Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Forensic Medicine and Clinical Toxicology, Tanta University, Tanta, Egypt.
Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Exp Mol Pathol. 2018 Feb;104(1):89-97. doi: 10.1016/j.yexmp.2018.01.002. Epub 2018 Jan 11.
The single most common cause of chronic pancreatitis (CP, a serious inflammatory disease) is chronic alcohol abuse, which impairs hepatic alcohol dehydrogenase (ADH, a major ethanol oxidizing enzyme). Previously, we found ~5 fold greater fatty acid ethyl esters (FAEEs), and injury in the pancreas of hepatic ADH deficient (ADH) vs. hepatic normal ADH (ADH) deer mice fed 3.5g% ethanol via liquid diet daily for two months. Therefore, progression of ethanol-induced pancreatic injury was determined in ADH deer mice fed ethanol for four months to delineate the mechanism and metabolic basis of alcoholic chronic pancreatitis (ACP). In addition to a substantially increased blood alcohol concentration and plasma FAEEs, significant degenerative changes, including atrophy and loss of acinar cells in some areas, ultrastructural changes evident by such features as swelling and disintegration of endoplasmic reticulum (ER) cisternae and ER stress were observed in the pancreas of ethanol-fed ADH deer mice vs. ADH deer mice. These changes are consistent with noted increases in pancreatic injury markers (plasma lipase, pancreatic trypsinogen activation peptide, FAEE synthase and cathepsin B) in ethanol-fed ADH deer mice. Most importantly, an increased levels of pancreatic glucose regulated protein (GRP) 78 (a prominent ER stress marker) were found to be closely associated with increased phosphorylated eukaryotic initiation factor (eIF) 2α signaling molecule in PKR-like ER kinase branch of unfolded protein response (UPR) as compared to X box binding protein 1S and activating transcription factor (ATF)6 - 50kDa protein of inositol requiring enzyme 1α and ATF6 branches of UPR, respectively, in ethanol-fed ADH vs. ADH deer mice. These results along with findings on plasma FAEEs, and pancreatic histology and injury markers suggest a metabolic basis of ethanol-induced pancreatic injury, and provide new avenues to understand metabolic basis and molecular mechanism of ACP.
慢性胰腺炎（CP，一种严重的炎症性疾病）最常见的单一病因是慢性酒精滥用，它会损害肝醇脱氢酶（ADH，一种主要的乙醇氧化酶）。此前，我们发现喂食 3.5%乙醇的肝 ADH 缺乏（ADH）鹿鼠的胰腺中脂肪酸乙酯（FAEE）和损伤比肝 ADH 正常（ADH）鹿鼠高约 5 倍，这些鹿鼠通过液体饮食每天喂食 2 个月。因此，我们在 ADH 鹿鼠中喂食乙醇 4 个月以确定乙醇诱导的胰腺损伤的进展，以阐明酒精性慢性胰腺炎（ACP）的机制和代谢基础。除了血液中乙醇浓度和血浆 FAEE 显著增加外，与 ADH 鹿鼠相比，喂食乙醇的 ADH 鹿鼠的胰腺还观察到明显的退行性变化，包括某些区域的腺泡细胞萎缩和丧失，超微结构变化表现为内质网（ER）池肿胀和瓦解以及 ER 应激。这些变化与在喂食乙醇的 ADH 鹿鼠中胰腺损伤标志物（血浆脂肪酶、胰腺胰蛋白酶原激活肽、FAEE 合酶和组织蛋白酶 B）的显著增加一致。最重要的是，与未折叠蛋白反应（UPR）的 X 盒结合蛋白 1S 和需要肌醇的酶 1α分支中的激活转录因子（ATF）6-50kDa 蛋白相比，发现胰腺葡萄糖调节蛋白（GRP）78（一种突出的 ER 应激标志物）的水平升高与磷酸化真核起始因子（eIF）2α信号分子密切相关，在 UPR 的 PKR 样 ER 激酶分支中，在喂食乙醇的 ADH 与 ADH 鹿鼠相比。这些结果以及血浆 FAEEs、胰腺组织学和损伤标志物的结果表明，乙醇诱导的胰腺损伤存在代谢基础，并为理解 ACP 的代谢基础和分子机制提供了新途径。
