Effects of OPC-6535 on lipopolysaccharide-induced acute liver injury in the rat: Involvement of superoxide and tumor necrosis factor-α from hepatic macrophages

Hasegawa, Tadashi; Sakurai, Kazumasa; Kambayashi, Yasuhiro; Saniabadi, Abby R.; Nagamoto, Hisashi; Tsukada, Katsuhiko; Takahashi, Atsushi; Kuwano, Hiroyuki; Nakano, Minoru

doi:10.1016/s0039-6060(03)00297-6

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…24 Tetomilast also has been reported to show therapeutic effects in IBD animal models as well as in other inflammatory diseases. 25 However, all these animal models were acute diseases and the efficacy of PDE4 inhibition in chronic inflammation as well as the detailed mode of action needs to be clarified. The present article describes that tetomilast suppressed in vitro production of TNF-␣ and IL-12 from human monocytes.…”

Section: Nflammatory Bowel Disease (Ibd) Is Represented By 2 Major mentioning

confidence: 99%

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

Ichikawa

Okamoto

Kamada

et al. 2008

Inflammatory Bowel Diseases

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Section: Nflammatory Bowel Disease (Ibd) Is Represented By 2 Major mentioning

confidence: 99%

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

Ichikawa

Okamoto

Kamada

et al. 2008

Inflammatory Bowel Diseases

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“…In the in vitro experiment, the direct effect of PAE on Kupffer cells (KC) was studied by isolating KCs from the livers of normal rat. Rat liver perfusion was performed using a modification of the two‐step collagenase perfusion technique introduced by previous studies [16,17]. The viability of KCs prepared was more than 95% as determined by trypan blue exclusion.…”

mentioning

confidence: 99%

Protective Effect of Extract from Paeonia lactiflora and Astragalus membranaceus against Liver Injury Induced by Bacillus Calmette‐Guérin and Lipopolysaccharide in Mice

Sun

Wei

Gui

et al. 2008

Basic Clin Pharma Tox

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Paeonia lactiflora and Astragalus membranaceus are two popular traditional Chinese medicines, commonly used in Chinese herb prescription to treat liver disease. The extract from the roots of P. lactiflora and A. membranaceus demonstrated better hepatoprotective activity than the herbs used individually as shown in our previous studies. The present study was carried out to investigate the effects of P. lactiflora and A. membranaceus extract on immunological liver injury in mice induced by Bacillus Calmette-Guérin and lipopolysaccharide (BCG/LPS) and to explore a possible mechanism. After administration of P. lactiflora and A. membranaceus (60, 120 and 240 mg/kg, intragastrically) daily for 10 days, the extract significantly reduced the degree of liver damage in BCG/LPS-induced liver injury, as well as the elevation of serum transaminase activities and level of nitric oxide in live injury mice. The extract also restored the decrease in superoxide dismutase and glutathione peroxidase activities and inhibited the formation of lipid peroxidative products. Moreover, P. lactiflora and A. membranaceus (60, 120 and 240 mg/kg, intragastrically) repressed high levels of tumour necrosis factor-α (TNF-α ) and interleukin-1 (IL-1) from peritoneal macrophages. In the primary cultured Kupffer cells, P. lactiflora and A. membranaceus also significantly decreased the production of TNF-α and IL-1 in cells stimulated with LPS (5 µ g/ml). These results suggest that P. lactiflora and A. membranaceus have a protective effect on BCG/LPS-induced liver injury mice, which might be associated with the antioxidant properties, ability to reduce nitric oxide production and suppression of Kupffer cell activity and pro-inflammatory mediator and cytokines production.

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“…55) Tetomilast reportedly reduces apoptosis among hepatocytes by reducing oxidation stress 56) and TNF-α production. 19) Our TUNEL data show that tetomilast reduces the incidence of PPE-induced apoptosis in the alveolar wall. On the other hand, we found no tetomilast-induced effect on numbers of Ki-67-positive cells, suggesting that tetomilast does not affect alveolar cell proliferation.…”

Section: Discussionmentioning

confidence: 64%

“…21) We previously showed that daily oral administration of tetomilast dosedependently reduces airway resistance and neutrophil accumulation in the lungs of cigarette smoke-induced pulmonary inflammation, and that dose of 10 mg/kg tetomilast is highly effective. 18) Moreover, it has been reported that tetmilast (10 mg/kg) suppressed cytokine production in a murine chronic colitis model. 20) Therefore, we decided the dose of tetomilast as 10 mg/kg in the present study.…”

Section: Methodsmentioning

confidence: 99%

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Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Baila

Ohno

Nagamoto

et al. 2012

Biological & Pharmaceutical Bulletin

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Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n 19, PPE n 19, PPE/Tetomilast n 18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxydeoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.Key words chronic obstructive pulmonary disease; tetomilast; oxidative stress; 8-hydroxy-deoxyguanosine Pulmonary emphysema is a chronic, progressive obstructive pulmonary disease pathologically defined as "dilation of the alveolar space without desmoplasia by breakdown of alveolar walls and degradation of gas exchange." 1-6) Among the numerous factors known to play key roles in the pathogenesis of the disease are inflammation, reactive oxygen species (ROS), smoking, α 1 -antitrypsin defects and disequilibrium between elastase and anti-elastase, as well as between matrix metalloproteases (MMPs) and tissue MMP inhibitor.7-9) Airflow limitation in chronic obstructive pulmonary disease (COPD) patients results from mucosal inflammation and edema, bronchoconstriction, increased secretions in the airways and loss of elastic recoil. Phosphodiesterase 4 (PDE4) is expressed in almost all inflammatory cell types. While PDE4 inhibitors are very efficacious at inhibiting pro-inflammatory mediator release from certain cell types (e.g. neutrophils, eosinophils), 10,11) there is evidence to suggest that dual inhibition of PDE4 is additive or synergistic at suppressing the activation/ functions of other cell types, which are thought to play a role in COPD (e.g. macrophages, dendritic cells, epithelial cells, lymphocytes, airway smooth muscle cells and endothelial cells).12-15) Tetomilast (6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]-pyridine-2-carboxylic acid), a PDE4 inhibitor was initially isolated in vitro as the lead compound in a series of thiazole derivatives with inhibitory effects on superoxide production by human neutrophils. Tetomilast exerts both vasoprotectant and anti-inflammatory effects, mediated by inhibition of PDE4 and superoxide production.16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been n...

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Effects of OPC-6535 on lipopolysaccharide-induced acute liver injury in the rat: Involvement of superoxide and tumor necrosis factor-α from hepatic macrophages

Cited by 11 publications

References 27 publications

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

Protective Effect of Extract from Paeonia lactiflora and Astragalus membranaceus against Liver Injury Induced by Bacillus Calmette‐Guérin and Lipopolysaccharide in Mice

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

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