CHEMOKINE/ CYTOKINE CONTROL OF EOSINOPHIL LUNG DAMAGE

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Asthma is defined as a chronic inflammatory disorder of the airways. Recurrent exacerbations that characterize the disordered lung function in asthma are associated with an increased inflammatory response. As described by the Global Initiative for Asthma, it effects an estimated 7% of the U.S. population, occurs among all ages and is significantly increasing in prevalence, cost of care, morbidity and mortality. It is well- accepted that airway diseases are characterized by an underlying inflammation in which many cells, particularly eosinophils (EOS), play a role. Once recruited and activated, EOS have the capability of synthesizing and releasing numerous pro-inflammatory mediators into the pulmonary microenvironment. Most asthmatics, even those with mild disease, show substantial chronic desquamating, eosinophilic bronchitis. This inflammation plays a role in disease pathogenesis since it contributes to bronchoconstriction, swelling of the airway wall and airway remodeling. Considering these airway diseases as inflammatory disorders has implications for diagnosis, prevention and therapeutic management. The focus of these proposed investigations is treatment of the underlying EOS-mediated inflammation, thus preventing permanent destruction of lung tissue. The overall objective of these proposed investigation is to identify EOS-selective cytokine(s) or chemokine(s) which may serve as therapeutic targets to decrease EOS recruitment, adhesion, inflammatory mediator release and delayed apoptosis and test these identified cytokines as candidates for an antisense oligonucleotides treatment approach. Experiments will be designed to explore the hypotheses that: EOS-selective cytokines increase pro-inflammatory mediator release and adherence of EOS to airway epithelial cells (specific aim 1), the airway epithelium is a paracrine source of EOS-active cytokines (specific aim 2), EOS apoptosis can be induced without release of pro-inflammatory mediators (specific aim 3), and antisense oligonucleotides can be used as an adjunctive therapeutic approach to specifically suppress expression of genes which direct the pro- inflammatory activities in EOS (specific aim 4). Understanding processes which control selective eosinophilia is an important prelude to development of more effective therapies for a variety of human diseases including asthma and allergies. Results of this research may assist in fulfillment of the priority research needs on effects of pharmacological treatment and immunotherapy in the long-term management of asthma as outlined by the Global Initiative for Asthma.