Mathematical model of chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, leading to its fibrotic destruction. There are currently no drugs that can stop or slow the progression of the disease. The etiology of the disease is multifactorial, whereas recurrent attacks of acute pancreatitis are thought to precede the development of CP. A better understanding of the pathology of CP is needed to facilitate improved diagnosis and treatment strategies for this disease. The present paper develops a mathematical model of CP based on a dynamic network that includes macrophages, pancreatic stellate cells, and prominent cytokines that are present at high levels in the CP microenvironment. The model is represented by a system of partial differential equations. The model is used to explore in silico potential drugs that could slow the progression of the disease, for example infliximab (anti-TNF-[Formula: see text]) and tocilizumab or siltuximab (anti-IL-6/IL-6R).

Local and Systemic Expression of Immunomodulatory Factors in Chronic Pancreatitis.

Inflammatory and fibrotic events that drive chronic pancreatitis (CP) are likely orchestrated via signaling of soluble cytokines and chemokines systemically and within the pancreas. However, a comprehensive summary of the expression of such factors during CP has not been reported to date. This information is important given continued interest in targeting cytokines that influence CP pathogenesis. Reported data on the expression change of soluble immunomodulatory factors in human CP patients were identified via a literature search using a single search term. Thirty-one articles meeting the prespecified inclusion criteria were identified to generate a compiled data summary. Compiled data demonstrated up-regulation of several factors in the blood or pancreas microenvironment of CP patients. Nine factors were elevated in both compartments, including fractalkine, IFN-γ, interleukin 1ß, IL-6, IL-8, macrophage inhibitory cytokine 1, neutrophil gelatinase-associated lipocalin, transforming growth factor ß, and tumor necrosis factor α. Most up-regulated factors could be classified into one of several functional groups, including inflammation, chemotaxis, angiogenesis, bone remodeling, extracellular matrix remodeling, and pain. After further validation, these factors may be used as biomarkers for disease diagnosis and identification of comorbidities, or as potential therapeutic targets.

Laser Capture Microdissection of Pancreatic Acinar Cells to Identify Proteomic Alterations in a Murine Model of Caerulein-Induced Pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by inflammation and fibrosis of the pancreas, leading to pain, parenchymal damage, and loss of exocrine and endocrine function. There are currently no curative therapies; diagnosis remains difficult and aspects of pathogenesis remain unclear. Thus, there is a need to identify novel biomarkers to improve diagnosis and understand pathophysiology. We hypothesize that pancreatic acinar regions contain proteomic signatures relevant to disease processes, including secreted proteins that could be detected in biofluids. METHODS: Acini from pancreata of mice injected with or without caerulein were collected using laser capture microdissection followed by mass spectrometry analysis. This protocol enabled high-throughput analysis that captured altered protein expression throughout the stages of CP. RESULTS: Over 2,900 proteins were identified, whereas 331 were significantly changed ≥2-fold by mass spectrometry spectral count analysis. Consistent with pathogenesis, we observed increases in proteins related to fibrosis (e.g., collagen, P<0.001), several proteases (e.g., trypsin 1, P<0.001), and altered expression of proteins associated with diminished pancreas function (e.g., lipase, amylase, P<0.05). In comparison with proteomic data from a public data set of CP patients, a significant correlation was observed between proteomic changes in tissue from both the caerulein model and CP patients (r=0.725, P<0.001). CONCLUSIONS: This study illustrates the ability to characterize proteome changes of acinar cells isolated from pancreata of caerulein-treated mice and demonstrates a relationship between signatures from murine and human CP.

Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo.

Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.

Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer.

The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant Kras to drive initiation and progression of PDAC in murine models. We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit anti-tumor activity against PDAC and decrease immune suppressive features of the disease. We used an aggressive genetically engineered PDAC model with mutant KrasG12D, tp53R270H, and Brca1 alleles (KPC-Brca1 mice). Mice with confirmed tumor burden were treated orally with vehicle or 30 mg/kg BMS-911543 daily for 14 days. Histologic analysis of pancreata from treated mice revealed fewer foci of adenocarcinoma and significantly decreased Ki67+ cells versus controls. In vivo administration of BMS-911543 significantly reduced pSTAT5 and FoxP3 positive cells within the pancreas, but did not alter STAT3 phosphorylation. Continuous dosing of KPC-Brca1 mice with BMS-911543 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.055). In vitro experiments demonstrated that PDAC cell lines were poorly sensitive to BMS-911543, requiring high micromolar concentrations to achieve targeted inhibition of Jak/STAT signaling. Similarly, BMS-911543 had little in vitro effect on the viability of both murine and human PDAC-derived stellate cell lines. However, BMS-911543 potently inhibited phosphorylation of pSTAT3 and pSTAT5 at low micromolar doses in human PBMC and reduced in vitro differentiation of Foxp3+ T regulatory cells. These results indicate that single agent Jak2i deserves further study in preclinical models of PDAC and has distinct inhibitory effects on STAT5 mediated signaling.