Carbon monoxide has antioxidative properties in the liver involving p38 MAP kinase pathway in a murine model of systemic inflammation

Brugger, Jürgen; Schick, Martin Alexander; Brock, Robert W.; Baumann, Anja; Muellenbach, Ralf Michael; Roewer, Norbert; Wunder, Christian

doi:10.1111/j.1549-8719.2010.00044.x

Cited by 19 publications

(16 citation statements)

References 43 publications

(55 reference statements)

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“…Indeed, involvement of p38 MAPK is well documented in many diseases, including inflammatory disorders. Especially, it has been shown that CO, one of the byproducts of HO-1, provides an anti-inflammatory effect through activation of p38 MAPK (3,19,32). Because both induction of HO-1 and anti-inflammatory effect of EP were reversed by the presence of SB203580, we believe that p38 plays a key role for EP-mediated HO-1 induction.…”

Section: Discussionmentioning

confidence: 78%

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Jang

Kim

Tsoyi

et al. 2012

Antioxidants & Redox Signaling

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Aims: We investigated the molecular mechanism by which ethyl pyruvate (EP) induces heme oxygenase-1 (HO-1) in RAW 264.7 cells and its effect on survival rate in cecal ligation and puncture (CLP)-induced wild-type (WT) and HO-1 knockout (HO-1 -/ -) septic mice. Results: EP induced HO-1 in a dose-and time-dependent manner, which was mediated through p38 mitogen-activated protein kinase (MAPK) and NF-E2-related factor 2 (Nrf2) signaling cascade in RAW 264.7 cells. EP significantly inhibited the lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS) expression and high-mobility group box 1 (HMGB1) release in RAW 264.7 cells. The inhibitory effect of EP on LPS-stimulated iNOS expression and HMGB1 release was reversed by transfection with siHO-1RNA in RAW 264.7 cells, but EP failed to reduce them in HO-1 -/ -peritoneal macrophages treated with LPS. Moreover, treatment of cells with glutathione ethyl ester (GSH-Et), SB203580 (p38 MAPK inhibitor), siHO-1, or p38-siRNA transfection inhibited anti-inflammatory effect of EP. Interestingly, both HO-1 induction and phosphorylation of p38 by EP were reversed by GSH-Et, and antioxidant redox elementluciferase activity by EP was reversed by SB203580 in LPS-activated cells. EP increased survival and decreased serum HMGB1 in CLP-WT mice, whereas it did not increase survival or decrease circulating HMGB1 in HO-1 -/ -CLP-mice. Innovation and Conclusion: Our work provides new insights into the understanding the molecular mechanism by showing that EP induces HO-1 through a p38 MAPK-and NRF2-dependent pathway by decreasing GSH cellular levels. We conclude that EP inhibits proinflammatory response to LPS in macrophages and increases survival in CLP-induced septic mice by upregulation of HO-1 level, in which p38 MAPK and Nrf2 play an important role. Antioxid. Redox Signal. 17, 878-889.

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Section: Discussionmentioning

confidence: 78%

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Jang

Kim

Tsoyi

et al. 2012

Antioxidants & Redox Signaling

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“…However, it is not only the direct effect of HO-1 on limiting heme levels in injury sites that mediates the beneficial outcome of HO-1 activity. Also, the cytoprotective and anti-inflammatory effects of the end products generated by heme degradation, CO and biliverdin/bilirubin, have proven pivotal in improving the success of graft transplantation (Soares et al, 1998; Immenschuh and Ramadori, 2000; Kato et al, 2003; Nakao et al, 2004; Lee et al, 2007; Brugger et al, 2010). …”

Section: Pharmacological Regulation Of Ho-1 and Its Effector Moleculementioning

confidence: 99%

Heme Oxygenase, Inflammation, and Fibrosis: The Good, the Bad, and the Ugly?

Lundvig¹,

Immenschuh²,

Wagener³

2012

Front. Pharmacol.

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Upon injury, prolonged inflammation and oxidative stress may cause pathological wound healing and fibrosis, leading to formation of excessive scar tissue. Fibrogenesis can occur in most organs and tissues and may ultimately lead to organ dysfunction and failure. The underlying mechanisms of pathological wound healing still remain unclear, and are considered to be multifactorial, but so far, no efficient anti-fibrotic therapies exist. Extra- and intracellular levels of free heme may be increased in a variety of pathological conditions due to release from hemoproteins. Free heme possesses pro-inflammatory and oxidative properties, and may act as a danger signal. Effects of free heme may be counteracted by heme-binding proteins or by heme degradation. Heme is degraded by heme oxygenase (HO) that exists as two isoforms: inducible HO-1 and constitutively expressed HO-2. HO generates the effector molecules biliverdin/bilirubin, carbon monoxide, and free iron/ferritin. HO deficiency in mouse and man leads to exaggerated inflammation following mild insults, and accumulating epidemiological and preclinical studies support the widely recognized notion of the cytoprotective, anti-oxidative, and anti-inflammatory effects of the activity of the HO system and its effector molecules. In this review, we address the potential effects of targeted HO-1 induction or administration of HO-effector molecules as therapeutic targets in fibrotic conditions to counteract inflammatory and oxidative insults. This is exemplified by various clinically relevant conditions, such as hypertrophic scarring, chronic inflammatory liver disease, chronic pancreatitis, and chronic graft rejection in transplantation.

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“…Another study indicated that exogenous CO was capable of effectively inhibiting inflammatory response and oxidative stress in the activated HuVEC 14. The exogenous administration of CO reduced the generation of reactive oxygen species (ROS) to prevent cell injury, this CO-dependent effect was shown to be independent of the activity of endogenous HO and the antioxidant potential of exogenous CO involved the activation of the p38 MAPK signal transduction pathway 15. Similar to nitric oxide (NO), CO mediates platelet aggregation and relaxes blood vessels via activating soluble guanylyl cyclase (sGC) and consequently elevating intracellular levels of cyclic guanosine-3', 5'-monophosphate (cGMP) in target tissues 16.…”

Section: Introductionmentioning

confidence: 99%

Influence of Carbon Monoxide on Growth and Apoptosis of Human Umbilical Artery Smooth Muscle Cells and Vein Endothelial Cells

Li¹,

Wang

Yang³

et al. 2012

Int. J. Biol. Sci.

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Carbon monoxide (CO) is a vasoactive molecule that is generated by vascular cells as a byproduct of heme catabolism and it plays an important physiological role in circulation system. In order to investigate whether exogenous CO can mediate the growth and proliferation of vascular cells, in this study, we used 250 parts per million (ppm) of CO to treat human umbilical artery smooth muscle cell (hUASMC) and human umbilical vein endothelial cell (HuVEC) and further evaluated the growth and apoptosis status of SMC and HuVEC. After SMC and HuVEC were exposed to CO for 7-day, the growth of SMC and HuVEC was significantly inhibited by CO in vitro on day 5 of CO exposure. And CO blocked cell cycle progress of SMC and HuVEC, more SMC and HuVEC stagnated at G0/G1 phase by flow cytometric analysis. Moreover, CO treatment inhibited SMC and HuVEC apoptosis caused by hydrogen peroxide through decreasing caspase 3 and 9 activities. To confirm the molecular mechanism of CO effect on SMC and HuVEC growth, we compared the gene expression profile in SMC and CO-treated SMC, HuVEC and CO-treated HuVEC. By microarray analysis, we found the expression level of some genes which are related to cell cycle regulation, cell growth and proliferation, and apoptosis were changed during CO exposure. We further identified that the down-regulated CDK2 contributed to arresting cell growth and the down-regulated Caspase 3 (CASP3) and Caspase 9 (CASP9) were associated with the inhibition of cell apoptosis. Therefore, CO exerts a certain growth arrest on SMC and HuVEC by inhibiting cell cycle transition from G0/G1 phase to S phase and has regulatory effect on cell apoptosis by regulating the expression of apoptosis-associated genes.

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Carbon monoxide has antioxidative properties in the liver involving p38 MAP kinase pathway in a murine model of systemic inflammation

Abstract: CO has direct antioxidant potential independently of any HO activity during systemic inflammation. The antioxidant effects afforded by CO involve the activation of the p38 MAPK pathway.

Cited by 19 publications

References 43 publications

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Heme Oxygenase, Inflammation, and Fibrosis: The Good, the Bad, and the Ugly?

Influence of Carbon Monoxide on Growth and Apoptosis of Human Umbilical Artery Smooth Muscle Cells and Vein Endothelial Cells

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