PubMed Health⌕ Search

Biomedical subjects

Markus M Lerch

Publications and source records attributed to Markus M Lerch.

At least 19 recordsLinked to original sources
PubMed2007

Why does pancreatic overstimulation cause pancreatitis?

Many animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen activation is an essential early event in the pathogenesis of secretagogue-induced pancreatitis. Early in the course of pancreatitis, lysosomal hydrolases colocalize with digestive zymogens and activate them. These activated zymogens then cause acinar cell injury and necrosis, a characteristic of pancreatitis. Besides being the site of initiation of injury in pancreatitis, acinar cells also synthesize and release cytokines and chemokines very early in the course of pancreatitis, which then attract and activate inflammatory cells and initiate the disease's systemic phase.

Animals↗
PubMed2006

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Base Sequence↗
PubMed2006

Germline mutations and gene polymorphism associated with human pancreatitis.

A wide range of mutations and polymorphisms in genes that relate to pancreatic function seem to be involved in the development of pancreatitis. Some of these genetic alterations lead to disease phenotypes with unequivocal mendelian inheritance patterns, whereas others seem to act as modifier genes in conjunction with environ-mental or, as yet unidentified, genetic cofactors. This article reviews germline changes in the genes for trypsin, pancreatic secretory trypsin inhibitor, the cystic fibrosis conductance regulator, lipid metabolism proteins, inflammatory mediators for cytokines, and cathepsin B.

Carrier Proteins↗
PubMed2006

Developmental and metabolic disorders of the pancreas.

The pancreas is an important exocrine and endocrine organ that develops from the dorsal and ventral anlagen during embryogenesis and arises from the endodermal lining of the duodenum within the first month of human embryonic life. A number of developmental disorders can either lead to anatomic abnormalities of the pancreas and its ducts, or can be part of complex disorders that affect multiorgan systems. Other genetic changes can lead to metabolic abnormalities that affect the pancreas exclusively or increase the lifetime risk for developing pancreatitis or pancreatic diabetes. This article reviews some of the developmental and metabolic disorders that can affect the endocrine and exocrine pancreas.

Beckwith-Wiedemann Syndrome↗
PubMed2006

Cell biology of pancreatic proteases.

More than 100 years ago it was proposed that pancreatitis essentially is a disease in which the pancreas undergoes autodigestion by its own prematurely activated digestive enzymes. Why and how digestive zymogens autoactivate within the pancreas early in the disease process has been a matter of controversy and debate. Some of the mechanisms that are considered to be involved indigestive protease activation are inherited and as of recently can be tested for clinically. Here we review the most recent progress in elucidating the mechanisms involved in the onset of pancreatitis. We specifically focus on serine and cysteine proteases in the autodigestive cascade that precedes acinar cell injury and the biochemical processes involved in their activation.

Animals↗
PubMed2006

Genetic basis and pancreatic biology of Johanson-Blizzard syndrome.

The most recent elucidation of an inherited disorder of the pancreas concerns the Johanson-Blizzard syndrome (JBS). Positional cloning identified loss-of-function mutations in the UBRI gene on the long arm of chromosome 15 to be the cause of JBS in more than a dozen patients. In patients with JBS the absence of UBRI results in early prenatal destruction of the exocrine pancreas that involves impaired apoptosis, induced necrosis, and prominent inflammation. Knockout mice with absent UBR1 expression suffer from exocrine pancreatic insufficiency and increased susceptibility to experimental pancreatitis. The UBR1 protein substrate, presumably impaired degradation of which causes JBS, is not yet known.

Abnormalities, Multiple↗
PubMed2006

Thoracic epidural analgesia augments ileal mucosal capillary perfusion and improves survival in severe acute pancreatitis in rats.

BACKGROUND: Acute pancreatitis has been linked to intestinal barrier dysfunction and systemic inflammatory response with high mortality. Thoracic epidural analgesia improves intestinal perfusion. The authors hypothesized that thoracic epidural analgesia influences microcirculation injury, inflammatory response, and outcome of acute pancreatitis in rats. METHODS: Control groups underwent a sham procedure or untreated pancreatitis induced by intraductal taurocholate injection. In the treatment groups, epidural analgesia was commenced immediately or after a 7-h delay. Fifteen hours after injury, the ileal mucosal perfusion was assessed by intravital microscopy. Thereby, the intercapillary area between all perfused capillaries and between continuously perfused capillaries only was used to differentially quantify total and continuous capillary mucosal perfusion. Villus blood flow and serum levels of amylase, lactate, and interleukin 6 were determined, and pancreatic injury was scored histologically. Seven-day survival was recorded in an additional 30 rats undergoing untreated pancreatitis or pancreatitis with epidural analgesia. RESULTS: In untreated pancreatitis, decreased total capillary perfusion increased the total intercapillary area by 24%. Furthermore, loss of continuous perfusion increased continuous intercapillary area to 228%. After immediate and delayed epidural analgesia, continuous perfusion was restored (P < 0.05). Blood flow decreased 50% in untreated pancreatitis but was preserved by epidural analgesia (P < 0.05). Biochemical and histologic signs of pancreatitis were not affected by epidural analgesia. Lactate and interleukin-6 levels increased in untreated pancreatitis, which was prevented in the treatment groups (P < 0.05). Epidural analgesia increased 7-day survival from 33% to 73% (P < 0.05). CONCLUSION: Thoracic epidural analgesia attenuated systemic response and improved survival in severe acute pancreatitis. These effects might be explained by improved mucosal perfusion.

Analgesia, Epidural↗
PubMed2006

The role of antibiotic prophylaxis in the treatment of acute pancreatitis.

Acute pancreatitis is an inflammatory disorder, but it is not generally caused by infectious agents. Yet, in tertiary referral hospitals, the majority of patients who die of necrotizing pancreatitis do so as a consequence of infectious complications. These generally develop late (2-4 weeks) in the disease process. This finding prompted the hypothesis that infectious pancreatitis complications, such as an abscess or an infected necrosis which can lead to death, can be reduced by treating patients who suffer, at least initially, from a sterile inflammatory disorder, with broad-spectrum antibiotics. Here we review the experimental foundations of this hypothesis, as well as the difficulties that were encountered when clinical trials were undertaken to confirm it. At present, there is still a case for treating necrotizing pancreatitis patients with broad-spectrum antibiotics (specifically carbapenems), but the extent of the beneficial effect and the number of patients expected to profit from this approach should not be overestimated.

Antibiotic Prophylaxis↗
PubMed2006

Pharmacological prevention and treatment of acute pancreatitis: where are we now?

Acute pancreatitis is a disease of increasing prevalence, unchanged mortality over many decades, and limited treatment strategies. Progress has been made in developing therapies that reduce the rate of endoscopic retrograde cholangiopancreatography (ERCP)-associated pancreatitis and in preventing infected pancreatic necrosis with intravenous carbapenems. Attempts at reducing pancreatic enzyme output or inhibiting the activity of digestive enzyme proteases have not yielded encouraging results - nor have anti-inflammatory strategies for the treatment of acute pancreatitis been found to be effective so far. Future therapeutic options that are presently being developed or under investigation attempt to restore pancreatic secretory function, interfere with inflammatory pathways in a more effective manner, or inhibit digestive enzyme proteases more selectively.

Analgesics↗
PubMed2005

Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.

Abnormalities, Multiple↗
PubMed2005

Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase.

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-lipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.

Adenocarcinoma↗
PubMed2005

Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence.

BACKGROUND/AIMS: Cholelithiasis is a common disorder in north-eastern Germany. Analyses of risk factors for gallstone formation in this population may have high explanatory power. Gender-specific risk factors for gallstone formation and their interactions were investigated by using data of the population-based Study of Health in Pomerania (SHIP). METHODS: Data of 4,202 persons aged 20-79 years were available. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on abdominal ultrasound. Multivariable analyses were performed to identify independent risk factors for gallstone formation. RESULTS: There were 468 persons (11.1%) with previous cholecystectomy and 423 persons (10.1%) with sonographic evidence of gallstones. Women had a twofold higher risk for cholelithiasis compared to men. Age, body mass index and low serum HDL cholesterol levels were independently associated with cholelithiasis in both men and women. In the male population, low alcohol and high coffee consumption and in the female population, low physical activity, were further independently related to gallstone formation. Additionally, sex-specific interactions between risk factors were found. CONCLUSIONS: Female sex, age and being overweight are major risk factors for gallstone formation in this region where cholelithiasis is a frequent disorder. Additional factors and interactions contribute to a gender-specific gallstone risk.

Adult↗
PubMed2005

Early events in acute pancreatitis.

Considerable progress in the understanding of the pathogenesis of acute pancreatitis is based on the conclusive finding that the initiation of the disease occurs within the acinar cell. Two lines of evidence have contributed to the progress in understanding the disease process: (1) the identification of patients with a hereditary form of pancreatitis as carriers of germline-mutations in the genes for cationic trypsinogen and the pancreatic secretory trypsin inhibitor and (2) the use of various transgenic and knock-out mouse strains in experimental models of acute pancreatitis. On the other hand, these studies have delivered several unexpected results that appear to be incompatible with long-standing dogmas and paradigms of pancreatic research. Further progress in knowledge will result if the well-characterized enzymatic properties of human enzymes that are involved in the initial activation cascade can be investigated under in vivo conditions in transgenic animals or in permanent acinar cell lines. Such studies will permit the development of effective strategies for the prevention and treatment of this disease.

Acute Disease↗
PubMed2005

Current management of acute pancreatitis.

The incidence of acute pancreatitis varies considerably between regions and is estimated at 5-80 per 100,000 population. The mortality rate of acute edematous-interstitial pancreatitis is below 1%, whereas 10-24% of patients with severe acute pancreatitis die. The early prognostic factors that can be used to determine whether the clinical course is likely to be severe are three or more signs of organ failure according to the Ranson or Imrie scores, the presence of nonpancreatic complications, and the detection of pancreatic necrosis by imaging techniques. Elevated C-reactive protein levels above 130 mg/l can also predict a severe course of acute pancreatitis with high sensitivity. Although no causal treatment exists, replacing the dramatic fluid loss that takes place in the early disease phase is critical and determines the patient's prognosis. Adequate pain relief with opiates is another therapeutic priority. In patients with pancreatic necrosis, the high mortality rate between the third and fourth week after the initial episode is determined largely by the development of pancreatic infection, and can therefore be reduced by early antibiotic treatment. Early enteral nutrition for the treatment of acute pancreatitis has been shown to be superior and much more cost-effective than parenteral nutrition. Infected pancreatic necrosis or pancreatic abscess are two of the few remaining indications for open surgery in acute pancreatitis. Even when indicated, surgery is frequently delayed or even replaced by minimally invasive surgical techniques.

Acute Disease↗
PubMed2005

Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats.

BACKGROUND & AIMS: Cadherins play an important role in cell-cell contact formation at adherens junctions. During the course of acute pancreatitis, adherens junctions are known to dissociate-a requirement for the interstitial accumulation of fluid and inflammatory cells-but the underlying mechanism is unknown. METHODS: Acute pancreatitis was induced in rats by supramaximal cerulein infusion. The pancreas and lungs were either homogenized for protein analysis or fixed for morphology. Protein sequencing was used to identify proteolytic cleavage sites and freshly prepared acini for ex vivo studies with recombinant proteases. Results were confirmed in vivo by treating experimental pancreatitis animals with specific protease inhibitors. RESULTS: A 15-kilodalton smaller variant of E-cadherin was detected in the pancreas within 60 minutes of pancreatitis, was found to be the product of E-cadherin cleavage at amino acid 394 in the extracellular domain that controls cell-contact formation, and was consistent with E-cadherin cleavage by leukocyte elastase. Employing cell culture and ex vivo acini leukocyte elastase was confirmed to cleave E-cadherin at the identified position, followed by dissociation of cell contacts and the internalization of cleaved E-cadherin to the cytosol. Inhibition of leukocyte elastase in vivo prevented E-cadherin cleavage during pancreatitis and reduced leukocyte transmigration into the pancreas. CONCLUSIONS: These data provide evidence that polymorphonuclear leukocyte elastase is involved in, and required for, the dissociation of cell-cell contacts at adherens junctions, the extracellular cleavage of E-cadherin, and, ultimately, the transmigration of leukocytes into the epithelial tissue during the initial phase of experimental pancreatitis.

Acute Disease↗