Ibudilast Suppresses MUC5AC Mucus Production through Inhibition of ERK1/2 Phosphorylation
Mucus hypersecretion is a hallmark of respiratory diseases, and excess airway mucus can worsen these conditions. Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2021/03/01, Vol.44(3), pp.404-409 |
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| creator | Ishibashi, Jumpei Saito, Kana Ishizaki, Takako Horie, Ichiro Isohama, Yoichiro |
| description | Mucus hypersecretion is a hallmark of respiratory diseases, and excess airway mucus can worsen these conditions. Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective in treating sputum and postnasal drip in patients with chronic airway inflammation. On the basis of the hypothesis that ibudilast could inhibit mucus production in the airway, in the present study, we examined the effects of ibudilast on the production of MUC5AC, a major protein component of mucus. In in vitro studies using NCI-H292 cells, ibudilast suppressed MUC5AC production induced by various stimuli. In addition, ibudilast inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation and MUC5AC gene transcription. Furthermore, it attenuated MUC5AC production and Muc5ac mRNA expression in lipopolysaccharide-treated mice in vivo. Collectively, these findings demonstrate that ibudilast has an inhibitory effect on mucus production, which could at least partly be attributed to the inhibition of ERK1/2 phosphorylation and the repression of MUC5AC gene transcription. |
| doi_str_mv | 10.1248/bpb.b20-00798 |
| format | Article |
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Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective in treating sputum and postnasal drip in patients with chronic airway inflammation. On the basis of the hypothesis that ibudilast could inhibit mucus production in the airway, in the present study, we examined the effects of ibudilast on the production of MUC5AC, a major protein component of mucus. In in vitro studies using NCI-H292 cells, ibudilast suppressed MUC5AC production induced by various stimuli. In addition, ibudilast inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation and MUC5AC gene transcription. Furthermore, it attenuated MUC5AC production and Muc5ac mRNA expression in lipopolysaccharide-treated mice in vivo. Collectively, these findings demonstrate that ibudilast has an inhibitory effect on mucus production, which could at least partly be attributed to the inhibition of ERK1/2 phosphorylation and the repression of MUC5AC gene transcription.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b20-00798</identifier><identifier>PMID: 33642548</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Cell Line ; Extracellular signal-regulated kinase ; extracellular signal-regulated kinase (ERK)1/2 ; Gene expression ; Gene silencing ; Humans ; Hydrogen Peroxide - pharmacology ; ibudilast ; Inflammation ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Male ; Mice, Inbred ICR ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; MUC5AC ; Mucin 5AC - antagonists & inhibitors ; Mucin 5AC - genetics ; Mucin 5AC - metabolism ; Mucus ; Mucus - metabolism ; mucus production ; Nicotiana ; Phosphodiesterase ; Phosphodiesterase inhibitors ; Phosphodiesterase Inhibitors - pharmacology ; Phosphorylation ; Phosphorylation - drug effects ; Pyridines - pharmacology ; Respiratory diseases ; Respiratory tract ; Respiratory tract diseases ; Smoke ; Sputum</subject><ispartof>Biological and Pharmaceutical Bulletin, 2021/03/01, Vol.44(3), pp.404-409</ispartof><rights>2021 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c702t-dbb8add538dd4c862d8bdc2920aec44ef985de3c79f95e8b3a01773b52678c083</citedby><cites>FETCH-LOGICAL-c702t-dbb8add538dd4c862d8bdc2920aec44ef985de3c79f95e8b3a01773b52678c083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33642548$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishibashi, Jumpei</creatorcontrib><creatorcontrib>Saito, Kana</creatorcontrib><creatorcontrib>Ishizaki, Takako</creatorcontrib><creatorcontrib>Horie, Ichiro</creatorcontrib><creatorcontrib>Isohama, Yoichiro</creatorcontrib><creatorcontrib>aLaboratory of Applied Pharmacology</creatorcontrib><creatorcontrib>bLaboratory for Systems Immunology</creatorcontrib><creatorcontrib>Faculty of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Tokyo University of Science</creatorcontrib><creatorcontrib>Sanyo-Onoda City University</creatorcontrib><title>Ibudilast Suppresses MUC5AC Mucus Production through Inhibition of ERK1/2 Phosphorylation</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>Mucus hypersecretion is a hallmark of respiratory diseases, and excess airway mucus can worsen these conditions. Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective in treating sputum and postnasal drip in patients with chronic airway inflammation. On the basis of the hypothesis that ibudilast could inhibit mucus production in the airway, in the present study, we examined the effects of ibudilast on the production of MUC5AC, a major protein component of mucus. In in vitro studies using NCI-H292 cells, ibudilast suppressed MUC5AC production induced by various stimuli. In addition, ibudilast inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation and MUC5AC gene transcription. Furthermore, it attenuated MUC5AC production and Muc5ac mRNA expression in lipopolysaccharide-treated mice in vivo. Collectively, these findings demonstrate that ibudilast has an inhibitory effect on mucus production, which could at least partly be attributed to the inhibition of ERK1/2 phosphorylation and the repression of MUC5AC gene transcription.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Extracellular signal-regulated kinase</subject><subject>extracellular signal-regulated kinase (ERK)1/2</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>ibudilast</subject><subject>Inflammation</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Male</subject><subject>Mice, Inbred ICR</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>MUC5AC</subject><subject>Mucin 5AC - antagonists & inhibitors</subject><subject>Mucin 5AC - genetics</subject><subject>Mucin 5AC - metabolism</subject><subject>Mucus</subject><subject>Mucus - metabolism</subject><subject>mucus production</subject><subject>Nicotiana</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase inhibitors</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Pyridines - pharmacology</subject><subject>Respiratory diseases</subject><subject>Respiratory tract</subject><subject>Respiratory tract diseases</subject><subject>Smoke</subject><subject>Sputum</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1v1DAYhC0EokvhyBVF4pzWn7F9rKJSVrSiAnrgZPkrjVdpHOz40H-Pd7csl9eS59HMaAD4iOAFwlRcmsVcGAxbCLkUr8AGEcpbhhF7DTZQItF2iIkz8C7nHawMxOQtOCOko5hRsQG_t6a4MOm8Nj_LsiSfs8_N3UPPrvrmrtiSm_sUXbFriHOzjimWx7HZzmMw4fAVh-b6xzd0iZv7MeZljOl50nvlPXgz6Cn7Dy_vOXj4cv2r_9refr_Z9le3ra1l1tYZI7RzjAjnqBUddsI4iyWG2ltK_SAFc55YLgfJvDBEQ8Q5MQx3XFgoyDn4fPRdUvxTfF7VLpY010iFqWSQyI7TSrVHyqaYc_KDWlJ40ulZIaj2Q6o6pKpDqsOQlf_04lrMk3cn-t9yFbg5AlUNVk9xnsLs_2fbzE2IU1QYYlRNKYVEQcQUpJDujyScdYii6tQfnXZ51Y_-FKXTGuzkD8UoVWR_TgVPqh11Un4mfwEuzpzB</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Ishibashi, Jumpei</creator><creator>Saito, Kana</creator><creator>Ishizaki, Takako</creator><creator>Horie, Ichiro</creator><creator>Isohama, Yoichiro</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20210301</creationdate><title>Ibudilast Suppresses MUC5AC Mucus Production through Inhibition of ERK1/2 Phosphorylation</title><author>Ishibashi, Jumpei ; 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| subjects | Animals Cell Line Extracellular signal-regulated kinase extracellular signal-regulated kinase (ERK)1/2 Gene expression Gene silencing Humans Hydrogen Peroxide - pharmacology ibudilast Inflammation Lipopolysaccharides Lipopolysaccharides - pharmacology Male Mice, Inbred ICR Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism MUC5AC Mucin 5AC - antagonists & inhibitors Mucin 5AC - genetics Mucin 5AC - metabolism Mucus Mucus - metabolism mucus production Nicotiana Phosphodiesterase Phosphodiesterase inhibitors Phosphodiesterase Inhibitors - pharmacology Phosphorylation Phosphorylation - drug effects Pyridines - pharmacology Respiratory diseases Respiratory tract Respiratory tract diseases Smoke Sputum |
| title | Ibudilast Suppresses MUC5AC Mucus Production through Inhibition of ERK1/2 Phosphorylation |
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