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Asthma is a chronic inflammatory disease. Reticular basement membrane (RBM) thickening is considered feature of airway remodelling (AR) particularly in severe asthma (SA). Omalizumab, mAb to IgE is effective in SA and can modulate AR. Herein we describe protein profiles of bronchial biopsies to detect biomarkers of anti-IgE effects on AR and to explain potential mechanisms/pathways. We defined the bronchial biopsy protein profiles, before and after treatment. Unsupervised clustering of baseline proteomes resulted in very good agreement with the morphometric analysis of AR. Protein profiles of omalizumab responders (ORs) were significantly different from those of non-omalizumab responders (NORs). The major differences between ORs and NORs lied to smooth muscle and extra cellular matrix proteins. Notably, an IgE-binding protein (galectin-3) was reliable, stable and predictive biomarker of AR modulation. Omalizumab down-regulated bronchial smooth muscle proteins in SA. These findings suggest that omalizumab may exert disease-modifying effects on remodelling components., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently not well controlled, despite intensive guideline-based therapy. The unique monoclonal antibody approved for patients with severe allergic asthma is omalizumab: a recombinant humanised murine against IgE antibodies. The aim of the present study is to investigate the effect of long-term anti-IgE on the thickening of the reticular basement membrane (RBM) and eosinophil infiltration in bronchial biopsies from patients with severe persistent allergic asthma. Biopsies were obtained from 11 patients with severe persistent allergic asthma before and after (12 months) treatment with omalizumab. RBM thickness and eosinophils were measured by using light microscope image analysis. A significant mean reduction in RBM thickness and eosinophil infiltration were measured after one-year omalizumab treatment. No correlation between eosinophil reduction and RBM thickness reduction was found. No correlation between each of the previous two parameters and clinical parameters was detected. In conclusion, our study showed that a substantial proportion of severe asthmatics reduced the original bronchial RBM thickness and eosinophil infiltration after one-year treatment with anti-IgE, thus emphasizing the possible role of omalizumab in affecting airway remodeling in severe persistent allergic asthma.

Background: In our previous in vitro model, allergen incubation of passively sensitized human airways reduced the response to salbutamol. However, whether cytokines play a role in this model is still unknown., Objective: To investigate interleukin 1beta and tumor necrosis factor a expression in allergen-challenged human airways., Methods: Nonasthmatic airways (n = 13) were passively sensitized by overnight atopic serum incubation and then challenged with allergen for 1 hour (n = 9). After repeated washouts, airways were immersed in physiologic salt solution for 6 hours and finally in formaldehyde for immunohistochemical studies. The effect of co-incubation in anti-interleukin 1beta and anti-tumor necrosis factor a specific neutralizing antibodies on salbutamol response was also studied (n = 4)., Results: No differences were found among control, sensitized, and challenged rings in the number of inflammatory cells. The percentage of basement membrane covered by epithelium was similar in the different conditions. There was a higher percentage of degranulating to total mast cells in allergen-challenged rings than in sensitized rings (P < .001). A significant correlation was observed between allergen-induced contraction and mast cell degranulation (r = 0.88; P < .001). The sensitization procedure was validated by paired allergen-induced contractions. No expression of the 2 cytokines was detectable up to 6 hours after allergen challenge, and specific neutralizing antibodies did not attenuate the impaired response to salbutamol in allergen-challenged rings., Conclusion: These data suggest that in our in vitro model of allergic inflammation, beta2 pathway dysfunction can occur without cytokine involvement, thus supporting previous results that suggest a role for leukotrienes.

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC (r2 = 0.25), reactivity to methacholine (r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge (r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated (r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.