Chronic obstructive pulmonary disease (COPD) has been increasing for the past years. Today COPD is the most common cause of death in the US and is classified amongst the top five killers. Other lung diseases such as atopic asthma have been steadily increasing in the population of industrialized countries. The prevalence of asthma over the past 20 years has increased by 100% and today it affects 10% of the U.S. population. Both patients affected by atopic asthma and patients with COPD develop airway obstruction. Unlike asthma airway obstruction in patient affected by COPD is progressive and mostly irreversible. Although, many similarities are shared between clinical features of allergic asthma and COPD, there are significant differences in the immunological mechanisms that underlie these two diseases. Atopic asthma is characterized by an overproduction of Th2 cytokines (IL-4, IL-5 and IL-13), peripheral blood eosinophilia and elevated IgE level to a specific allergen. COPD is usually caused by tobacco smoke that disrupts the epithelial barrier and induces a migration of different cell type such as neutrophils, macropages, T lymphocytes and natural killer cells through the airway epithelium. In contrast to asthma, CD4+ T cells that infiltrate the inflamed lung are mainly Th1 cells. However, recent studies showed that bronchoalveolar fluid lavage (BALF) from patients with COPD have an increased number of Th2 cells making the distinction between these two diseases more complex. Furthermore, it has been recently shown that a new CD4+ T cells subset termed Th17, which is distinct from Th1 and Th2, play a role in allergic asthma. Our preliminary results indicate that IL-17A and IL-17 F levels, which are two major Th17 cytokines, are increased locally and systemically in smokers with COPD when compared to smokers without COPD. Based on these observations, we hypothesize that Th17 play a role in the pathogenesis of COPD.
In specific Aim 1 A, we will test the hypothesis that IL-17 production is increased in patients affected by COPD when compared to patients without COPD.
In Aim 1 B, we will determine the molecules and signaling pathway(s) involved in the up-regulation of Th17 and in COPD, respectively. In a second Aim, we will characterize the major IL-17-producing cells in lung tissues affected by COPD. Understanding the role of Th17 cytokines in the pathogenesis of COPD will provide better therapeutic approaches.
This research is relevant to public health because it addresses the role of Th17 cytokines and invariant Natural Killer T cells (iNKT) cells in a life-threatening disease, which is chronic obstructive pulmonary disease (COPD). Therefore, this study is important because it is novel and it will permit us to develop effective therapies to prevent it.