Abstract
BackgroundSymptoms associated with acute pancreatitis can be debilitating, and treatment remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis.MethodsAcute pancreatitis was induced in adult male C57Bl/6J mice by administering cerulein (8 injections of 50 µg/kg I.P., spaced an hour apart), with XPro1595 (10 mg/kg, S.C.) or vehicle being administered approximately 18 h after the last injection. Serum was collected 6 or 18 h after the last cerulein injection, pancreatic tissue was collected 2 and 7 days post-induction, and brain hippocampal tissue was collected at 7 days post-induction. The animal’s pain level was assessed 3, 5 and 7 days post-induction.ResultsThe induction of acute pancreatitis promoted a strong increase in serum amylase levels, which had receded back to baseline levels by the next morning. XPro1595 treatment began after amylase levels had subsided at 18 h, and prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model.ConclusionOverall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis.
Highlights
Pancreatitis is a leading cause for gastrointestinal disease-related hospital admissions, with symptoms including moderate to severe upper abdominal epigastric pain, nausea and vomiting [1]
Cerulein administration induces a temporary increase in serum amylase levels in mice To confirm whether 8 intraperitoneal injections of cerulein space an hour apart, over the course of 7 h increases serum amylase levels, we collected serum 6 and 18 h after the last cerulein injection
Selective inhibition of soluble form of tumor necrosis factor (TNF) (solTNF) prevents immune cell infiltration into the pancreas following cerulein‐induction of acute pancreatitis Forty eight hours after acute pancreatitis induction, vehicle-treated mice had a significant influx of inflammatory cells, as observed by hematoxylin and eosin (H&E) (Fig. 2a, b, g)
Summary
Pancreatitis is a leading cause for gastrointestinal disease-related hospital admissions, with symptoms including moderate to severe upper abdominal epigastric pain, nausea and vomiting [1]. It has long been known that TNF production promotes the induction of inflammatory genes, recruitment of immune cells and acinar cell death [2,3,4,5], and this prompted investigation of traditional TNF inhibitory therapies to prevent or reduce these pathologies and associated symptoms. The abundance of side-effects in these traditional TNF inhibitors (including immunological dysfunction and even the induction of pancreatitis itself [10,11,12,13]), combined with their apparent inability to reduce mortality in sepsis patients [14, 15] dampened enthusiasm for their further use in patients with pancreatitis. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis
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