Bronchial asthma is an inflammatory disease of the airways with an increasing trend. The persistent inflammation of the airways in bronchial asthma is associated with a continuous production of inflammatory cytokines and generates structural alterations known as "remodelling" which, in turn, permanently compromise the respiratory function. The Section of "Immunopatologia e Farmacologia Clinica e Sperimentale dell'Apparato Respiratorio" has been involved over the last several years in the study of the inflammatory mechanisms in patients with bronchial asthma. In particular, we have recently been involved in studying the mechanism underlying the persistence of inflammation in the airways of asthmatic subjects. It has been demonstrated the role of the activation of a pro-inflammatory transcription factor, NFkB, in the pathogenesis and in the clinical assessment of bronchial asthma. These mechanisms were studied in children as well as in adults with bronchial asthma. In particular, the study performed in children, demonstrated that moderate and severe pediatric asthma includes two different sub-groups: high and low producers respectively, classified on the basis of the production of IL-8 and GM-CSF and on the basis of the NFkB activation. The direct relationship between the activation of NFkB and the release of inflammatory cytokines with a crucial role in the pathogenesis of bronchial asthma was demonstrated by experiments aimed to decrease the release of pro-inflammatory mediators via the block of NFkB activation by a specific inhibitor (PDTC). These studies have also clarified the mechanisms underlying the persistence of NFkB activation in severe bronchial asthma. In the absence of cell activation, NFkB is anchored and trapped within the cytoplasm by a family of endogenous inhibitors known as IkB. During cell activation promoted by inflammatory stimuli, specific kinases (IKK) are activated and, in turn, these kinases phosphorylate the NFkB inhibitors promoting their degradation. In asthmatic subjects, because of an increased expression and activation of IKKb, the most important NFkB inhibitor, IkBa, is highly phosphorilated and undergoes an increased degradation. The direct consequence of this phenomenon is represented by the translocation of NFkB from the cytoplasm into the nucleus where it activates the transcription of pro-inflammatory genes thus contributing to the amplification of the inflammatory responses in the airways of asthmatic subjects. The airways inflammation in severe asthma is also supported by the NFkB activation at the level of the proliferating bronchial epithelium. The clinical outcomes of these findings will provide further diagnostic useful tools to identify sub-groups of patients who, despite a high dose steroid treatment, maintain a severe airway inflammation and, consequently, have a high risk of airway remodelling.
References
La Grutta S. et al. Clinical and biological heterogeneity in children with moderate asthma. Am J Respir Crit Care Med. 2003; 167:1490-5.
Gagliardo R. et al. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003;168:1190-8.
Vignola AM. et al. Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma. J Allergy Clin Immunol. 2001; 108:738-46.
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