• Jennifer L Larson-Casey, Linlin Gu, Patricia L Jackson, David E Briles, Joanetha Y Hale, J Edwin Blalock, J Michael Wells, Jessy S Deshane, Yong Wang, Dana Davis, Veena B Antony, Adriana V F Massicano, Suzanne E Lapi, and A Brent Carter.
• 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2018 Nov 15; 198 (10): 128813011288-1301.

RationaleCigarette smoking is prevalent in the United States and is the leading cause of preventable diseases. A prominent complication of smoking is an increase in lower respiratory tract infections (LRTIs). Although LRTIs are known to be increased in subjects that smoke, the mechanism(s) by which this occurs is poorly understood.ObjectivesDetermine how cigarette smoke (CS) reduces reactive oxygen species (ROS) production by the phagocytic NOX2 (NADPH oxidase 2), which is essential for innate immunity in lung macrophages.MethodsNOX2-derived ROS and Rac2 (Ras-related C3 botulinum toxin substrate 2) activity were determined in BAL cells from wild-type and Rac2-/- mice exposed to CS or cadmium and in BAL cells from subjects that smoke. Host defense to respiratory pathogens was analyzed in mice infected with Streptococcus pneumoniae.Measurements And Main ResultsNOX2-derived ROS in BAL cells was reduced in mice exposed to CS via inhibition of the small GTPase Rac2. These mice had greater bacterial burden and increased mortality compared with air-exposed mice. BAL fluid from CS-exposed mice had increased levels of cadmium, which mediated the effect on Rac2. Similar observations were seen in human subjects that smoke. To support the importance of Rac2 in the macrophage immune response, overexpression of constitutively active Rac2 by lentiviral administration increased NOX2-derived ROS, decreased bacterial burden in lung tissue, and increased survival compared with CS-exposed control mice.ConclusionsThese observations suggest that therapies to maintain Rac2 activity in lung macrophages restore host defense against respiratory pathogens and diminish the prevalence of LRTIs in subjects that smoke.

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