Figure 2.

Working model of the pathways by which PTHrP functions in the exocrine pancreas. Pancreatic damage induced by injurious agents such as alcohol results in upregulation of PTHrP expression. PTHrP may be targeted directly at the transcriptional and/or post-transcriptional levels, or may be upregulated downstream of cytokines whose levels are elevated as a result of pancreatic damage, including TNF-α and TGF-β. PTHrP released by acinar cells in turn functions via an autocrine and/or paracrine pathway to induce cytokine and chemokine release, leading to an inflammatory response. Acinar cell-secreted PTHrP may also function by a paracrine pathway to activate PSCs. PSCs also release PTHrP in response to injury, leading to their activation. The net result is development of Acute Pancreatitis. Further exposure to risk factors, accompanied by release of PTHrP, would perpetuate the pro-inflammatory and pro-fibrotic response. These multiple episodes of acute pancreatitis (Recurrent Acute Pancreatitis) may eventually lead to Chronic Pancreatitis, with chronic inflammation and scarring. Since a history of pancreatitis is a significant risk factor for PDA, preventing or limiting development of CP through prophylactic use of inhibitors of the PTHrP signaling pathway may reduce the risk for this cancer.