Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) is classically characterized as a circulating hormonal system primarily through the production of the physiologically active product angiotensin II (Ang II) that plays a crucial role in the regulation of blood pressure, fluid and electrolyte homeostasis. In addition to this circulating RAS, numerous tissues and organs have been recently demonstrated to exhibit their own RAS products and activities. Such an intrinsic RAS can modulate the specific local functions of their respective tissues and organs, frequently in a paracrine and autocrine manner. Recent findings from our laboratories and others have made a significant contribution on the expression, localization, regulation, and potential role of a local RAS in the pancreas. Although, it is quite intriguing that components of the local pancreatic RAS are responsive to various physiological and pathophysiological conditions, the crucial role of this system in regulating the exocrine and endocrine functions and ultimately the clinical relevance to pancreatic disease is still largely equivocal. Of particular interest in this context are the actions of pancreatic RAS on the growth, anti-proliferation and free radical generation in the pancreas. The aims of the current article focus on the emerging data on the local pancreatic RAS; its involvement in exocrine acinar and endocrine islet aspects, and the clinical significance in the pancreas are particularly addressed. The target for the local pancreatic RAS may provide a new insight into future management of various clinical conditions including islet transplants, diabetes mellitus, pancreatic cancer, pancreatitis and cystic fibrosis.
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PMID:A local pancreatic renin-angiotensin system: endocrine and exocrine roles. 1267 70

Previous studies showed that a local pancreatic renin-angiotensin system (RAS) was upregulated in experimental acute pancreatitis. RAS inhibition could attenuate pancreatic inflammation and fibrosis, which casts a new light on the role of the pancreatic RAS in pancreatitis. The present study explores the prophylactic and therapeutic potentials, and possible molecular mechanism for the antagonism of angiotensin II receptors on the changes in the severity of pancreatic injury induced by acute pancreatitis. Experimental pancreatitis was induced by an intraperitoneal injection of supra-maximal dose of cerulein. The differential effects of angiotensin II receptors inhibitors losartan and PD123319 on the pancreatic injury were assessed by virtue of using the pancreatic water content, biochemical and histological analyses. Blockade of the AT(1) receptor by losartan at a dose of 200microg/kg could markedly ameliorate the pancreatic injury induced by cerulein, as evidenced by biochemical and histopathological studies. However, blockade of the AT(2) receptor by PD123319 appeared not to provide any beneficial role in cerulein-induced pancreatic injury. Both prophylactic and therapeutic treatments with losartan were effective against cerulein-induced pancreatic injury. The protective action of losartan was linked to an inhibition of NAD(P)H oxidase activity, thus consequential oxidative modification of pancreatic proteins in the pancreas. Inhibition of the AT(1) receptor, but not AT(2) receptor, may play a beneficial role in ameliorating the severity of acute pancreatitis. The differential effects of AT(1) and AT(2) inhibitors on cerulein-induced pancreatic injury might be due to the distinctive mechanism of the AT(1) and AT(2) receptors on the activation of NAD(P)H oxidase. Thus the protective role of AT(1) receptor antagonist, losartan, could be mediated by the inhibition of NAD(P)H oxidase-dependent generation of reactive oxygen species (ROS).
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PMID:Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis. 1464 97

The pancreas contains a local renin-angiotensin system (RAS), which is subject to activation by experimental pancreatitis. In the exocrine pancreas, angiotensin II receptor subtypes AT1 and AT2 have been localized in the pancreatic ducts, blood vessels and acinar cells. We hypothesize that local RAS activities may have a potential role in regulating pancreatic acinar digestive enzyme secretion. The present study was designed to elucidate firstly the existence of RAS components in pancreatic acinar cells and their regulation by acute pancreatitis. Secondly, the differential roles of AT1 and AT2 receptors in controlling digestive enzyme secretion from dispersed functional pancreatic acini were also investigated. The mRNA levels of RAS components were assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Acinar secretions were assayed by the measurement of alpha-amylase and lipase activities. Induction of acute pancreatitis was achieved by hyperstimulation of two intraperitoneal (i.p.) injections of cerulein (50 microg/kg/h). Results from RT-PCR showed that the mRNA levels of the major RAS components (angiotensinogen, AT1 and AT2 receptors) were expressed in isolated rat pancreatic acinar cells, and they were upregulated during pancreatitis. Exogenous addition of angiotensin II could stimulate a dose-dependent release of digestive enzymes from the acinar cells. Administration of the selective AT1 receptor antagonist losartan significantly inhibited the acinar digestion enzyme secretion in both normal and pancreatitis-induced acini. However, a specific AT2 receptor blocker PD123319 did not exhibit such a suppressive effect. These data indicate the existence of an acinar RAS in the pancreas of potential importance in the physiological regulation of digestive enzyme secretion. The differential actions of AT1 and AT2 receptors and their upregulation may have clinical relevance to the pathogenesis and management of acute pancreatitis.
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PMID:The role of the pancreatic renin-angiotensin system in acinar digestive enzyme secretion and in acute pancreatitis. 1512 Apr 83

Acute pancreatitis (AP) is an inflammatory disease characterized by tissue edema, necrosis and hemorrhage. The mortality rate associated with this disease is particularly high when the inflammation has become systemic. Recently, activation of the pancreatic renin-angiotensin system (RAS) was shown to play a role in AP. The present study investigated whether administering an AT1 receptor antagonist decreases the severity of AP and pancreatitis-induced systemic inflammation, particularly pulmonary injury. Rats with AP-associated lung injury were induced by multiple doses of caerulein, which was demonstrated in the previous studies. Three injections of losartan (200 microg/ kg/h) were given 30 min prior to the first injection of caerulein. The results demonstrated that caerulein injections resulted in significant increases in pancreatic and pulmonary myeloperoxidase (MPO) activities, and losartan treatment attenuates these effects. Lung microvascular permeability was also significantly improved by losartan treatment. Losartan prevented caerulein-induced pancreatic and pulmonary morphological alterations, but not elevations in serum alpha-amylase or pancreas/body weight ratio. These data indicate that losartan treatment can attenuate pancreatic and lung injury. Thus, the implication is that a blockade of AT1 receptors may have a clinical application for the treatment of AP and, perhaps more importantly, subsequent pulmonary complications.
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PMID:AT1 receptor antagonism ameliorates acute pancreatitis-associated pulmonary injury. 1644 93

The systemic renin-angiotensin system (RAS) plays an important role in regulating blood pressure, electrolyte and fluid homeostasis. However, local RASs also exist in diverse tissues and organs, where they play a multitude of autocrine, paracrine and intracrine physiological roles. The existence of a local RAS is now recognized in pancreatic acinar, islet, duct, endothelial and stellate cells, the expression of which is modulated in response to physiological and pathophysiological stimuli such as hypoxia, pancreatitis, islet transplantation, hyperglycaemia, and diabetes mellitus. This pancreatic RAS has been proposed to have important endocrine and exocrine roles in the pancreas, regulating local blood flow, duct cell sodium bicarbonate secretion, acinar cell digestive enzyme secretion, islet beta-cell (pro)insulin biosynthesis, and thus, glucose-stimulated insulin release, delta-cell somatostatin secretion, and pancreatic cell proliferation and differentiation. It may further mediate oxidative stress-induced cell inflammation, apoptosis and fibrosis. Further exploration of this system would probably offer new insights into the pathogenesis of pancreatitis, diabetes, cystic fibrosis and pancreatic cancer formation. New therapeutic targets and strategies might thus be suggested.
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PMID:The physiology of a local renin-angiotensin system in the pancreas. 1721 53

The renin-angiotensin system contributes to pathological processes in a variety of organs. In the pancreas, blocking the angiotensin II (AII) type 1 receptor (AT1) attenuates pancreatic fibrogenesis in animal models of pancreatitis. Because the role of the AII type 2 receptor (AT2) in modulating pancreatic injury is unknown we investigated the role of AT2 in pancreatic injury and fibrosis. Pancreatic fibrosis was induced by repetitive cerulein administration in C57BL/6 wild-type (WT) or AT2-deficient (AT2-/-) mice and assessed by morphology and gene expression at 10 days. There was no difference between WT and AT2-/- mice in the degree of acute pancreatic injury as assessed by amylase release at 9 and 12 h and by histological examination of the pancreas at 12 h. In contrast, parenchymal atrophy and fibrosis were more pronounced in AT2-/- mice compared with WT mice at 10 days. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for alpha-smooth muscle actin and by immunocytochemistry; PSC activation was further increased in AT2-/- mice compared with WT mice. The level of pancreatic transforming growth factor-beta1 mRNA and protein after repetitive cerulein treatment was higher in AT2-/- mice than in WT mice. Our results demonstrate that, in contrast to AT1 receptor signaling, AT2 receptor signaling modulates protective antifibrogenic effects in a mouse model of cerulein-induced pancreatic fibrogenesis. We propose that the effects of AII on injury-induced pancreatic fibrosis may be determined by the balance between AT1 and AT2 receptor signaling.
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PMID:Protective role of angiotensin II type 2 receptor signaling in a mouse model of pancreatic fibrosis. 1903 39

The intraorgan renin-angiotensin system (RAS) plays an important role in the pathophysiology of a variety of diseases and has been implicated in fibrogenesis. The role of RAS in the development of chronic pancreatitis is not well established. The blockade of RAS in rat models with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor 1 (AT1) blockers (ARBs) mostly have reduced pancreatic inflammation and fibrosis with a few exceptions. At the same time, the use of ACEi and ARBs in humans is associated with a modest risk of acute pancreatitis. The aim of this study was to elucidate the effect of the AT1 signaling pathway in the development of pancreatitis using AT1a- and AT1b-deficient mice as well as the ARB losartan. Chronic pancreatitis was induced by repetitive cerulein administration in C57BL/6J wild-type (WT) and AT1a- and AT1b-deficient mice (AT1a-/- and AT1b-/-), and pancreatic injury was assessed at day 10. Pancreatic weight of cerulein treated groups was significantly reduced. There was severe parenchymal atrophy and fibrosis assessed by histological examination. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for alpha-smooth muscle actin. No differences were seen between cerulein-treated WT, AT1a-/- , AT1b-/- mice, or losartan treated-WT mice with regards to morphological or molecular alterations induced by cerulein. Our results demonstrate that AT1a and AT1b receptor pathways do not seem to be essential for the development of pancreatitis in the mouse model of pancreatitis induced by repetitive cerulein injury.
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PMID:Angiotensin II signaling through the AT1a and AT1b receptors does not have a role in the development of cerulein-induced chronic pancreatitis in the mouse. 2041 21

Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis.
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PMID:Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis. 2617 Jul 33

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin-angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT1 ) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.
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PMID:The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases. 3019 85

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT1R axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT1R axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.
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PMID:The ACE-2 in COVID-19: Foe or Friend? 3234 44


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