Bhatia Vandanajay, Kim Sung O K, Aronson Judith F, Chao Celia, Hellmich Mark R, Falzon Miriam
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Regul Pept. 2012 Apr 10;175(1-3):49-60. doi: 10.1016/j.regpep.2012.01.006. Epub 2012 Jan 23.
Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis.
胰腺炎是一种常见且可能致命的坏死性炎症性疾病，有急性和慢性两种表现形式。目前的证据表明，在急性胰腺炎（AP）反复发作期间积累的损伤可导致慢性疾病，这与胰腺癌风险增加有关。虽然甲状旁腺激素相关蛋白（PTHrP）在正常生理和疾病状态中发挥多种作用，但其在胰腺炎中的功能此前尚未得到研究。在此我们表明，在雨蛙肽诱导的AP小鼠模型中，PTHrP水平会短暂升高。酒精作为AP和慢性胰腺炎（CP）的一个风险因素，其处理也会增加PTHrP水平。雨蛙肽和乙醇的这些作用分别在分离的原代腺泡细胞和星状细胞以及永生化腺泡和星状细胞系AR42J和irPSCc3中很明显。乙醇使腺泡细胞和星状细胞对雨蛙肽的PTHrP调节作用敏感。用PTHrP（1-36）处理腺泡细胞会增加炎症介质白细胞介素-6（IL-6）和细胞间黏附蛋白（ICAM-1）的表达，提示存在潜在的自分泌环。PTHrP还会增加AR42J细胞的凋亡。星状细胞介导与胰腺炎相关的纤维化反应；PTHrP（1-36）会增加原代和永生化星状细胞中I型前胶原和纤连蛋白的mRNA水平。PTH1R拮抗剂PTHrP（7-34）可抑制雨蛙肽和乙醇对IL-6和I型前胶原水平的影响。这些研究共同确定PTHrP是与酒精性胰腺炎相关的炎症和纤维化反应的潜在介质。
