Pancreas-Specific Ablation of β1 Integrin Induces Tissue Degeneration by Disrupting Acinar Cell Polarity
Pancreas-Specific Ablation of β1 Integrin Induces Tissue Degeneration by Disrupting Acinar Cell Polarity
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DOI：
10.1053/j.gastro.2010.02.043
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发表时间：
2010-06-01
期刊：
影响因子：
29.4
通讯作者：
Crawford, Howard C.
中科院分区：
文献类型：
--
作者：
Bombardelli, Lorenzo;Carpenter, Eileen S.;Crawford, Howard C.
背景与目的：整合素与基底膜的接触是决定上皮细胞极性的主要因素。β1整合素异源二聚体是胰腺腺泡细胞基底膜的主要受体，其功能是合成消化酶并将其定向分泌到中央管腔。腺泡的异常分泌和实质对消化酶活性的暴露会导致器官损伤和胰腺炎。方法：将β1整合素条件性基因敲除小鼠与Ptf1a-Cre小鼠杂交，去除胰腺中的β1整合素。用组织学和免疫细胞化学方法对老龄和雨蛙素处理组小鼠的组织病理学进行评价。体外用蓝蛋白刺激负载FM1-43确定定向分泌。结果：胰腺特异的β1整合素消融可导致器官进行性变性，伴局灶腺泡细胞坏死和导管化生，并伴有广泛的炎症和胶原沉积。β1整合素缺失的胰腺对蓝蛋白诱导的急性胰腺炎高度敏感，表现出损伤程度增加，再生没有损失。变性的β1整合素缺失的胰腺以腺泡细胞极性的破坏为标志。蛋白激酶C epsilon通常定位于细胞顶端，存在于细胞质中，可导致细胞内消化酶的激活。β1整合素缺失的腺泡细胞不分青红皂白地分泌到所有的膜表面，这与观察到的Munc18c基侧膜定位的丢失是一致的，Munc18c通常阻止消化酶的基础分泌。结论：消融β1整合素可破坏腺泡细胞的极性，使胰腺实质暴露于消化酶，从而导致器官萎缩。
BACKGROUND & AIMS: Integrin contact with basement membrane is a major determinant of epithelial cell polarity. beta 1 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. METHODS: beta 1 integrin conditional knockout mice were crossed to Ptf1a-Cre mice to ablate beta 1 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. RESULTS: Pancreas-specific ablation of beta 1 integrin led to progressive organ degeneration, associated with focal acinar cell necrosis and ductal metaplasia along with widespread inflammation and collagen deposition. beta 1 Integrin-null pancreata were highly susceptible to cerulein-induced acute pancreatitis, displaying an enhanced level of damage with no loss in regeneration. Degenerating beta 1 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. beta 1 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. CONCLUSIONS: Ablation of beta 1 integrin induces organ atrophy by disrupting acinar cell polarity and exposing the pancreatic parenchyma to digestive enzymes.