The overall objective of this research was to determine the mechanism by which arsenic alters Club (formerly Clara) cell protein (CC16) production and the role of induced CC16 in altering lung structure and function following early life exposure to arsenic. Drs. Lantz and Chen recently identified a set of proteins, mostly markers of systemic inflammation, whose serum levels were strongly related to exposure to cigarette smoking and impaired lung function. In several independent cohorts, baseline serum CC16 levels have been associated with decreased subsequent incidence of airflow limitation, accelerated decline of lung function, and mortality in up to 40 years of follow-up. These findings were in accord with prior results from the same lab, in which CC16 knockout mice exhibited increased airway inflammation and alveolar remodeling when exposed to side-stream (environmental) cigarette smoke exposure compared with wild-type animals. Preliminary data collected under this Pilot Project showed that arsenic, whether ingested or inhaled, leads to significantly decreased CC16 expression in the lung, with increased airway reactivity. However, the specific function of CC16 in arsenic-induced lung abnormality remains unclear. These preliminary data were used to support a newly funded R01 (R01 ES027013-01A1).