Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

Abstract

Pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis and in the desmoplastic reaction of pancreatic cancer. When PSCs are stimulated by oxidative stress, ethanol and its metabolite acetaldehyde, and cytokines, the phenotype of quiescent fat-storing cells converts to myofibroblastlike activated PSCs, which then produce extracellular matrix, adhesion molecules, and various chemokines in response to cytokines and growth factors. Recent data suggest that PSCs have a phagocytic function. Plateletderived growth factor is a potent stimulator of PSC proliferation. Transforming growth factor beta, activin A, and connective tissue growth factor also play a role in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops. Following pancreatic damage, pathophysiological processes that occur in the pancreas, including pancreas tissue pressure, hyperglycemia, intracellular reactive oxygen species production, activation of protease-activated receptor 2, induction of cyclooxygenase 2, and bacterial infection play a role in sustaining pancreatic fibrosis through increased PSC proliferation and collagen production by PSCs. Targeting PSCs might be an effective therapeutic approach in chronic pancreatitis. Various substances including vitamin A, vitamin E, polyphenols, peroxisome proliferator-activated receptor gamma ligands, and inhibitors of the renin-angiotensin system show great promise of being useful in the treatment of chronic pancreatitis.

Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma

“…The tumor microenvironment or desmoplastic stroma in PDAC is home to many cellular and molecular components. Reciprocal growth factor signaling results in strong expression of growth factors such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) (20). Impaired paracrine signaling between CAFs and cancer cells and alterations in the ECM microenvironment caused by depletion of CAFs may directly contribute to changes in cancer cells, leading to acquisition of epithelialmesenchymal transition (EMT), a stem cell-like phenotype, and dedifferentiation.…”

The role of P2X7 receptors in tissue fibrosis: a brief review

“…Fibrogenesis is also associated with activation of pancreatic stellate cells (PSCs). It has been reported that PDGF and TGF-β1 play key roles in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops [75][76][77]. In the early stage of pancreatic damage, quiescent PSCs undergo a transformation into α-SMA expressing myofibroblast-like cells, which then produce extracellular matrix leading to proliferation and collagen production [78].…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…Despite this fact, data from animal studies have shown that acetaldehyde by itself does not elicit directly acute pancreatitis [111,112]. Conversely, some studies support the involvement of acetaldehyde in both pancreatic fibrosis and carcinogenesis [16,[113][114][115][116][117]. Dysbiotic gut microbiota is able to convert both exogenous and endogenous ethanol to acetaldehyde in a dose-dependent manner [70].…”