Restoring macrophage function in cystic fibrosis

点击翻译按钮获取中文摘要

Summary This Administrative Supplement is in response to NOT-HL-19-724 (Notice of Special Interest (NOSI): Availability of Administrative and Revision Supplements to Expand Vaping Research and Understand EVALI). ). The original grant (5R01AI124121-04) is focused on understanding the role of the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR) on exacerbated inflammation in the airways. Patients with mutations in this ion channel leading to its malfunction develop Cystic Fibrosis (CF), a disease associated with impaired bacterial clearance and increased lung inflammation, which ultimately results in lung failure. As an ion channel, CFTR regulates fluid homeostasis in the lung. In addition, our published studies demonstrated for the first time that macrophages lacking functional CFTR had impaired autophagy resulting in excessive inflammatory profile. Relevant to this Supplement, findings from our group revealed that pollutants, such as cigarette smoke and the psychoactive ingredient present in marijuana delta-9-tetrahydrocannabinol (THC), negatively regulate CFTR leading to “acquired CFTR dysfunction”. In addition to inflammation, the CFTR ion channel plays also a role in fluid homeostasis in the lung such as edema. Within the past few months, several people were hospitalized and many died after developing lung disease linked to vaping: “e-cigarette, or vaping, product use-associated lung injury” called EVALI which is characterized by excessive lung inflammation and pulmonary edema. We therefore hypothesize that inhibition/decrease of CFTR function by THC and/or vitamin E acetate will contribute to EVALI. In Aim 1, we will determine the effect of the different agents present in vaping preparations associated with EVALI on lung inflammation. Mice will be exposed to vaping preparations and a comprehensive assessment of lung inflammation (multiplex, flow cytometry, RNAseq) will be performed. In Aim 2, we will establish the role of the CFTR ion channel on EVALI-like phenotype. Here we propose to use a mouse model that expresses different levels of CFTR (WT, Hets, and KO). CFTR activators will also be tested to evaluate their ability to reduce vaping- induced lung inflammation.