Optimization of anesthetic/sedative regimen for pulmonary pathophysiology in cystic fibrosis patients

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Project Summary The median age for survival of cystic fibrosis (CF) patients is still in the mid 40s and pulmonary deterioration is the major cause of mortality for CF patients. Because respiratory exacerbation can worsen the course of their respiratory status in an irreversible manner, mitigating any complications is critical to improve their quality of life and life span. CF patients present to surgery and other procedures at various stages of their lives and frequently experience respiratory complications. Neutrophil-mediated lung inflammation associated with colonized bacteria and mechanical ventilation-induced injury are considered as important factors contributing to perioperative pulmonary complications. Flagellin is a primary stimulant of lung tissue by Pseudomonas aeruginosa, a major colonized strain in CF airway. Flagellin stimulation induces recruitment of activated neutrophils and causes lung injury. Neutrophil activation is also involved in the lung injury by mechanical ventilation. Our preliminary study showed that volatile anesthetics attenuated Toll like receptor (TLR)5 and flagellin-mediated lung injury in the mouse model. The result suggested that volatile anesthetics might attenuate lung injury caused by colonized bacteria in CF patients. General anesthesia is frequently required for surgery and other procedures and provided by volatile and intravenous anesthetics. We and others have shown that volatile anesthetics are immunomodulatory. Our preliminary data suggested that volatile anesthetics could hinder TLR5 activation in immunocompetent subjects. We previously showed that volatile anesthetics also attenuated adhesion molecule β2 integrins. Our preliminary data suggested that β2 integrins were involved in ventilation-induced lung injury. This study aims to test our hypothesis that in CF volatile anesthetics would attenuate 1) Pseudomonas aeruginosa-mediated lung injury and 2) mechanical ventilation- induced lung injury using CF transgenic mice and patients’ lung. This will be studied under two Aims: (Aim 1) Determine the role of anesthetic drugs on pulmonary function in a CF preclinical model in vivo (Aim 2) Determine the role of anesthetic drugs on lung slice cultures using CF lung tissue ex vivo. Upon the successful completion of the proposal, we will do clinical study to determine the optimal anesthetic regimen for people with CF. Because all the drugs tested are in clinical use, we expect that clinical translation is quite feasible. In addition, we plan to develop new drugs that attenuate lung injury but are devoid of anesthetic effects using volatile anesthetics as a prototype for general use in CF patients. In addition, this study is critical because we will assess the effect of anesthetics in immunocompromised setting, which is important information from clinical standpoint, but has not been tested yet.