Grant: Project Grant

Climate change has greatly increased forest fires and the exposure of Canadians to wildfire smoke. Hospital admissions rise on smoky days because people with moderate lung disease have a sudden increase in the severity of their symptoms, or "exacerbation", which may be triggered by a respiratory infection or the smoke itself. Mucus normally protects the airways from inhaled microbes and pollutants and helps to clear them from the lungs, however clearance fails when the mucus becomes too concentrated due to excess production or insufficient fluid on the airway surface. Salt transport through the CFTR channel drives the fluid secretion that liquifies mucus but its function is reduced by mutations in the CFTR gene that cause cystic fibrosis (CF) and by cigarette smoke exposure that causes chronic obstructive pulmonary disease (COPD). We recently found that wildfire smoke inhibits CFTR and therefore is expected to increase exacerbations and their severity. How wildfire and cigarette smoke impairs CFTR at the molecular level is not known, but understanding the mechanisms could allow the development of therapeutics that aim to reduce exacerbations during wildfire smoke exposure. We will collect smoke from burning forest material and study its effects on human lung cells to understand how it inhibits CFTR. The diseases COPD, asthma and CF are all more severe in females than males. We will determine if CFTR inhibition by wildfire smoke is more pronounced in female cells and leads to more severe exacerbations in female mice using a model of COPD. Finally, we will test novel CFTR modulators and antioxidants for their ability to protect CFTR against the inhibition by wildfire smoke in vitro, and against exacerbations in vivo that are triggered by infection. These studies will improve our mechanistic understanding of wildfire smoke toxicity and may accelerate the development of therapeutics to reduce exacerbations during the increasingly prolonged wildfire season.