Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma
Jing Ying Ma1, Satyanarayana Medicherla1, Irene Kerr, Ruban Mangadu, Andrew A Protter, Linda S Higgins1Scios Inc, Fremont, CA, USA 1Jing Ying Ma and Satyanarayana Medicherla contributed equally to this workAbstract: p38 Mitogen-activated protein kinase (MAPK) plays a critical role in the activation...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2008-11-01
|
| Series: | Journal of Asthma and Allergy |
| Online Access: | http://www.dovepress.com/selective-p38alpha-mitogen-activated-protein-kinase-inhibitor-attenuat-a2575 |
| _version_ | 1828949216017252352 |
|---|---|
| author | Jing Ying Ma Satyanarayana Medicherla Irene Kerr Ruban Mangadu Andrew A Protter Linda S Higgins |
| author_facet | Jing Ying Ma Satyanarayana Medicherla Irene Kerr Ruban Mangadu Andrew A Protter Linda S Higgins |
| author_sort | Jing Ying Ma |
| collection | DOAJ |
| description | Jing Ying Ma1, Satyanarayana Medicherla1, Irene Kerr, Ruban Mangadu, Andrew A Protter, Linda S Higgins1Scios Inc, Fremont, CA, USA 1Jing Ying Ma and Satyanarayana Medicherla contributed equally to this workAbstract: p38 Mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. We investigated the anti-inflammatory effects of a p38α-selective MAPK inhibitor (SD-282) in a mouse transgenic (CC10:IL-13) asthma model. The CC-10-driven over-expression of IL-13 in the mouse lung/airway has been shown to result in a remarkable phenotype recatitulating many features of asthma and characterized by eosinophilic and mononuclear inflammation, with airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot–Leyden-like crystal, and airway sub-epitheilial fibrosis. Here we show how activated p38 MAPK can be observed in the lungs at the onset of asthma ie, around 8 weeks of age in both female and male mice. We also show that administration of a p38α MAPK selective inhibitor, SD-282 at 30 or 90 mg/kg, twice a day for a period of four weeks beginning at the onset of asthma, significantly reduced the inflammation (p < 0.001); hyperplasia of airway epithelium (p < 0.05); goblet cell metaplasia and mucus hypersecretion (p < 0.001) and reduced lung remodeling and fibrosis (p < 0.01), alleviating the severity of lung damage as measured by a composite score (p < 0.05). Furthermore, SD-282 significantly reduced activated p38 MAPK in the lymphocytes and epithelial cells (p < 0.001). Simultaneously, identical studies were conducted with an anti-fibrotic TGFβR1 kinase inhibitor (SD-208) which demonstrated anti-fibrotic but not anti-inflammatory properties. These findings suggest that the p38α-selective MAPK inhibitor may have dual therapeutic potential in attenuating both the inflammatory component and the fibrotic component of asthma and other Th2-polarized inflammatory lung diseases.Keywords: inflammation, asthma, fibrosis, p38α-selective MAPK inhibitor, SD-282, phosphorylated p38 MAPK, TGFβ inhibitor, SD-208, phosphorylated SMAD2/3 |
| first_indexed | 2024-12-14T06:02:19Z |
| format | Article |
| id | doaj.art-634535ee149043a6befd185ea329637b |
| institution | Directory Open Access Journal |
| issn | 1178-6965 |
| language | English |
| last_indexed | 2024-12-14T06:02:19Z |
| publishDate | 2008-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Asthma and Allergy |
| spelling | doaj.art-634535ee149043a6befd185ea329637b2022-12-21T23:14:23ZengDove Medical PressJournal of Asthma and Allergy1178-69652008-11-012008default3144Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthmaJing Ying MaSatyanarayana MedicherlaIrene KerrRuban MangaduAndrew A ProtterLinda S HigginsJing Ying Ma1, Satyanarayana Medicherla1, Irene Kerr, Ruban Mangadu, Andrew A Protter, Linda S Higgins1Scios Inc, Fremont, CA, USA 1Jing Ying Ma and Satyanarayana Medicherla contributed equally to this workAbstract: p38 Mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. We investigated the anti-inflammatory effects of a p38α-selective MAPK inhibitor (SD-282) in a mouse transgenic (CC10:IL-13) asthma model. The CC-10-driven over-expression of IL-13 in the mouse lung/airway has been shown to result in a remarkable phenotype recatitulating many features of asthma and characterized by eosinophilic and mononuclear inflammation, with airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot–Leyden-like crystal, and airway sub-epitheilial fibrosis. Here we show how activated p38 MAPK can be observed in the lungs at the onset of asthma ie, around 8 weeks of age in both female and male mice. We also show that administration of a p38α MAPK selective inhibitor, SD-282 at 30 or 90 mg/kg, twice a day for a period of four weeks beginning at the onset of asthma, significantly reduced the inflammation (p < 0.001); hyperplasia of airway epithelium (p < 0.05); goblet cell metaplasia and mucus hypersecretion (p < 0.001) and reduced lung remodeling and fibrosis (p < 0.01), alleviating the severity of lung damage as measured by a composite score (p < 0.05). Furthermore, SD-282 significantly reduced activated p38 MAPK in the lymphocytes and epithelial cells (p < 0.001). Simultaneously, identical studies were conducted with an anti-fibrotic TGFβR1 kinase inhibitor (SD-208) which demonstrated anti-fibrotic but not anti-inflammatory properties. These findings suggest that the p38α-selective MAPK inhibitor may have dual therapeutic potential in attenuating both the inflammatory component and the fibrotic component of asthma and other Th2-polarized inflammatory lung diseases.Keywords: inflammation, asthma, fibrosis, p38α-selective MAPK inhibitor, SD-282, phosphorylated p38 MAPK, TGFβ inhibitor, SD-208, phosphorylated SMAD2/3http://www.dovepress.com/selective-p38alpha-mitogen-activated-protein-kinase-inhibitor-attenuat-a2575 |
| spellingShingle | Jing Ying Ma Satyanarayana Medicherla Irene Kerr Ruban Mangadu Andrew A Protter Linda S Higgins Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma Journal of Asthma and Allergy |
| title | Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma |
| title_full | Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma |
| title_fullStr | Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma |
| title_full_unstemmed | Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma |
| title_short | Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma |
| title_sort | selective p38 amp alpha mitogen activated protein kinase inhibitor attenuates lung inflammation and fibrosis in il 13 transgenic mouse model of asthma |
| url | http://www.dovepress.com/selective-p38alpha-mitogen-activated-protein-kinase-inhibitor-attenuat-a2575 |
| work_keys_str_mv | AT jingyingma selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma AT satyanarayanamedicherla selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma AT irenekerr selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma AT rubanmangadu selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma AT andrewaprotter selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma AT lindashiggins selectivep38ampalphamitogenactivatedproteinkinaseinhibitorattenuateslunginflammationandfibrosisinil13transgenicmousemodelofasthma |