Hardcastle J, Harwood M D, Taylor C J
Department of Biomedical Science, University of Sheffield, Sheffield, UK.
J Pharm Pharmacol. 2004 Mar;56(3):329-38. doi: 10.1211/0022357022863.
Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl- secretion and changes in absorption being reported. We have examined the effects of the disease on Na(+)-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na(+)-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)-dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the DeltaF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.
囊性纤维化（CF）患者的肠道转运功能紊乱，有报道称其存在氯离子分泌缺陷和吸收改变。我们研究了该疾病对小肠钠依赖性葡萄糖吸收的影响。通过监测正常（瑞士）小鼠和携带ΔF508突变的转基因CF（Cftr(tm1Eur)和Cftr(tm2Cam)）小鼠完整及剥离肠片的短路电流（SCC）变化，以及CF患儿和正常对照者空肠活检组织中的变化，来监测活性葡萄糖吸收情况。在刷状缘膜囊泡（BBMVs）中测量肠腔膜上钠依赖性葡萄糖摄取。瑞士小鼠空肠和中肠的完整及剥离肠片对葡萄糖的SCC呈浓度依赖性增加。两种制剂中的表观Km值相似，但剥离肠片中的表观Vmax更大。这种差异并非由于剥离肠片中神经活性丧失，因为河豚毒素不影响完整肠片中葡萄糖诱导的SCC。在野生型Cftr(tm1Eur)小鼠的空肠和中肠剥离肠片中也观察到类似结果，但在CF小鼠的组织中，表观Vmax值显著降低。CF（Cftr(tm2Cam)）小鼠中肠的完整肠片也得到了较低的Vmax。然而，CF患者的空肠活检组织显示，葡萄糖依赖性SCC升高。与野生型和瑞士小鼠的BBMVs相比，CF（Cftr(tm1Eur)）小鼠的BBMVs中钠依赖性摄取并未降低。得出的结论是，与人类肠道不同，携带ΔF508突变的CF转基因小鼠模型中肠道葡萄糖吸收减少，但在分离的刷状缘膜制剂中无法检测到这一点。CF转基因小鼠模型可能无法准确反映人类疾病中肠道功能障碍的所有方面。
