Airway pathology in severe asthma is related to airflow obstruction but not symptom control.

BACKGROUND: Patients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment. METHODS: Fifty severe asthmatics received prednisone 40 mg/d for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 µg twice daily + budesonide/formoterol 200/6 µg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction. RESULTS: Airway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta-positive cells within Asm bundles, in addition to lower numbers of chymase-positive mast cells in the submucosa compared to patients with nonpersistent obstruction. CONCLUSIONS: Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.

Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma.

BACKGROUND: Airway inflammation in asthma involves innate immune responses. Toll-like receptors (TLRs) and thymic stromal lymphopoietin (TSLP) are thought to be involved in airway inflammation, but their expression in asthmatics' both large and small airways has not been investigated. OBJECTIVE: To analyse the expression of TLR2, TLR3, TLR4 and TSLP in large and small airways of asthmatics and compare their expression in smoking and non-smoking asthmatics; to investigate whether TLR expression is associated with eosinophilic or neutrophilic airway inflammation and with Mycoplasma pneumoniae and Chlamydophila pneumoniae infection. METHODS: Using immunohistochemistry and image analysis, we investigated TLR2, TLR3, TLR4 and TSLP expression in large and small airways of 24 victims of fatal asthma, FA, (13 non-smokers, 11 smokers) and nine deceased control subjects (DCtrl). TLRs were also measured in 18 mild asthmatics (MA) and 12 healthy controls (HCtrl). M. pneumoniae and C. pneumoniae in autopsy lung tissue were analysed using real-time polymerase chain reaction. Airway eosinophils and neutrophils were measured in all subjects. RESULTS: Fatal asthma patients had higher TLR2 in the epithelial and outer layers of large and small airways compared with DCtrls. Smoking asthmatics had lower TLR2 levels in the inner and outer layers of the small airways than non-smoking asthmatics. TSLP was increased in the epithelial and outer layers of the large airways of FA. FA patients had greater TLR3 expression in the outer layer of large airways and greater TLR4 expression in the outer layer of small airways. Eosinophilic airway inflammation was associated with TLR expression in the epithelium of FA. No bacterial DNA was detected in FA or DCtrls. MA and HCtrls had only a small difference in TLR3 expression. CONCLUSIONS AND CLINICAL RELEVANCE: Increased expression of TLR 2, 3 and 4 and TSLP in fatal asthma may contribute to the acute inflammation surrounding asthma deaths.

Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma.

BACKGROUND: Altered deposition of extracellular matrix (ECM) in the airway smooth muscle (ASM) layer as observed in asthma may influence ASM mechanical properties. We hypothesized that ECM in ASM is associated with airway function in asthma. First, we investigated the difference in ECM expression in ASM between asthma and controls. Second, we examined whether ECM expression is associated with bronchoconstriction and bronchodilation in vivo. METHODS: Our cross-sectional study comprised 19 atopic mild asthma patients, 15 atopic and 12 nonatopic healthy subjects. Spirometry, methacholine responsiveness, deep-breath-induced bronchodilation (ΔR(rs) ) and bronchoscopy with endobronchial biopsies were performed. Positive staining of elastin, collagen I, III and IV, decorin, versican, fibronectin, laminin and tenascin in ASM was quantified as fractional area and mean density. Data were analysed using Pearson's or Spearman's correlation coefficient. RESULTS: Extracellular matrix expression in ASM was not different between asthma and controls. In asthmatics, fractional area and mean density of collagen I and III were correlated with methacholine dose-response slope and ΔR(rs) , respectively (r = 0.71, P < 0.01; r = 0.60, P = 0.02). Furthermore, ASM collagen III and laminin in asthma were correlated with FEV(1) reversibility (r = -0.65, P = 0.01; r = -0.54, P = 0.04). CONCLUSION: In asthma, ECM in ASM is related to the dynamics of airway function in the absence of differences in ECM expression between asthma and controls. This indicates that the ASM layer in its full composition is a major structural component in determining variable airways obstruction in asthma.

High-affinity immunoglobulin E receptor expression is increased in large and small airways in fatal asthma.

BACKGROUND: IgE and its high-affinity receptor FcɛRI play an important role in allergy and asthma. The distribution of FcɛRI expression in the airways and within the airway wall, however, is largely unknown. OBJECTIVE: In this study, we aimed to map the distribution of FcɛRI in different layers of large airways (LA) and small airways (SA) in lung tissue from non-smoking and smoking patients who died of asthma [fatal asthma (FA)] and non-smoking controls (CTR). METHODS: Postmortem lung tissue from 24 cases of non-smoking FA, 13 smoking FA patients and from 19 subjects who died of non-pulmonary causes (CTR) was immunohistochemically stained for FcɛRI and AA1 (mast cell tryptase marker). The expression of these markers was analysed in inner, muscle, and outer layers of both LA and SA by image analysis. RESULTS: FcɛRI expression was higher in non-smoking and smoking FA compared with CTR in the inner and outer layer of SA. In the outer layer of LA, FcɛRI expression was higher in non-smoking FA compared with CTR. AA1 was higher in non-smoking FA compared with smoking FA and CTR in the outer layer of the SA, which was correlated with FcɛRI in this layer. CONCLUSION: Our results show that the expression of FcɛRI is higher in both LA and SA in FA compared with CTR. These differences are predominantly found in the outer layer where they can be attributed in part to the increased mast cell numbers. These results indicate an increased capacity to mount IgE-mediated reactions in FA, both in LA and SA.