RICERCA ITALIANA     

Susceptibility and activation mechanisms of tissue and cellular response induced by the antigen in asthma

Università degli Studi di Catania

Abstract

Asthma is a complex disorder characterised by airway chronic inflammation, airflow obstruction, which is reversible either spontaneously or in response to pharmacological treatment, and bronchial hyperresponsiveness to a large variety of bronchoconstrictive stimuli.A number of cells and mediators partecipate to the inflammatory process of airways.
Aim of the study will be to investigate some of the mechanisms inducing bronchial inflammation in patients with asthma. In particular it will be assessed the complex interaction among different stimuli such as allergens and isocianates and the role of the immune system, bronchial epithelium and smooth muscle. <<<

Principal Investigator

Giuseppe DI MARIA Università degli Studi di CATANIA

Research Objectives

Aim of the study is to investigate some of the mechanisms inducing bronchial inflammation in patients with asthma. In particular it will be assessed the complex interaction among different stimuli such as allergens, isocianates and infection and the role of the immune system, bronchial epithelium and smooth muscle
The role of allergens and their components in priming of T cells and determining their shift towards Th1 or Th2 phenotypes in experimental animals and humans will be clarified.The role of sfingosine in contracting/relaxing activity of airway smooth muscle will be characterised. Levels and changes of leukotrienes, cytokines and chemokines in the airways will be characterized either during clinical stability or at exacerbation, and will be related to the pharmacological treatment. <<<

Timescale

24 months

National and international background

Asthma is a complex disorder characterised by airway chronic inflammation, reversible airflow obstruction, either spontaneously or in response to pharmacological treatment, and bronchial hyperresponsiveness to a large variety of bronchoconstrictive stimuli. Signs and symptoms characterising the clinical picture of this disease are the direct consequence of airway inflammation/obstruction, thus their severity may vary strikingly. For similar reasons, the consequences of asthma on pulmonary function may be also different. Thus asthma is a variable, heterogeneous disease caused by a number of factors both genetic and environmental that act together in determining the occurrence of the disease and its severity. Despite many studies on asthma have helped in understanding the pathogenesis, and improving treatment of the disease, in recent years the prevalence of asthma has increased steadily. Nowadays, due to its high prevalence asthma represents one of the most challenging disease for the health costs afforded by many westernised countries.
Cells and mediators participate to airway inflammation in asthma, often interacting throughout mechanisms that are largely unknown or incompletely understood and that contribute to initiate and maintain the inflammatory process. A number of studies have demonstrated that lymphocytes, eosinophils, mast cells, and airway epithelium all play a prominent role in this process. It is now widely accepted that following the recognition of a specific antigen (allergen), activated T lymphocytes produce a variety of cytokines and chemokines which in turn cause the recruitment of other inflammatory cells in the lung as well as the production of specific IgE from B lymphocytes. The IgE molecules bind to the high affinity receptors (FcRI) that are expressed on the cell membrane of mast cells and basophils. Subsequent binding between IgE and the specific antigen causes the activation and degranulation of these cells, thus leading to the release of a variety of chemical substances either preformed or newly synthesized upon cell activation. These substances are responsible for both early and late phase response of allergic asthma. In addition, during this process, mast cells and basophils produce several cytokines and chemokines that contribute to amplify the cascade of inflammatory events. It is noteworthy that several studies have demonstrated that also airway smooth muscle cells may be responsible not only for the asthmatic bronchocostriction, but also for the modulation of the immune response in the airways. A bulk of data demonstrate the importance of the cellular network orchestrated by cytokines and chemokines in determining airway inflammation and subsequent tissue damage and remodelling in asthma. This importance is further supported by the observation that airway inflammation and edema can be demonstrated even in asymptomatic patients either in the presence or in the absence of increased thickness of the basement membrane underneath airway epithelium.
Several environmental factors or stimuli are able to induce asthma. These factors include, infectious agents and chemical compounds, that frequently precipitate asthma attacks in susceptible individuals. It is non yet clear, however, if the mechanisms of airway inflammation are specific for a given trigger of asthma or dependent by the genetic determinants of the disease. It has been suggested, for example, that the inflammatory process of asthma due to isocyanates may be directly mediated by the activity of specific T cells having both Th1 and Th2 profiles. In allergen-induced asthma, the same allergen components are able to prime the immune response in a way that results in a shift towards a Th2 profile. Finally, the relationship between respiratory tract infections and airway inflammation is somewhat controversial. In fact , whereas infections appear to act as a protective factor against the occurrence of asthma, it is well known that viral infections can determine asthma either directly by means of epithelial damage, and the subsequent production of cytokines and chemokines, or through the synergistic effect of allergens and air pollution. A better understanding of these mechanisms could help in designing new preventive and therapeutic strategies to achieve a better control of asthma. <<<