Pancreatic blood flow in cats with chronic pancreatitis

Reber, Howard A.; Karanjia, N D; Álvarez, Carlos; Widdison, Adam L.; Leung, Felix W.; Ashley, Stanley W.; Lutrin, Frank J.

doi:10.1016/0016-5085(92)90861-r

Cited by 83 publications

(30 citation statements)

References 25 publications

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“…Acidosis increases the risk and severity of pancreatitis in humans and has been shown to sensitize to pancreatitis responses in in vivo and in vitro animal studies (3,19,22,35,36,38,41). Disruption of acinar cell gap junctions by global Cx32 knockout increases the severity of acute cerulein-induced pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

Low pH enhances connexin32 degradation in the pancreatic acinar cell

Reed

Kolodecik

Husain

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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tracellular pH is observed in a number of clinical conditions and can sensitize to the development and worsen the severity of acute pancreatitis. Because intercellular communication through gap junctions is pH-sensitive and modulates pancreatitis responses, we evaluated the effects of low pH on gap junctions in the rat pancreatic acinar cell. Decreasing extracellular pH from 7.4 to 7.0 significantly inhibited gap junctional intracellular communication. Acidic pH also significantly reduced levels of connexin32, the predominant gap junction protein in acinar cells, and altered its localization. Increased degradation through the proteasomal, lysosomal, and autophagic pathways mediated the decrease in connexin32 under low-pH conditions. These findings provide the first evidence that low extracellular pH can regulate gap junctional intercellular communication by enhancing connexin degradation. cell pH; gap junctions; protein degradation; cell-cell interaction; pancreas; acinar cell GAP JUNCTIONS ARE INTERCELLULAR membrane channels composed of connexins that allow the movement of Ͻ1,000-Da molecules, including ions, secondary messengers, and small metabolites between cells. Gap junctions in pancreatic acinar cells are composed mainly of connexin32 (Cx32) (29). In Cx32-deficient mice, mild reversible cerulein-induced pancreatitis is converted to severe disease (8). Correspondingly, irsogladine, which strengthens gap junctional coupling, attenuates the severity of cerulein-induced pancreatitis in rats (15). These studies suggest that cell-to-cell communication through gap junctions plays an important role in modulating pancreatitis responses.Gap junctional intercellular communication (GJIC) is affected by two parameters: the number of hemichannels at the membrane and the gating of these hemichannels. Gating refers to the mechanism by which the intercellular passage of molecules is restricted and is dependent on the unitary conductance and open probability of each channel (32). Although connexin gating provides a rapid mechanism to modulate GJIC, regulation of connexin degradation has been proposed as another mechanism for controlling gap junction assembly and function (33). Cx32 degradation is complex, with established roles for proteasomal and lysosomal pathways (20,23,45). The autophagic pathway has been implicated in the degradation of some connexins (2, 6, 26) but has not been studied for Cx32.Acute and chronic reductions of extracellular pH are observed in a range of disease conditions and increase the risk and severity of acute pancreatitis. Using a cerulein model of pancreatitis, we have shown that reducing extracellular pH sensitizes to zymogen activation and cellular injury in vitro and pancreatitis in vivo (3). When exposed to acidic conditions, cells treated with a physiological, low dose of cerulein display pancreatitis responses similar to responses to supramaximal doses of cerulein (3, 39). However, the mechanism responsible for the injurious effects of lowering extracellular pH remains unclear. Low pH lea...

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Section: Discussionmentioning

confidence: 99%

Low pH enhances connexin32 degradation in the pancreatic acinar cell

Reed

Kolodecik

Husain

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Evidence suggests that duct obstruction with resulting raised intraductal pressure 2 , pancreatic ischaemia 3 , neuronal injury and neuroimmune interaction 4 contribute to pain in pancreatitis. Furthermore, long-term morphine use can result in morphine-induced hyperalgesia characterized by reduced cold-induced pain tolerance 5 .…”

Section: Introductionmentioning

confidence: 99%

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis

Bramis

Gordon-Weeks

Friend

et al. 2012

British Journal of Surgery

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Background: Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis. Conclusion:This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation.

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“…These events can be also observed in the animal model of chronic pancreatitis (23,39). In this model, the restrictive fibrotic capsule enveloping the gland prevents dissipation of the main pancreatic duct pressure.…”

Section: Discussionmentioning

confidence: 74%

Pressure activates rat pancreatic stellate cells

Watanabe

Nagashio

Asaumi

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Pancreatic stellate cells (PSCs) play a central role in development of pancreatic fibrosis. In chronic pancreatitis, pancreatic tissue pressure is higher than that of the normal pancreas. We here evaluate the effects of pressure on the activation of rat PSCs. PSCs were isolated from the pancreas of Wistar rat using collagenase digestion and centrifugation with Nycodenz gradient. Pressure was applied to cultured rat PSCs by adding compressed helium gas into the pressure-loading apparatus to raise the internal pressure. Cell proliferation rate was assessed by 5-bromo-2Ј-deoxyuridine (BrdU) incorporation. MAPK protein levels and ␣-smooth muscle actin (␣-SMA) expression were evaluated by Western blot analysis. Concentration of activated transforming growth factor-␤1 (TGF-␤1) secreted from PSCs into culture medium was determined by ELISA. Collagen type I mRNA expression and collagen secretion were assessed by quantitative PCR and Sirius red dye binding assay, respectively. Application of pressure significantly increased BrdU incorporation and ␣-SMA expression. In addition, pressure rapidly increased the phosphorylation of p44/42 and p38 MAPK. Treatment of PSCs with an MEK inhibitor and p38 MAPK inhibitor suppressed pressure-induced cell proliferation and ␣-SMA expression, respectively. Moreover, pressure significantly promoted activated TGF-␤1 secretion, collagen type I mRNA expression, and collagen secretion. Our results demonstrate that pressure itself activates rat PSCs and suggest that increased pancreatic tissue pressure may accelerate the development of pancreatic fibrosis in chronic pancreatitis. activation; fibrosis; chronic pancreatitis; mitogen-activated protein kinase; transforming growth factor-␤

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Pancreatic blood flow in cats with chronic pancreatitis

Cited by 83 publications

References 25 publications

Low pH enhances connexin32 degradation in the pancreatic acinar cell

Low pH enhances connexin32 degradation in the pancreatic acinar cell

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis

Pressure activates rat pancreatic stellate cells

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