Chemical pancreatectomy treats chronic pancreatitis while preserving endocrine function in preclinical models
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
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Research Article Endocrinology Gastroenterology

Chemical pancreatectomy treats chronic pancreatitis while preserving endocrine function in preclinical models

Abstract

Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%–2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid–treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.

Authors

Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes

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Figure 7

Chemical pancreatectomy ablates exocrine pancreas, resolves inflammation, and ameliorates pain in cerulein-induced CP.

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Chemical pancreatectomy ablates exocrine pancreas, resolves inflammation...
(A) Immunostaining for amylase was positive in vehicle+saline and negative in AcA-treated groups while cerulein+saline group showed abnormal patchy amylase staining typical of CP. (B) Immunostaining for CD3 showed presence of lymphocytes only in the cerulein+saline group, indicating chronic inflammation. (C) Immunostaining for cytokeratin showed absence of ducts only in the AcA-treated groups, indicating involution of the ducts. (D) Abdominal von Frey monofilament testing was performed following the two 8-week cycles of i.p. cerulein or vehicle and revealed that cerulein+saline group exhibited significant mechanical allodynia pain as compared with cerulein+AcA group, as well as compared with both vehicle-treated groups, indicating that AcA treatment resolved the pain in cerulein-induced CP. n = 8/group. One-way ANOVA followed by Holm-Šidák test for multiple comparisons. F3,28=7.884; P = 0.0006. (E) Levels of CGRP (calcalpha) mRNA were quantified by RT-PCR from DRGs harvested from the 4 subgroups. In keeping with the in vivo pain assessment, there was a significant upregulation in the cerulein+saline (n = 5) group compared with the other 3 groups, cerulein+AcA (n = 3), vehicle+saline (n = 4), and vehicle+AcA (n = 4), indicating that AcA treatment reversed the cerulein-induced upregulation in CGRP mRNA levels. One-way ANOVA followed by Holm-Šidák test for multiple comparisons. F3,12=9.015; P = 0.0021. Illustrative histology results from 4 animals per time point are shown. Scale bars: 200 μm. Data are presented as mean ± SD. Only significant P values are depicted.