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RESEARCH PROGRAM

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Keywords
REMODELING; AIRWAY SMOOTH MUSCLE; INFLAMMATORY MEDIATORS

New insights of inflammation and remodeling in airway obstructive deseases

Università degli Studi di Genova
Abstract
There are multiple cellular and molecular pathways leading to inflammation, remodelling and chronicization in obstructive airways diseases. The Th2-type inflammation with eosinophilia existing in some disorders without obstruction (e.g. persistent rhinitis and eosinophilic bronchitis) is a good starting point to investigate novel mechanism of inflammation. Recently, some experimental models of inflammation-remodelling, involving the intrinsic properties of the smooth muscle cells and independent of the Th2 inflammation, have been proposed. Among these mechanisms are: rhinoviral infections, bradikinin, vascular remodelling, desensitization of beta2 receptors. All these phenomena, alone or in combination, may contribute to those structural and functional changes in smooth muscle, which result in increased bronchial responsiveness and reduced bronchial calibre.
These coordinated projects have the aim of investigating the following aspects:

- role of acethylcholine, bradikinin and VEGF in contractile remodelling of smooth muscle cell;
- desensitizing effect of leukotrienes and thromboxanes on Beta2 receptors;
- effects on the release of acethylcholine from bovine smooth muscle of INFgamma and lambda and of the supernatant of rhinovirus-infected epithelial cells;
- signal trasduction of cysLT and TP receptors and mechanims regulating the desensitization of beta2 receptors;
- production of interferons and acethylcholine by >>>

Principal Investigator
Giorgio Walter CANONICA Università degli Studi di GENOVA
Research Objectives
The present research programme has the general aim of investigating some aspects of bronchial inflammation and remodelling in obstructive diseases that are poorly known, yet suspected to play a crucial role.
The following aspects will be considered:
- role of acethylcholine, bradykinin and vascular endothelial growth factor (VEGF) in the contractile remodelling of human airway smooth muscle cells;
- signal trasduction by leukotrienes (cysLT) and thromboxane (TP) receptors and mechanisms that regulate the eterologous desensitization ob beta2 receptors;
- effects of rhinoviral infection of epithelial cells in regulating the production of interferons and acethylcholine;
- role of bradykinin in the process leading to fibroblast-myofibroblast remodelling, remodelling of the human airway smooth muscle cell and production of VEGF;
- VEGF expression and vascular permeability in asthma.

The research project involves 5 interdependent Units.

Canonica: To assess the effects of acethylcholine, BK and VEGF in remodelling the human airway smooth muscle cells; in cooperation with Rovati and Vancheri, to assess the effects of thromboxanes and leukotrienes in eterologous desenzitization of the beta2 receptor; in cooperation with Papi, to evaluate the effect of interferons and supernatant from rhinovirus infected epithelial cells on acethylcholine release from bovine bronchial tissue; in cooperation with Chetta to >>>

Timescale
24 months
National and international background
The "remodelling" is defined as a chronic alteration of the cellular and molecular components of the bronchial airways (1). Indeed there are multiple and redundant pathogenic mechanisms leading to both inflammation and remodelling.
Asthma is characterized by a global remodelling of the bronchial wall. The bronchial epithelium is thinner than in normals, repairing processes are slow and polarized towards the secretion of growth factors. Moreover, the vagal activity is increased and there is an increased release of acetylcholine. Mucinous glands are hyperthrophic and secrete large amount of mucus (2). In asthma, but not in COPD, the subepithelial connective layer is thicker than in normals, and a similar finding is present in subjects with perennial rhinitis but not asthma (3). It has been shown that an inverse correlation exists between subepithelial thickening and bronchial hyperresponsiveness (4,5). This suggest that subepithelial changes may act as a protective factor that limits the maximal bronchoconstriction achievable. In submucosa, there is an abnormal activation of fibroblasts, myofibroblast are present (6) and an excess of deposition of intercellular matrix, associated with neoangiogenesis.
This latter aspect is present also in COPD, but not in eosinophilic bronchitis. A central role seems to be played by the Vascular Endotehelial Growth Factor (VEGF) that has a broad spectrum of activities including angiogenesis and increase of vascular >>>