Melatonin protects from hepatic reperfusion injury through inhibition of IKK and JNK pathways and modification of cell proliferation

Liang, Rui; Nickkholgh, Arash; Hoffmann, Katrin; Kern, Michael; Schneider, H; Sobirey, Michael; Zorn, Markus; Büchler, Markus W.; Schemmer, Peter

doi:10.1111/j.1600-079x.2008.00596.x

Cited by 60 publications

(59 citation statements)

References 48 publications

(50 reference statements)

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“…Both receptors are coupled to G proteins, and their activation results in changes in intracellular cyclic nucleotides (cAMP and cGMP), modifying various downstream signaling pathways. Melatonin has been shown to inhibit JNK, c-Jun, and NF-B cascades (23,30), all major regulators of the immune response and apoptosis, which are key processes during VILI.…”

Section: Discussionmentioning

confidence: 99%

“…Although melatonin did not significantly decrease the proinflammatory cytokines measured (IL-1␤, IL-6, and TNF-␣) at this short time point, it did significantly increase IL-10 levels, thus altering the pro-to-anti-inflammatory cytokine balance. IL-10 is known to inhibit the release of other proinflammatory cytokines (30), and longer duration studies would be needed to further explore the effects of melatonin on proinflammatory cytokine expression. In addition, IL-10 can have direct effects on immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Effects of melatonin in an experimental model of ventilator-induced lung injury

Pedreira

García-Prieto

Parra

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice ( n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O], and high-pressure ventilation (peak inspiratory pressure 25 cmH2O, PEEP 0 cmH2O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1β, IL-6, TNF-α, and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF-α, IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-α, IL-1β, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of melatonin in an experimental model of ventilator-induced lung injury

Pedreira

García-Prieto

Parra

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The pineal hormone melatonin has been demonstrated to possess distinct protective potential in models of oxidative stress, i.e., local (486,726) and systemic (528, 529) I/R injury of the liver as well as liver exposure to acetaminophen (535) and cyclosporine (668). The proposed mechanisms of protection are said to involve direct inactivation of ROS and nitrogen species (791) and indirect effects by inducing antioxidative enzymes (617) and by improving the balance between NO and ET (958).…”

Section: Immunomodulatory and Pleiotropic Agentsmentioning

confidence: 99%

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Vollmar

Menger²

2009

Physiological Reviews

425

368

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The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.

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“…In previous studies, melatonin exerts the protective effects against hepatic I/R through several signaling pathways. Melatonin protects the liver against I/R injury through inhibition of IkB kinase and c-Jun N-terminal kinase pathways [24]. Moreover, the protective mechanisms of melatonin in hepatic I/R injury are associated with heme oxygenase-1 (HO-1) induction [25].…”

Section: Discussionmentioning

confidence: 99%