Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
Gastroenterology. 2010 Jun;138(7):2531-40, 2540.e1-4. doi: 10.1053/j.gastro.2010.02.043. Epub 2010 Feb 23.
BACKGROUND & AIMS: Integrin contact with basement membrane is a major determinant of epithelial cell polarity. beta1 integrin heterodimers are the primary receptors for basement membrane in pancreatic acinar cells, which function to synthesize and directionally secrete digestive enzymes into a central lumen. Aberrant acinar secretion and exposure of the parenchyma to digestive enzyme activity lead to organ damage and pancreatitis.
beta1 integrin conditional knockout mice were crossed to Ptf1a-Cre mice to ablate beta1 integrin in the pancreas. Histopathology of aged and cerulein-treated mice were assessed by histology and immunocytochemistry. Directional secretion was determined in vitro by FM1-43 loading with cerulein stimulation.
Pancreas-specific ablation of beta1 integrin led to progressive organ degeneration, associated with focal acinar cell necrosis and ductal metaplasia along with widespread inflammation and collagen deposition. beta1 Integrin-null pancreata were highly susceptible to cerulein-induced acute pancreatitis, displaying an enhanced level of damage with no loss in regeneration. Degenerating beta1 integrin-null pancreata were marked by disruption of acinar cell polarity. Protein kinase C epsilon, normally localized apically, was found in the cytoplasm where it can lead to intracellular digestive enzyme activation. beta1 Integrin-null acinar cells displayed indiscriminate secretion to all membrane surfaces, consistent with an observed loss of basolateral membrane localization of Munc18c, which normally prevents basal secretion of digestive enzymes.
Ablation of beta1 integrin induces organ atrophy by disrupting acinar cell polarity and exposing the pancreatic parenchyma to digestive enzymes.
整合素与基底膜的接触是上皮细胞极性的主要决定因素。β1 整合素异二聚体是胰腺腺泡细胞基底膜的主要受体，其功能是将消化酶合成并定向分泌到中央腔中。腺泡细胞分泌异常和实质暴露于消化酶活性会导致器官损伤和胰腺炎。
将β1 整合素条件性敲除小鼠与 Ptf1a-Cre 小鼠杂交，以在胰腺中敲除β1 整合素。通过组织学和免疫细胞化学评估老年和 Cerulein 处理小鼠的组织病理学变化。通过 Cerulein 刺激加载 FM1-43 来测定定向分泌。
胰腺特异性敲除β1 整合素导致进行性器官退化，伴有局灶性腺泡细胞坏死和导管化生，以及广泛的炎症和胶原沉积。β1 整合素缺失的胰腺对 Cerulein 诱导的急性胰腺炎高度敏感，表现出增强的损伤程度而没有再生丧失。退化的β1 整合素缺失的胰腺以腺泡细胞极性破坏为特征。正常定位于顶端的蛋白激酶 C epsilon 位于细胞质中，可导致细胞内消化酶激活。β1 整合素缺失的腺泡细胞显示出对所有膜表面的无差别分泌，与 Munc18c 的基底外侧膜定位丧失一致，Munc18c 通常可防止消化酶的基底分泌。
通过破坏腺泡细胞极性和使胰腺实质暴露于消化酶，敲除β1 整合素可诱导器官萎缩。
