Combined treatment with SB203580 and dexamethasone suppresses non-typeable Haemophilus influenzae-induced Th17 inflammation response in murine allergic asthma

• Published in: European journal of pharmacology 2019-11, Vol.862, p.172623-172623, Article 172623
• Main Authors: Wang, Guoqiang, Pang, Zhiqiang, Chen-Yu Hsu, Alan, Guan, Xuewa, Ran, Nan, Yuan, Yuze, Wang, Ziyan, Guo, Yingqiao, Zheng, Ruipeng, Wang, Fang
• Format: Article
• Language: English
• Subjects: Airway hyper-responsiveness; Animals; Asthma - drug therapy; Asthma - immunology; Asthma - microbiology; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Disease Models, Animal; Drug Therapy, Combination; Female; Haemophilus influenzae - immunology; Humans; Imidazoles - pharmacology; Imidazoles - therapeutic use; Inflammation - drug therapy; Inflammation - immunology; Inflammation - microbiology; Lung - cytology; Lung - drug effects; Lung - immunology; Mice; Mucin 5AC - metabolism; Mucin-5B - metabolism; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Non-typeable Haemophilus influenzae; Ovalbumin - administration & dosage; Ovalbumin - immunology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; Respiratory Mucosa - cytology; Respiratory Mucosa - drug effects; Respiratory Mucosa - immunology; SB203580; Signal Transduction - drug effects; Signal Transduction - immunology; Steroid-resistant asthma; Symptom Flare Up; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 inflammation response
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.172623

Accumulating evidence suggests that non-typeable Haemophilus influenzae (NTHi) infection drives the development of steroid-resistant allergic airway disease (SRAAD), exacerbates clinical symptoms, worsens quality of life, and accounts for most of the related healthcare burden. The poor understanding of the pathogenesis of SRAAD deters the development of more effective therapeutic strategies. Here, we established a murine model of NTHi infection-induced exacerbation of allergic airway disease. We showed that NTHi infection drove Th 17-mediated pulmonary neutrophilic inflammation, aggravated airway hyper-responsiveness, and upset the balance of MUC5AC and MUC5B expression. Dexamethasone treatment effectively inhibited the features of allergic airway disease but failed to reduce NTHi-induced exacerbation, which was associated with the hyper-phosphorylation of p38 mitogen-activated protein kinase (MAPK). Interestingly, inhibition of p38 using a specific inhibitor (SB203580) only partly suppressed the airway hyper-responsiveness and mucus hyper-secretion but failed to abrogate the infection-induced neutrophilic inflammatory response in SRAAD. However, SB203580 and dexamethasone co-treatment substantially suppressed all the features of NTHi-induced SRAAD. Our findings highlight the importance of p38 MAPK in the pathogenesis of NTHi-induced steroid resistance, and this combined treatment approach may be a novel strategy against steroid-resistant asthma.