Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Kinjo, Nao; Kawanaka, Hirofumi; Akahoshi, Tomohiko; Yamaguchi, Shohei; Yoshida, Daisuke; Anegawa, Go; Konishi, Kozo; Tomikawa, Morimasa; Tanoue, Kazuo; Tarnawski, Andrzej S.; Hashizume, Makoto; Maehara, Yoshihiko

doi:10.1152/ajpgi.90329.2008

Cited by 33 publications

(31 citation statements)

References 44 publications

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“…These results were inconsistent with those of Hong et al (1998), who noted similar effects of rebamipide against liver damage induced by endotoxic shock. Further, the present results confirmed previously reported data from several studies that comment on the anti-oxidant activity imparted by rebamipide (Hahm et al 1997;Kinjo et al 2008;Tokuhara et al 2008).…”

Section: Discussionsupporting

confidence: 92%

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Zakaria

El‐Sisi

2016

Journal of Immunotoxicology

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Prostaglandin E 2 (PGE 2 ) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE 2 , this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl 4 ). Groups of Wistar rats received intraperitoneal (IP) injections of CCl 4 (0.45 ml/kg [0.72 g CCl 4 /kg]) over the course of for 4 weeks. Sub-sets of CCl 4 -treated rats were also treated concurrently with rebamipide at 60 or 100 mg/kg. At 24 h after the final treatments, liver function and oxidative stress were indirectly assessed. The extent of hepatic fibrosis was evaluated using two fibrotic markers, hyaluronic acid (HA) and pro-collagen-III (Procol-III); isolated liver tissues underwent histology and were evaluated for interleukin (IL)-10 and PGE 2 content. The results indicated that treatment with rebamipide significantly inhibited CCl 4 -induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl 4 . Fibrotic marker assays revealed that either dose of rebamipide decreased the host levels of Procol-III and HA that had become elevated due to the CCl 4 . At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl 4 -induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE 2 and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl 4 and that this effect may, in part, be mediated by an induction of PGE 2 and IL-10 in the liver itself. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 92%

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Zakaria

El‐Sisi

2016

Journal of Immunotoxicology

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“…Intragastric administration ameliorates oxidative stress, reduces nitration of tyrosine residues of ERK, and reverses delayed mucosal healing occurring in PHG. It reversed the increased susceptibility to ethanol-induced injury and reversed the delayed healing after gastric injury in rats with PHG [145] . Kinjo et al [145] reported that administration of rebamipide in rats with PHG, significantly decreased lipid peroxide and nitrotyrosine and nitration of ERK by peroxynitrite in PHG mucosa, therefore normalizing ERK activation and restoring normal gastric mucosal healing after ethanol injury.…”

Section: Vasopressin and Terlipressinmentioning

confidence: 86%

“…It reversed the increased susceptibility to ethanol-induced injury and reversed the delayed healing after gastric injury in rats with PHG [145] . Kinjo et al [145] reported that administration of rebamipide in rats with PHG, significantly decreased lipid peroxide and nitrotyrosine and nitration of ERK by peroxynitrite in PHG mucosa, therefore normalizing ERK activation and restoring normal gastric mucosal healing after ethanol injury. Rebamipide requires further study as a therapy for PHG [119] .…”

Section: Vasopressin and Terlipressinmentioning

confidence: 86%

“…Kawanaka et al [144] showed impaired endoplasmic reticulum serine/ threonine kinase-2 (ERK2) activation after oxidative stress in rat gastric mucosa; ERK2 normally protects against cellular stress by inducing cell proliferation in gastric mucosa. Kinjo et al [145] showed that enhanced nitration of ERK by peroxynitrite is involved in impaired MAPK (ERK) signaling in PHG, which impairs mucosal healing and promotes mucosal injury. The levels of lipid peroxide and nitrotyrosine that tend to promote gastric injury increased significantly in rats with PHG as compared to controls.…”

Section: Apoptosis: Wu Et Almentioning

confidence: 99%

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Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

Gjeorgjievski¹

2016

WJH

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AIM:To describe the pathophysiology, clinical presentation, natural history, and therapy of portal hypertensive gastropathy (PHG) based on a systematic literature review. METHODS:Computerized search of the literature was performed via PubMed using the following medical subject headings or keywords: "portal" and "gastropathy"; or "portal" and "hypertensive"; or "congestive" and "gastropathy"; or "congestive" and "gastroenteropathy". The following criteria were applied for study inclusion: Publication in peer-reviewed journals, and publication since 1980. Articles were independently evaluated by each author and selected for inclusion by consensus after discussion based on the following criteria: Well-designed, prospective trials; recent studies; large study populations; and study emphasis on PHG. RESULTS:PHG is diagnosed by characteristic endoscopic findings of small polygonal areas of variable erythema surrounded by a pale, reticular border in a mosaic pattern in the gastric fundus/body in a patient with cirrhotic or non-cirrhotic portal hypertension. Histologic findings include capillary and venule dilatation, congestion, and tortuosity, without vascular fibrin thrombi or inflammatory cells in gastric submucosa. PHG is differentiated from gastric antral vascular ectasia by a different endoscopic appearance. The etiology of PHG is inadequately understood. Portal hypertension is necessary but insufficient to develop PHG because many patients have portal hypertension without PHG. Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy PHG increases in frequency with more severe portal hypertension, advanced liver disease, longer liver disease duration, presence of esophageal varices, and endoscopic variceal obliteration. PHG pathogenesis is related to a hyperdynamic circulation, induced by portal hypertension, characterized by increased intrahepatic resistance to flow, increased splanchnic flow, increased total gastric flow, and most likely decreased gastric mucosal flow. Gastric mucosa in PHG shows increased susceptibility to gastrotoxic chemicals and poor wound healing. Nitrous oxide, free radicals, tumor necrosis factor-alpha, and glucagon may contribute to PHG development. Acute and chronic gastrointestinal bleeding are the only clinical complications. Bleeding is typically mild-to-moderate. Endoscopic therapy is rarely useful because the bleeding is typically diffuse. Acute bleeding is primarily treated with octreotide, often with concomitant proton pump inhibitor therapy, or secondarily treated with vasopressin or terlipressin. Nonselective β-adrenergic receptor antagonists, particularly propranolol, are used to prevent bleeding after an acute episode or for chronic bleeding. Iron deficiency anemia from chronic bleeding may require iron replacement therapy. Transjugular-intrahepaticportosystemic-shunt and liver transplantation are highly successful ultimate therapies because they reduce the underlying portal hypertension. SYSTEMA...

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“…Indeed, parietal cell loss and impaired acid secretion have been reported as consequences of portal hypertensive gastropathy (1,24). Moreover, in portal hypertensive gastric mucosa, tyrosine nitration has been reported as a result of peroxynitrite formation from elevated superoxide and nitric oxide production (26,37). Enzymes integral to mitochondrial oxidative phosphorylation (e.g., aconitase and ATP synthase), as well as SOD2 itself, have been demonstrated to be targets of inactivation by tyrosine nitration (13,14,35).…”

mentioning

confidence: 99%

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

Jones

Zhu

Sarino

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Jones MK, Zhu E, Sarino EV, Padilla OR, Takahashi T, Shimizu T, Shirasawa T. Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice. Am J Physiol Gastrointest Liver Physiol 301: G537-G546, 2011. First published June 30, 2011 doi:10.1152/ajpgi.00177.2011Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P Ͻ 0.05) reduction in total gastric SOD activity and a 93% (P Ͻ 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P Ͻ 0.0001) and 44% (P Ͻ 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P Ͻ 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P Ͻ 0.0001) and 40% (P Ͻ 0.0005), respectively. There was a fourfold (P Ͻ 0.02) increase in gastric mucosal apoptosis and 41% (P Ͻ 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.

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Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Cited by 33 publications

References 44 publications

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

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Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Cited by 33 publications

References 44 publications

Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2

Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2

Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

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Product

Resources

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Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂