metallothionein and Pancreatitis

Zinc (Zn) is an essential, common metal in animal tissues. Zn levels were elevated in only four tissues after Zn administration, the highest increase being in the pancreas. Zn concentration was increased by metallothionein induction. Metallothionein-bound Zn significantly reduced the toxicity of the metals Cd, Cu and Hg. It should be noted that tissue Zn levels are different in experimental animals and humans. Acute pancreatitis was observed following the injection of a large dose of Zn. Different metals have different target organs. Using metal pathology, treatments may be developed to save patients suffering from hepatic and renal diseases because Zn is used to a model animal of hepatic or renal disease.

Topics: Amylases; Animals; Humans; Metallothionein; Mice; Pancreatitis; Zinc

Treatment of patients with acute pancreatitis has greatly improved due to a better understanding of the pathophysiology of the disease. This pathophysiology includes the activation and release of pancreatic enzymes in the interstitium, the autodigestion of the pancreas, and a multiple organ dysfunction after their release into the systemic circulation. Moreover, significant evidence exists that synthesis and release of proinflammatory cytokines and chemokines are also responsible for the local injury and systemic dispersion of the inflammation. The use of knockout mice devoid of active pro- or anti-inflammatory mediators allows examination of the effects of a specific cytokine without any drawbacks induced by pharmacological manipulations. The results obtained from these genetically modified mice show that numerous mediators have a major role in the pathophysiology of acute pancreatitis. They also clearly demonstrate that a single genetic deletion cannot completely prevent the occurrence of pancreatic or distant organ injury. However, the fact that the immune system is characterized by redundancies of ligands and receptors complicates the full understanding of each report. The utility of such experimental models might have limitations, and a full extrapolation of experimental data from genetically modified mice to humans must be done with caution.

Topics: Acute Disease; Animals; Cathepsin B; Cytokines; Disease Models, Animal; Intercellular Adhesion Molecule-1; Metallothionein; Mice; Mice, Knockout; Pancreatitis; Receptors, CCR1; Receptors, Chemokine; Receptors, Neurokinin-1; Superoxide Dismutase

The aims of the present studies were to measure the concentrations of zinc (Zn), copper (Cu), and metallothionein and the Cu/Zn superoxide dismutase activity as elements engaged in an essential manner in the prooxidative and antioxidative balance of organism and to demonstrate the degree to which metallothionein and Cu/Zn superoxide dismutase are involved in the inflammatory processes occurring in the pancreas.. The concentration of metallothionein was measured by immunoenzymatic method. Serum Cu/Zn superoxide dismutase activity was determined using a commercial test. The measurements of Zn and Cu concentrations in serum were assessed with the use of flame atomic absorption spectrometry.. Lowered serum Zn concentration and higher Cu level were observed in the serum of patients with chronic exacerbated pancreatitis and chronic pancreatitis. The significant increase of metallothionein concentration and Cu/Zn superoxide dismutase activity was observed in the blood of patients with chronic exacerbated pancreatitis and chronic pancreatitis. In slices of the pancreas during pancreatitis, we observed in immunohistochemical reaction the variable involvement of Cu/Zn superoxide dismutase and metallothionein.. The results presented in these studies indicate an essential and variable involvement of antioxidants such Cu/Zn superoxide dismutase and metallothionein and disordered Cu and Zn homeostasis depending on the progression of inflammatory processes in patients with pancreatitis.

Topics: Acute Disease; Adult; Aged; Case-Control Studies; Copper; Female; Humans; Immunohistochemistry; Male; Metallothionein; Middle Aged; Pancreatitis; Pancreatitis, Chronic; Superoxide Dismutase; Zinc

Metallothionein (MT) is a low-molecular weight intracellular protein, rich in sulfhydryl residues, and able to bind bivalent metals. MT, like Zn, is a component of the diversified elements of antioxidant system. Recent studies have shown that reactive oxygen species play a role in the pathogenesis and development of chronic pancreatitis. The aim of the study was to identify immunohistochemically (LSAB2-HRP; DAKOCytomation) the localization of metallothionein and to determine MT expression in 9 patients with chronic pancreatitis. Our studies confirm that MT is present in exocrine and endocrine cells of patients with chronic pancreatitis and chronic pancreatitis with concomitant diabetes. They also indicate increased expression of MT, particularly in acinar cells of the pancreas. This suggests that MT is greatly involved in homeostasis of the pancreas and synthesis of pancreatic hormones.

Topics: Adult; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Female; Granuloma, Plasma Cell; Humans; Immunoenzyme Techniques; Islets of Langerhans; Male; Metallothionein; Middle Aged; Pancreas; Pancreatic Cyst; Pancreatitis; Protein Isoforms

Oxidative stress has been proposed to play a role in the early events of acute pancreatitis, and metallothionein (MT) can provide protection against oxidative stress. Using transgenic mice, we characterized the effects of depletion of MT-I and -II, or overexpression of MT-I, on pancreatic responses during cerulein-induced acute pancreatitis. In MT-I/-II knockout mice, repeated injections of cerulein caused (a) higher serum amylase levels at 3 and 7 h after the initiation of acute pancreatitis; (b) earlier and stronger upregulation of oxidative stress-responsive genes, including heme oxygenase (HO)-1 and c-fos; and (c) exacerbated tissue damage (edema and polymorphonuclear neutrophil infiltration) compared with nontransgenic 129/SvCPJ mice. Total pancreatic glutathione (GSH + GSSG) content was similar between the knockout and nontransgenic 129/SvCPJ mice. Interestingly, during acute pancreatitis, CD-1 mice pretreated with L-buthionine-[S,R]-sulfoximine (BSO), which dramatically depleted pancreatic GSH, also had more severe pancreatitis, based on the same three criteria listed above, relative to untreated controls. No effects were observed with BSO treatment alone. Finally, during cerulein-induced acute pancreatitis, MT-I overexpressing transgenic mice (>20-fold increase in pancreatic MT-I content) had lower serum alpha-amylase levels between 7 and 24 h and delayed upregulation of HO-1 mRNA levels, but no difference in c-fos mRNA induction relative to the appropriate strain of nontransgenic mice. Diminished tissue damage (particularly cellular necrosis) was noted in these MT-I overexpressing transgenic mice. Total pancreatic GSH content was similar in these transgenic and nontransgenic mice during cerulein-induced acute pancreatitis. These studies suggest that pancreatic MT can function as an intracellular antioxidant as does GSH and that these intracellular antioxidants play a protective role during cerulein-induced acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Buthionine Sulfoximine; Ceruletide; Glutathione; Heme Oxygenase (Decyclizing); Male; Metallothionein; Mice; Mice, Knockout; Mice, Transgenic; Pancreas; Pancreatitis; Proto-Oncogene Proteins c-fos; RNA, Messenger

Oxidative stress and the inflammatory response may play roles in the pathogenesis of acute pancreatitis. Herein, we characterized pancreatic expression of oxidative stress-responsive genes [c-fos, heme oxygenase-1 (HO-1), and metallothionein-I (MT-I)] and cytokine genes [interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha)] during caerulein-induced acute pancreatitis in the mouse. c-fos, HO-1, and MT-I mRNAs were coordinately and rapidly (3-7 h) upregulated, and HO-1 and MT-I protein levels were increased slightly in the pancreas during acute pancreatitis. In addition, IL-1 beta, IL-6, and TNF-alpha mRNAs were rapidly (7 h) upregulated in the pancreas, and intrapancreatic IL-1 beta and IL-6 protein levels rapidly increased (3-fold and 6.4-fold, respectively) during acute pancreatitis. These studies suggest that oxidative stress and inflammation each occur in the pancreas during the early stages of acute pancreatitis. However, under a limited set of experimental conditions, we found that an insult that causes pancreatic oxidative stress (diethylmaleate) or one that induces an inflammatory response (bacterial lipopolysaccharide), or a combination of these agents, did not cause the changes characteristic of acute pancreatitis. Therefore, simply inducing oxidative stress and/or inflammation may be insufficient to initiate acute pancreatitis.

Topics: Acute Disease; alpha-Amylases; Animals; Ceruletide; Cloning, Molecular; Cytokines; Escherichia coli; Genes, fos; Glutathione; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Interleukin-1; Interleukin-6; Lipopolysaccharides; Male; Membrane Proteins; Metallothionein; Mice; Mice, Inbred Strains; Oxidative Stress; Pancreas; Pancreatitis; Proto-Oncogene Proteins c-fos; RNA, Messenger; Transcription, Genetic; Tumor Necrosis Factor-alpha

Recent findings have suggested that oxygen-derived free radicals play an important role in the development and progression of acute pancreatitis. Therefore, the present study was designed to investigate whether metallothionein, a free radical scavenger, can protect against acute pancreatitis. Rats were injected intraperitoneally with zinc, followed by either an infusion of cerulein at 10 micrograms/kg for 4 h or a retrograde injection with 100 microliters/100 g body weight of 5% sodium taurocholate into the pancreaticobiliary duct, in order to induce acute pancreatitis. Zn administration significantly increased the levels of both metallothionein and reduced glutathione in the pancreas; the metallothionein levels reached a peak of 83-fold of normal levels after 24 h. The indications of acute pancreatitis, as well as the mortality, were improved by Zn treatment before the onset of acute pancreatitis. Immunohistochemical studies showed that metallothionein accumulated in the acini of the pancreas in the Zn-treated groups, and with strong staining around the periphery of the vacuoles in the group treated with both Zn and cerulein. These findings suggested that Zn increased both metallothionein and glutathione levels in the pancreas and exerted a beneficial effect against ceruleinor taurocholate-induced acute pancreatitis in rats.

Topics: Acute Disease; Animals; Ceruletide; Free Radical Scavengers; Free Radicals; Glutathione; Immunohistochemistry; Male; Metallothionein; Pancreas; Pancreatitis; Rats; Rats, Wistar; Taurocholic Acid; Thiobarbituric Acid Reactive Substances; Zinc