Journal of the Pancreas Open Access

Keywords

Fibrosis; FOY 305; IS 741; Inflammation; Pancreatitis, Chronic; Protease Inhibitors

Abbreviations

alpha-SMA: alpha-smooth muscle actin; CCK: cholecystokinin; COX-2: cyclooxygenase-2; DBTC: dibutyltin dichloride; ECM: extracellular matrix; hPFCs: human pancreatic periacinar fibroblast-like cells; IL-1beta: interleukin- 1beta; IL-6: interleukin-6; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; OLETF: Otsuka Long-Evans Tokushima Fatty; PDGF: platelet-derived growth factor; PLA2: phospholipase A2; PPAR-gamma: peroxisome proliferator-activated receptor-gamma; PSCs: pancreatic stellate cells; TGF-beta: transforming growth factor-beta; TNBS: trinitrobenzene sulfonic acid; TNF-alpha: tumor necrosis factor-alpha

INTRODUCTION

Chronic pancreatitis is an irreversible progressive disease characterized by damage to both the exocrine and the endocrine components of the pancreas, eventually resulting in significant exocrine insufficiency and diabetes [1]. The key histopathologic features of chronic pancreatitis are pancreatic fibrosis, acinar atrophy, chronic inflammation, and distorted and blocked ducts [1]. Therapeutic strategies to treat chronic pancreatitis are mostly symptomatic and very limited. In the pancreas, pancreatic stellate cells (PSCs) play a pivotal role in fibrogenesis, and their activation has been recognized as a key event in fibrogenesis [2, 3, 4, 5, 6, 7, 8]. In response to pancreatic injury or inflammation, PSCs transform into myofibroblast- like phenotypes expressing alphasmooth muscle actin (alpha-SMA) (activated state), proliferate, and synthesize and secrete increased amounts of extracellular matrix (ECM) proteins, particularly collagens and fibronectin. Moreover, it is well-known that the activation of proteases such as trypsin and plasmin is involved in the process of inflammation in the pancreas [9]. For the development of an effective therapy, it is of particular importance to elucidate the mechanisms underlying the processes of inflammation and PSC activation in the pancreas.

Many in vitro experiments using PSCs have shown their key roles in the activation and/or proliferation process for cytokines (e.g., transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) [6, 7]), angiotensin II [10, 11, 12], peroxisome proliferator-activated receptor-gamma (PPARgamma) [13], PI 3-kinase [14, 15], and mitogen-activated protein kinase (MAPK) pathways [14, 16, 17, 18, 19]. For example, a blockade of the receptors for TGF-beta, PDGF, and angiotensin II and activation of PPAR-gamma is likely to provide therapeutic benefit in patients with chronic pancreatitis. On the other hand, several in vivo experimental studies have shown beneficial effects of antifibrotic drugs on chronic pancreatitis. Agents showing benefit in experimental chronic pancreatitis include angiotensin- converting enzyme inhibitor [20], angiotensin II receptor antagonist [21], PPAR-gamma ligand [22, 23], vitamin E [24], cyclooxygenase-2 (COX-2) inhibitor [25], soluble TGF-beta receptor (blockade of TGF-beta signaling) [26] and the serine protease inhibitor camostat [27, 28, 29, 30]. In this chapter, we focus on the effect of antiproteases on fibrosis in experimental chronic pancreatitis.

Experimental Models of Chronic Pancreatitis

There are several experimental models of chronic pancreatitis for investigating the mechanisms responsible for the development of chronic pancreatitis. PSCs are the principle effector cells in pancreatic fibrosis of these experimental models.

Trinitrobenzene Sulfonic Acid (TNBS)- Induced Chronic Pancreatitis

Infusion of TNBS into the pancreatic duct of rats causes a pancreatic necroinflammation followed by pancreatic fibrosis within four weeks [31]. In TNBS-treated rats, alpha-SMA-positive PSCs are found in the fibrotic areas.

Dibutyltin Dichloride (DBTC)-Induced Chronic Pancreatitis

This model involves a single intravenous administration of DBTC (6-8 mg/kg body weight) to rats [32]. The rats develop moderate to severe pancreatitis within one week, followed by fibrosis within four weeks after DBTC injection.

Chronic Pancreatitis Induced by Repetitive Intraperitoneal Injections of Cerulein

In mice, the induction of repeated episodes of acute pancreatitis via intraperitoneal injections of cerulein (50 μg/kg body weight every hour for six hours) induces pancreatic fibrosis similar to that of human chronic pancreatitis [26, 33, 34].

Spontaneous Chronic Pancreatitis in WBN/Kob Rats

The characteristic lesions of chronic pancreatitis (acinar atrophy, inflammatory cell infiltration, and fibrosis) develop spontaneously in this strain of rats. These lesions appear focally at approximately 12 weeks of age [35].

Camostat Mesilate

Camostat mesilate, an oral synthetic serine protease inhibitor, inhibits trypsin, kallikrein, thrombin, plasmin and C1 esterase [36], and has been used clinically for the treatment of chronic pancreatitis in Japan [37]. Since the activation of trypsinogen in the pancreas is considered to be a trigger reaction in the development of pancreatitis [9], the pharmacological effect of camostat mesilate on chronic pancreatitis depends on its inhibitory effect on the serine proteases, especially trypsin. In support of the clinical use of camostat mesilate, animal studies have demonstrated both preventive and therapeutic effects on pancreatic exocrine dysfunction and fibrosis in WBN/Kob rats [27, 28]. Oral administration of camostat mesilate increases pancreatic exocrine secretion and causes hypertrophy of the pancreas in normal rats by means of an increase in endogenous cholecystokinin (CCK) release [38, 39, 40]. Several previous studies have revealed that exogenous and endogenous CCK can accelerate pancreatic regeneration after an attack of acute pancreatitis [41, 42, 43]. These results suggest the possibility that camostat mesilate inhibits pancreatic fibrosis via endogenous CCK release in WBN/Kob rats. Thus, we have investigated the effect of camostat mesilate on pancreatic fibrosis and atrophy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats which have a total and selective defect of CCK-1 receptor gene expression [44, 45], and show extreme atrophy and fibrosis of the pancreas with age [46, 47]. In these studies, oral administration of camostat mesilate also inhibits pancreatic inflammation and prevents fibrosis and atropy of the pancreas in the OLETF rats through the suppression of IL-1beta, interleukin-6 (IL-6), TNF-alpha, TGF-beta, and PSCs [48, 49]. Recently, Gibo et al. have revealed that the oral administration of camostat mesilate exerts beneficial effects on DBTC-induced chronic pancreatitis in rats by inhibiting monocyte recruitment and PSC activation [30]. In addition, they have demonstrated that camostat mesilate inhibits lipopolysaccharide (LPS)-stimulated productions of monocyte chemoattractant protein-1 (MCP-1) and TNF-alpha in monocytes, and proliferation and MCP-1 production of PSCs in vitro. Camostat mesilate can also inhibit PDGF-stimulated proliferation and TGFbeta1- stimulated collagen synthesis of human pancreatic periacinar fibroblast-like cells (hPFCs) [50] which are considered to be PSCs. In all, camostat mesilate is likely to attenuate experimental chronic pancreatitis by inhibiting chronic inflammation and activation of PSCs induced by cytokines and growth factors.

IS-741

Originally, the N-(2-sulfonylamino-5-trifluoromethyl- 3-pyridyl) carboxamide derivative IS-741 was prepared and evaluated as a phospholipase A2 (PLA2) inhibitor [51, 52]. Moreover, it is shown that IS-741 has an anti-inflammatory effect through its inhibitory action on cell adhesion in a rat colitis model induced by dextran sulfate sodium and in a rat acute necrotizing pancreatitis model [53, 54]. The administration of IS-741 suppresses inflammatory cell infiltration and subsequent pancreatic fibrosis in WBN/Kob rats and DBTC-induced chronic pancreatitis [55, 56]. Recently, Kaku T et al. have demonstrated that the administration of IS-741 suppresses macrophage infiltration and PSC activation in DBTC-induced chronic pancreatitis [56]. Therefore, it is likely that the inhibitory effect of IS-741 on pancreatic fibrosis is due to its inhibitory effects on macrophage infiltration into the pancreas and on PLA2 activity.

Conclusion

Among antiproteases, camostat mesilate, an oral synthetic serine protease inhibitor, has been shown to suppress the progression of fibrosis in experimental chronic pancreatitis. However, the amount of camostat mesilate in experimental chronic pancreatitis is about five times as much as a general dose of camostat mesilate used for patients with chronic pancreatitis in Japan [30]. The oral administration of camostat mesilate increases endogenous CCK release, and subsequently stimulates pancreatic exocrine secretion and pancreatic growth in normal rats [38, 39, 40]. In healthy humans, the oral administration of camostat mesilate for four weeks (2 g/day, approximately three times as much as the usual dosage for human chronic pancreatitis) can also increase the size of the pancreas and CCK release after test meal stimulation [57]. From these observations, there is the possibility that camostat mesilate may stimulate pancreatic growth in patients with chronic pancreatitis. This possibility still remains to be seen. It is necessary to clarify in future studies whether camostat mesilate provides therapeutic benefits in patients with chronic pancreatitis.

Conflict of interest

The authors have no potential conflicts of interest

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