Airway remodeling can be defined as changes in the composition, content, and organization of the cellular and molecular constituents of the airway wall. Airway remodeling is a characteristic feature of asthma, and has important functional implications. These structural changes include epithelial detachment, subepithelial fibrosis, increased airway smooth muscle (ASM) mass, decreased distance between epithelium and ASM cells, goblet cell hyperplasia, mucus gland hyperplasia, proliferation of blood vessels and airway edema and changes in the cartilage. Each can contribute to airway hyperreactivity (AHR), and may eventually lead to irreversible airflow obstruction with disease progression. Structural changes can be observed from early onset of the disease and thus remodeling is thought to be characteristic of asthma. Some aspects of airway remodeling can be explained as a consequence of TH2 inflammation, although it has also been suggested that the exaggerated inflammation and remodeling seen in asthmatic airways is the consequence of abnormal injury and repair responses stemming from the susceptibility of bronchial epithelia to components of the inhaled environment. According to this view, remodeling occurs by way of a noninflammatory mechanism, where inflammation of airways and altered structure and function of the airways are parallel and interacting factors. Airway remodeling in established asthma is poorly responsive to current therapies, such as inhalation of corticosteroids and administration of beta(2)-agonists, antileukotrienes, and theophylline.

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Asthma is characterized by eosinophilic airway inflammation and remodeling of the airway wall. Features of airway remodeling include increased airway smooth muscle (ASM) mass. However, little is known about the interaction between inflammatory eosinophils and ASM cells. In this study, we investigated the effect of eosinophils on ASM cell proliferation. Eosinophils were isolated from peripheral blood of mild asthmatics and non-asthmatic subjects and co-cultured with human primary ASM cells. ASM proliferation was estimated using Ki-67 expression assay. The expression of extracellular matrix (ECM) mRNA in ASM cells was measured using quantitative real-time PCR. The role of eosinophil derived Cysteinyl Leukotrienes (CysLTs) in enhancing ASM proliferation was estimated by measuring the release of leukotrienes from eosinophils upon their direct contact with ASM cells using ELISA. This role was confirmed either by blocking eosinophil-ASM contact or co-culturing them in the presence of leukotrienes antagonist. ASM cells co-cultured with eosinophils, isolated from asthmatics, but not non-asthmatics, had a significantly higher rate of proliferation compared to controls. This increase in ASM proliferation was independent of their release of ECM proteins but dependent upon eosinophils release of CysLTs. Eosinophil-ASM cell to cell contact was required for CysLTs release. Preventing eosinophil contact with ASM cells using anti-adhesion molecules antibodies, or blocking the activity of eosinophil derived CysLTs using montelukast inhibited ASM proliferation. Our results indicated that eosinophils contribute to airway remodeling during asthma by enhancing ASM cell proliferation and hence increasing ASM mass. Direct contact of eosinophils with ASM cells triggers their release of CysLTs which enhance ASM proliferation. Eosinophils, and their binding to ASM cells, constitute a potential therapeutic target to interfere with the series of biological events leading to airway remodeling and Asthma.

The results show that chemokines from airway epithelial cells cause ASM cell migration and might potentially play a role in the process of airway remodelling in asthma.

A 65-year-old