采集了活动性UC患者、非活动性UC患者及对照受试者的结肠内环境样本。我们监测了一种关键的PMN黏附分子CD11b。检测对照PMN时，活动性UC直肠透析液上调CD11b的效果几乎与N-甲酰甲硫氨酰亮氨酰苯丙氨酸（上调132%）一样有效（上调115%）。检测非活动性UC患者的PMN时，基线CD11b比对照PMN高50%。相反，直肠透析液未能上调非活动性UC患者PMN的CD11b，实际上还下调了CD11b。用UC直肠透析液预孵育对照PMN后，其对PMN激活剂的CD11b反应从上调转变为下调，类似于非活动性UC患者的PMN。细胞内钙水平的变化与CD11b的这些变化平行。直肠透析液诱导的CD11b和钙的变化与我们之前关于直肠透析液诱导ROS产生变化的研究结果一致。因此，结肠内环境中因子的总体净效应是对PMN功能进行一致且可预测的调节——在UC中具有促炎作用，在对照受试者中具有抗炎作用。这些因子可能是UC病理生理学的关键部分。
