Thursday, April 25, 2024
4/25/2024
PROJECT ABSTRACT Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have shown that asthma is the most important risk factor for COPD that develops through a course of low lung function from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic underlying mechanisms of this progression. Club cell secretory protein (CC16) has been described for its potential as a biological marker of lung epithelial cell injury and recent studies by our group concluded that low circulating CC16 levels predict impaired lung function growth in childhood and increased risk of asthma or COPD in adult life. In our cohort, adults with asthma with low serum CC16 levels and elevated levels of antibodies against M. pneumoniae (Mp) have a striking 8-fold increase in their odds of developing airflow limitation. These studies highlight the critical need for an intact immune system that protects against lung function decline and provide evidence that persistent early life infections may be a previously overlooked link in understanding progression of asthma into severe asthma with fixed airflow limitation. We developed a mouse model of early life exposure to Mp in which WT or CC16 deficient mice are infected pre-weaning and assessed for lung function in adulthood and found that CC16-/- mice have persistent airway inflammation and a striking >1000% over baseline airways resistance as compared to WT controls, which is likely attributed to inflammation and airway remodeling. The overall hypothesis is that CC16 plays a protective role during Mp-driven inflammation that is dependent on binding to its newly discovered receptor, the integrin VLA-4. The action of CC16 attenuates lung inflammation, remodeling and airway hyperresponsiveness. This hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of CC16 deficiency on pulmonary inflammation, remodeling and lung function using M. pneumoniae infection mouse models that include comparisons between an early life and adult infections, 2) Determine if the mechanism by which CC16 protects against inflammation, remodeling and loss of lung function is dependent on the VLA-4 receptor, and 3) Determine the impact of CC16 deficits in association with Mp infection on inflammation, remodeling factors and lung function using data and samples from multiple human longitudinal cohorts. This proposal is innovative in that we have identified a previously unknown receptor for CC16, adhesion molecule VLA-4 and we employ a novel translational approach to test our hypothesis using ex vivo studies, animal models, and human samples from well-characterized local and international cohorts. The proposed research is significant in that these findings will describe a new mechanism by which CC16 functions in a protective manner and may be immediately applicable to other pulmonary pathogens. Since CC16 is an informative and predictive biomarker, our studies may provide a novel therapeutic approach for treating individuals with low circulating CC16 in order to prevent lung function decline over time.
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