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Macrophage Rac2 Is Required to Reduce the Severity of Cigarette Smoke–induced Pneumonia

Year: 2018
Type: article
Abstract: RATIONALE: Cigarette 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. OBJECTIVES: Determine 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. METHODS: 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 RESULTS: NOX2-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. CONCLUSIONS: These 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.
DOI: 10.1164/rccm.201712-2388oc
Authors: 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, A. Brent Carter
Language: English
Subfield: Immunology
Open Access status: green
Funders: American Lung Association, University of Toronto, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: Vaccine potential of the proline-rich domain of pneumococcal surface protein A, The Role of PGP in COPD-associated Pulmonary Hypertension, HL-A New Pathway for Neutrophil-induced Airway Inflammation, UAB Neuroscience Core Center, Myeloid-Derived Regulatory Cells in Asthma, Acquired LTA4H Dysfunction in COPD, PGP, A Possible Biomarker for COPD Exacerbations and or Progression, Environmental Cadmium and COPD, G5174234711, Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity, Asbestos toxicity is modulated by MCU-mediated macrophage apoptosis resistance, Genetics of Smoke-Altered LTA4H in COPD, A Novel Exosomal Inflammatory Pathway
OpenAlex ID: W2808553989
FWCI: 0.751
Cites: 50
Cited by: 15
Related to: 10