CC16 in childhood and resilience to early airflow limitation in adult life

University Of Arizona, Tucson AZ

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Abstract

PROJECT SUMMARY/ABSTRACT Up to 50% of cases of chronic obstructive pulmonary disease (COPD) develop the disease through a lung function trajectory characterized by an impaired lung function growth in childhood, without necessarily experiencing a faster decline in adult life. This “low flier” trajectory is associated with early low-grade systemic inflammation and can lead to the development of COPD through an intermediate stage of “pre-COPD” in which lung function deficits, respiratory symptoms, and small airway abnormalities are present and identify at-risk individuals years before the disease is fully manifest. However, at present the factors that confer resilience to the low flier trajectory and may, in turn, modify its sequelae on pre-COPD remain unknown. Here, we propose that Club cell secretory protein (CC16), a pneumoprotein with critical anti-inflammatory properties, plays a key role in protecting from the risk of early airflow limitation and other pre-COPD phenotypes linked to impaired lung function growth in childhood. Although it is mainly produced by club cells and other non- ciliated airway epithelial cells, CC16 can be readily measured in circulation and work completed during the previous funding period has demonstrated that this molecule is likely to exert direct protective effects against airway obstruction partly through anti-inflammatory properties by reducing adhesion of activated leukocytes to endothelial cells and, in turn, preventing their lung infiltration. In this renewal application, we intend to extend these tantalizing findings by establishing the role of circulating CC16 in childhood as a resilience factor against early airflow limitation and pre-COPD phenotypes in young adult life. In epidemiological and experimental studies, we will also evaluate whether these CC16 effects counteract those induced by early systemic inflammation (assessed by an inflammatory score of 5 proteins that we have recently linked to low lung function growth). To accomplish these goals, we will expand our CC16 Epi Consortium to include eight international birth cohorts and establish one of the largest respiratory epidemiological consortia to date. Aim 1 - To determine whether deficits in circulating CC16 in childhood predict the presence of airflow limitation and other pre-COPD phenotypes in young adult life in a large international consortium of birth cohorts. Aim 2 - To determine whether low circulating CC16 and systemic inflammation in childhood have combined effects on risk for pre-COPD phenotypes by young adult life. Aim 3 - To determine whether leukocytes from low fliers with early systemic inflammation have increased propensity to adhere to the endothelium ex vivo, and whether their adhesion to endothelial cells can be reduced with recombinant CC16 (rCC16). The proposed work will shed new light on the role of CC16 in resilience against pre-COPD and may pave the way to novel CC16-centered strategies to prevent and/or mitigate the long-term sequelae of early COPD.