The tripeptide analog feG ameliorates severity of acute pancreatitis in a caerulein mouse model

Abstract

Acute pancreatitis (AP) is associated with significant morbidity and mortality; however, there is no specific treatment for this disease. A novel salivary tripeptide analog, feG, reduces inflammation in several different animal models of inflammation. The aims of this study were to determine whether feG reduced the severity of AP and modifies the expression of pancreatic ICAM-1 mRNA during AP in a mouse model. AP was induced in mice by hourly (x12) intraperitoneal injections of caerulein. A single dose of feG (100 microg/kg) was coadministered with caerulein either at time 0 h (prophylactic) or 3 h after AP induction (therapeutic). Plasma amylase and pancreatic MPO activities and pancreatic ICAM-1 mRNA expression (by RT-PCR) were measured. Pancreatic sections were histologically assessed for abnormal acinar cells and interstitial space. AP induction produced a sevenfold increase in plasma amylase, a tenfold increase in pancreatic MPO activity, and a threefold increase in interstitial space, and 90% of the acinar cells were abnormal. Prophylactic treatment with feG reduced the AP-induced plasma amylase activity by 45%, pancreatic MPO by 80%, the proportion of abnormal acinar cells by 30%, and interstitial space by 40%. Therapeutic treatment with feG significantly reduced the AP-induced abnormal acinar cells by 10% and the interstitial space by 20%. Pancreatic ICAM-1 mRNA expression was upregulated in AP and was reduced by 50% with prophylactic and therapeutic treatment with feG. We conclude that feG ameliorates experimental AP acting at least in part by modulating ICAM-1 expression in the pancreas.

Prevention and amelioration of rodent endotoxin-induced lung injury with administration of a novel therapeutic tripeptide feG

“…These data demonstrate that feG does not require immunological or inflammatory pre-stimulation, such as that provided by the induction of acute pancreatitis in our previous model, to be effective. The tripeptide FEG (PheeGlueGly), derived from submandibular gland peptide T, and its synthetic counterpart, feG, inhibits cardiac, pulmonary and intestinal anaphylactic activity [5], and decreases pulmonary and pancreatic inflammation, with increased potency [4,26]. Previous mechanistic studies suggest that in vitro feG inhibits stimulated human and rat neutrophil expression of CD11b, and inhibits the expression of CD49d and CD16 antibody binding to peritoneal rat neutrophils [5].…”

“…The resultant cell pellet was analysed by trypan blue (SigmaeAldrich) exclusion light microscopy and Diff Quik (Lab Aids, NSW, Australia) staining for total cell count and cell differential count [19]. The bottom left lobe was then resected and stored at À80 C for subsequent MPO extraction and assay [4].…”

“…In vitro experiments previously suggested that feG requires pre-stimulation (such as with platelet-activating factorstimulation, ovalbumin or carrageenan) in order to decrease neutrophil chemotaxis in both humans and rat cell culture models [8]. In vivo we have similarly shown that inflammation and tissue damage in injured lung and pancreas tissue is significantly reduced, and respiratory function is improved, in mouse and rat models of acute pancreatitis-associated lung injury where feG is administered prior to lung injury (prophylactically) or after the initiation of lung injury (therapeutically), but following the potential pre-stimulation of pancreatic injury in both incidences [4,6]. However, the ability of feG to similarly prevent or ameliorate inflammatory damage in the lung without pre-stimulation has not been previously investigated.…”

Tripeptide feG Prevents and Ameliorates Acute Pancreatitis-Associated Acute Lung Injury in a Rodent Model

“…13 To evaluate the temporal development of injury in the lung at the point of therapeutic feG intervention, reduced in mouse models of AP when feG is administered prior to initiation of AP, that is, prophylactically. 9 Therefore, it was hypothesized that feG would similarly reduce neutrophil recruitment, infi ltration, and activation during ALI and ameliorate the infl ammatory cascade, thereby reducing the severity of lung damage. However, the ability of feG to similarly prevent or ameliorate infl ammatory damage in ALI has not been previously investigated.…”

“…The pancreas was harvested for myeloperoxidase (MPO) activity, estimation of wet-to-dry weight ratio, and histologic examination. 9,16 The control group received intraperitoneal and intratracheal saline.…”