BACKGROUND: About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). METHODS: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. RESULTS: The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. CONCLUSION: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.
BACKGROUND: About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). METHODS: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. RESULTS: The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. CONCLUSION:Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.
Authors: F M C Silva; E E Oliveira; A C C Gouveia; A S S Brugiolo; C C Alves; J O A Correa; J Gameiro; J Mattes; H C Teixeira; A P Ferreira Journal: Clin Exp Immunol Date: 2017-03-31 Impact factor: 4.330
Authors: Taylor A Doherty; Pejman Soroosh; Naseem Khorram; Satoshi Fukuyama; Peter Rosenthal; Jae Youn Cho; Paula S Norris; Heonsik Choi; Stefanie Scheu; Klaus Pfeffer; Bruce L Zuraw; Carl F Ware; David H Broide; Michael Croft Journal: Nat Med Date: 2011-04-17 Impact factor: 53.440
Authors: Ilse M E Beck; Wim Vanden Berghe; Linda Vermeulen; Keith R Yamamoto; Guy Haegeman; Karolien De Bosscher Journal: Endocr Rev Date: 2009-11-04 Impact factor: 19.871
Authors: Pankaj K Bhavsar; Bruce D Levy; Mark J Hew; Michael A Pfeffer; Shamsah Kazani; Elliot Israel; Kian Fan Chung Journal: Respir Res Date: 2010-06-07