Persistence of childhood asthma into adult life has been conclusively linked to long-term lung function deficits and an increased susceptibility to non-fully reversible airflow limitation, the hallmark of chronic obstructive pulmonary disease. Yet, at the present time there are neither established prediction models nor available biomarkers for early risk identification of long-term sequelae in childhood asthma. In preliminary studies, we found early levels of circulating CC16 ? a pneumoprotein that is produced mainly by club cells in the distal airways and can be measured in circulation ? to be associated with resilience to subsequent lung function deficits and persistent asthma. Of note, these effects were independent of known risk factors for persistent disease. In addition, we found CC16-/- mice to have lung function deficits, airway alterations, and susceptibility to infections by Mycoplasma pneumoniae as compared with wild-type animals. These findings support CC16 in early school age as a strong and independent factor for resilience to persistent disease and long-term sequelae in children with asthma, and suggest that CC16 may exert these effects by modulating susceptibility and responses to airway infections. The present proposal addresses 1) the identification of early determinants of circulating CC16 levels by school-age; 2) the value of levels and trajectories of circulating CC16 in childhood as predictors of persistence and severity of asthma into adult life; and 3) the evaluation of airway responses to asthma pathogens as a potential mechanism mediating CC16 effects on persistent disease.
Persistence of childhood asthma into adult life has been linked to long-term lung function deficits and an increased risk for chronic obstructive pulmonary disease, a disease with a heavy morbidity and mortality burden. Yet, at the present time there are no factors that can be used for early identification of children with asthma at risk for persistence of disease into adult life. In preliminary studies, we found low levels of CC16 in blood ? a protein that is produced mainly in the lungs but can be measured in blood ? to be associated with subsequent lung function deficits and persistent asthma. The present proposal aims to (1) identify the early determinants of circulating CC16, (2) use circulating CC16 in childhood to predict persistence and severity of asthma into adult life, and (3) determine whether these effects are mediated by altered responses of the airways to infections.
| Martinez, Fernando D; Guerra, Stefano (2018) Early Origins of Asthma. Role of Microbial Dysbiosis and Metabolic Dysfunction. Am J Respir Crit Care Med 197:573-579 |
| Zhai, Jing; Stern, Debra A; Sherrill, Duane L et al. (2018) Trajectories and Early Determinants of Circulating CC16 from Birth to Age 32 Years. Am J Respir Crit Care Med 198:267-270 |
