Asthma affects 5-10% of the population and is characterized by persistent symptoms, airflow limitation and frequent exacerbations. Interleukin-13 (IL-13) plays a central role in the most common phenotype of asthma, but the molecular mechanisms responsible for the modulation of its effects are not fully understood. Surfactant Protein A (SP-A), a member of the collectin family and an important component of innate immunity in the lung, modulates host immune responses to inhaled insults by binding to specific receptors with in the collagen and lectin domains and regulating the subsequent inflammatory pathways. We have shown that SP-A function is defective in asthma which could arise from both genetic variation and/or pathological modification to protein structure. Our preliminary data strongly implicate a novel role for SP-A in regulating IL-13 signaling in asthma through EGFR and Stat3, two critical mediators that are known to regulate airway inflammation and mucin production. The overall goal of this translational proposal is to determine the mechanisms by which SP-A regulates IL-13 signaling in human asthma and evaluate the therapeutic effects of specific SP-A peptides that inhibit IL-13 signaling and resolve type 2 airway inflammation. The studies described in this proposal have significant potential to provide a novel therapeutic approach for asthma. Based upon our data, we propose the novel hypothesis that SP-A significantly suppresses allergic inflammation through disruption of IL-13- dependent IL-6/EGFR/Stat3 signaling pathways and the crucial anti-inflammatory properties of SP-A are rendered ineffective in asthmatic subjects as a consequence of SP-A genotype and cytokine milieu. Specific SP-A peptides can rescue this dysfunction, offering a novel therapeutic alternative for asthma. We will test this hypothesis through a combination of experimental approaches including primarily human studies supported by translational animal models. We will first determine whether specific SP-A2 polymorphisms alter the ability of SP-A to regulate IL-13- signaling in the context of asthma (Aim 1). Next, we will determine the mechanism by which SP-A mediates a potentially novel signaling axis involving IL- 6/EGFR/Stat3 in the setting of IL-13 exposure (Aim 2). Third, we will determine the effectiveness of SP-A replacement therapy in mouse models of asthma (Aim 3). This project focuses on airway innate immunity in asthma, the central theme of this U19 application. This project interacts with Project 2 as both projects dissect the contribution of genetic variations of the innate immune mediators SP-A and Tollip in type 2 inflammation and infection. Project 1 synergizes with Project 3 which will elucidate the ability of the lipid portion of surfactant, POPG (Project 3) to attenuate the exuberant inflammation associated with infection in the setting of asthma and innate immune dysfunction. Our findings challenge the prevailing view of SP-A as only an opsonin for infectious pathogens; we propose it is a complex functional protein that regulates innate immunity of asthma and type 2 inflammation. The project will also investigate a novel therapeutic alternative for treatment.
