Durgampudi Chandra, Noel Pawan, Patel Krutika, Cline Rachel, Trivedi Ram N, DeLany James P, Yadav Dhiraj, Papachristou Georgios I, Lee Kenneth, Acharya Chathur, Jaligama Deepthi, Navina Sarah, Murad Faris, Singh Vijay P
Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania.
Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
Am J Pathol. 2014 Jun;184(6):1773-84. doi: 10.1016/j.ajpath.2014.02.015.
Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O-positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate-induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.
肥胖患者在急性胰腺炎（AP）期间预后较差。既往AP动物模型发现，肥胖啮齿动物可能存在基线促炎状态，其预后更差。我们的目的是研究脂肪酸急性脂解生成对AP局部严重程度和全身并发症的作用。对人类胰腺炎后坏死组织进行不饱和脂肪酸（UFA）和饱和脂肪酸分析。设计了一种胆源性AP模型，通过导管内单独注射甘油三亚油酸酯或与化学性质不同的脂肪酶抑制剂奥利司他或西替利司他联合注射，来复制人类相关变量。测量AP病因参数以及局部和全身严重程度的预后指标。胰腺炎后坏死组织患者均为肥胖患者，15例中有13例为胆源性AP。胰腺炎后坏死组织中UFA含量丰富。导管内注射甘油三亚油酸酯，无论是否使用脂肪酶抑制剂，均导致油红O阳性区域，类似于胰腺内脂肪。两种脂肪酶抑制剂均降低了甘油三亚油酸酯诱导的血清脂肪酶、UFA、胰腺坏死、血清炎症标志物、全身损伤和死亡率的升高，但未降低血清丙氨酸氨基转移酶、胆红素或淀粉酶。我们得出结论，UFA在人类坏死组织中含量丰富，通过脂解急性生成UFA会加重胰腺坏死、全身炎症以及与重症AP相关的损伤。抑制脂解可减少UFA生成并改善AP的这些预后，而不会干扰其诱发过程。
