Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma

Abstract

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 mg/ ml) and dexamethasone (10 28 and 10 26 M). Supernatants were assayed for cytokines using an ELISAbased method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. Results: The inhibition of LPS-induced interleukin (IL)1b, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1a release by dexamethasone (10 26 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.

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

“…Similar effects are seen with JNK, ERK and JAK3 depending upon the specific stimulus driving steroid insensitivity in vitro [7]. In severe asthmatic patients, there is also a significant reduction in MKP-1 expression in alveolar macrophages after steroid exposure, correlating with increased p38 MAPK activity [11].…”

“…There is altered expression of markers of epithelial proliferation such as an increased expression of the proliferation marker, Ki67, and reduced expression of Bcl-2, a negative regulator of epithelial cell death [82]. Studies in alveolar macrophages and blood mononuclear cells from patients with severe asthma confirmed the presence of CS insensitivity, associated with an increase in p38 MAPK activity [11,83].…”

“…These actions are mutually inhibitory and, in the case of p38 and JNK, may relate to induction of the dual-specificity MAPK phosphatase 1 (MKP-1), which thereby attenuates MAPK activation [10]. Importantly, p38 MAPK-mediated GR phosphorylation can attenuate GR function [7,11].…”

“…Combination of corticosteroids or possibly more promiscuous drugs that bind to two or more of these receptors may result in an enhanced antiinflammatory profile over that seen with current corticosteroids, particularly in patients with severe disease [210]. Several key signalling pathways are involved in the inflammatory response [211,212] and also in the modulation of corticosteroid responsiveness in asthma and COPD [11,[213][214][215][216].…”

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

“…It can be demonstrated in peripheral blood mononuclear cells and alveolar macrophages, and in resident cells such as airway smooth muscle cells from patients with severe asthma [166][167][168][169], but the relationship of these in vitro studies to in vivo responses is not well understood. Corticosteroid insensitivity has been associated with different comorbid conditions such as obesity [170], smoking [171], low vitamin D levels [172,173], and non-eosinophilic (low-Th2 inflammation) mainly in adults [174].…”