Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin's anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2-related factor 2, and others. Melatonin's effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole's anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin's anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2012.01014.x

A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives.

Background:
Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis.

Methods:
A Medline/PubMed search (January 1966 to December 2005) with manual cross-referencing was conducted. All relevant articles investigating the pancreatic microcirculatory anatomy and the effect of pancreatitis on the microcirculation were included.

Results:
The pancreas is susceptible to ischaemic insult, which can exacerbate acute pancreatitis. There is also increasing evidence of pancreatic and systemic microvascular disturbances in the pathogenesis of pancreatitis, including vasoconstriction, shunting, inadequate perfusion, and increased blood viscosity and coagulation. These processes may be caused or exacerbated by ischaemia–reperfusion injury and the development of oxygen-derived free radicals.

Conclusion:
Acute pancreatitis impairs the pancreatic and systemic microcirculation, which is a key pathological process in the development of severe necrotizing disease. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Disturbances of the microcirculation in acute pancreatitis

Acute pancreatitis leads to various degrees of interstitial edema, acinar cell damage, hemorrhage, and the recruitment of leukocytes into the damaged gland. 1,2 Oxygen free radicals (OFRs) have been implicated as an important factor in the pathogenesis and progress of this disease. As highly reactive biochemical species, OFRs exert their pathophysiologic effects by directly attacking lipids 3 and proteins 4 in the biologic membranes at the local site of generation and cause their dysfunction. 5,6 Indirectly, they act on the arachidonic acid cascade by two mechanisms. First, they increase the production of thromboxane, which lowers tissue circulation by its potent platelet-aggregating and vasoconstricting effects. 7 Second, they enhance the production of leukotriene B4, which promotes the activation of leukocytes 8 and the discharge of lysosomal enzymes. 9 These changes contribute to further cell damage.

Since the first study by Sanfey et al, 10 many publications have addressed the role of OFRs in acute pancreatitis in both experimental 11,12 and clinical respects. 13 In most of these reports, an indirect approach was chosen to investigate their pathophysiologic role by applying different types of radical scavengers. 11,13 Most of these studies showed that free radical scavengers significantly ameliorated, but did not inhibit the characteristic changes observed with acute pancreatitis; OFRs are thus considered to be important mediators within this disease.

From in vitro studies, there is clear evidence that pancreatic acinar cells are susceptible to oxidative stress. Different oxygen radical species induce severe acinar cell damage in a dose- and time-dependent manner, which led to the conclusion that OFRs may be the crucial event for initiating the pathophysiologic changes of acute pancreatitis. 12 Surprisingly, only a few studies have been performed to investigate the potential of OFRs to induce the typical enzymatic and morphologic alterations of acute pancreatitis in vivo, and their results are controversial. 14,15 As a consequence, the question of whether OFRs act as mediator or as initiating event in acute pancreatitis under in vivo conditions remains unanswered. In the present study we aimed to address this issue in an in vivo experimental set-up.

Pathophysiologic role of oxygen free radicals in acute pancreatitis: initiating event or mediator of tissue damage?

Background—Reactive oxygen species and related oxidative damage have been implicated in the initiation of acute pancreatitis. Changes in these parameters during disease progression merit further investigation. 
Aims—To evaluate changes and the clinical relevance of superoxide radicals, endogenous antioxidants, and lipid peroxidation during the course of acute pancreatitis. 
Patients and methods—Superoxide radicals (measured as lucigenin amplified chemiluminescence), ascorbic acid, dehydroascorbic acid, α tocopherol, and lipid peroxidation (measured as thiobarbiturate reactive substances) were analysed in blood samples from 56 healthy subjects, 30 patients with mild acute pancreatitis, and 23 patients with severe acute pancreatitis. The association with grades of disease severity was analysed. Measurements were repeated one and two weeks after onset of pancreatitis. 
Results—In the blood from patients with acute pancreatitis, there were increased levels of the superoxide radical as well as lipid peroxides. There was notable depletion of ascorbic acid and an increased fraction of dehydroascorbic acid. Changes in α tocopherol were not great except in one case with poor prognosis. Differences between severe and mild acute pancreatitis were significant (p<0.01). Variable but significant correlations with disease severity scores were found for most of these markers. The normalisation of these indexes postdated clinical recovery one or two weeks after onset of disease. 
Conclusions—Heightened oxidative stress appears early in the course of acute pancreatitis and lasts longer than the clinical manifestations. The dependence of disease severity on the imbalance between oxidants and natural defences suggests that oxidative stress may have a pivotal role in the progression of pancreatitis and may provide a target for treatment. 



Keywords: acute pancreatitis; free radicals; superoxides; antioxidants; lipid peroxidation

https://gut.bmj.com/content/gutjnl/42/6/850.full.pdf

Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis

The cellular events leading to acute pancreatitis are not well defined and the mechanism by which known aetiological factors initiate the disease process remains to be established. Inflammatory mediators have recently been implicated as potential early markers of disease severity and may help elucidate the pathophysiology of the disease. Oxidative stress is emerging as a common effector of the acinar cell injury in experimental acute pancreatitis and clinical findings indicate that neutrophil activation is a significant early event. In common with neutrophil-mediated tissue damage in states of tissue hypoperfusion, acute pancreatitis shows many features of an ischaemia-reperfusion injury. Increased levels of phospholipase A2 have been demonstrated; this enzyme induces synthesis of prostaglandins and platelet-activating factor, a potent inflammatory mediator. New therapeutic approaches to the complications of acute pancreatitis may be through manipulation of such mediators of inflammation.

Inflammatory mediators in acute pancreatitis

This study aimed to assess the role of oxygen free radicals in acute pancreatitis. Acute pancreatitis was induced in rats by infusion of the CCK-analogue cerulein (5 micrograms/kg per hour) for 30 minutes, 3.5 hours, and 12 hours. After the infusion, serum enzymes and conjugated tissue dienes and malondialdehyde were measured and tissue samples were subjected to electron and light microscopy. Electron microscopy after 30 minutes showed moderate intracellular alterations. After 3.5 hours of cerulein infusion interstitial oedema and intravascular margination of granulocytes in the pancreatic gland were seen. After 12 hours histological evaluation showed pronounced zymogen degranulation, extensive tissue necrosis, and migration of granulocytes into the tissue. Amylase and lipase activities increased 15 and 35-fold respectively during this time. After 30 minutes of cerulein infusion conjugated dienes and malondialdehyde increased, they reached their peak after 3.5 hours and decreased to normal values after 12 hours. Treatment with superoxide dismutase (100,000 U/kg/hour) and catalase (400,000 U/kg/hour) either before or after the start of the cerulein infusion prevented lipid peroxidation and reduced zymogen degranulation and tissue necrosis. Tissue oedema and inflammatory response, however, were not affected in any of the treated rats. Oxygen free radicals are instrumental in the development of acute pancreatitis. Even after its onset, scavenger treatment reduced the tissue damage normally observed.

https://gut.bmj.com/content/gutjnl/31/10/1138.full.pdf

Oxygen free radicals in acute pancreatitis of the rat.

Oxygen free radicals inacutepancreatitis ofthe rat

Die akute Pankreatitis ist morphologisch gekennzeichnet durch schwere Schaden an den Acinuszellen. Das endoplasmatische Reticulum dieser Zellen erscheint dilatiert, die Zellorganellen zeigen bereits im fruhen Stadium der Erkrankung erhebliche Veranderungen. Gleichzeitig finden sich haufig intracellular autophagische Vacuolen, die im weiteren Verlauf an Grose zunehmen. Daruber inaus entwickelt das Pankreas ein ausgepragtes Gewebsodem, Granulocyten und Makrophagen akkumulieren in den Capillaren und Venolen und wandern in das Gewebe ein (1).

Die Bedeutung der Sauerstoffradikale in der Pathogenese der akuten Pankreatitis

No AccessZuversicht in Literatur und MusikManfred GasparManfred GasparManfred Gaspar M. A., Studium der Psychologie, Soziologie, Geschichte der Medizin, Sozialpädagogik, ist Psychoonkologe im Städtischen Krankenhaus Kiel.Search for more papers by this authorPublished Online:Feb 2022https://doi.org/10.13109/leid.2022.11.1.87SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail About Previous article Next article FiguresReferencesRelatedDetails Download book coverVolume 11Issue 1January 2022 ISSN: 2192-1202eISSN: 2196-8217HistoryPublished online:February 2022 PDF download 

Zuversicht in Literatur und Musik

Die akute Pankreatitis ist morphologisch gekennzeichnet durch schwere Schaden an den Acinuszellen mit ausgepragtem Gewebsodem und Akkumulation von Granulocyten und Makrophagen im Gewebe

M. Gaspar

Papers

Oxygen free radicals in acute pancreatitis of the rat.

Oxygen free radicals inacutepancreatitis ofthe rat

Die Bedeutung der Sauerstoffradikale in der Pathogenese der akuten Pankreatitis

Zuversicht in Literatur und Musik

Die Bedeutung der Sauerstoffradikale in der akuten Pankreatitis