MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction

• Published in: PloS one Vol. 11; no. 12; p. e0167169
• Main Authors: Boehme, Stefen A, Franz-Bacon, Karin, Ludka, John, DiTirro, Danielle N, Ly, Tai Wei, Bacon, Kevin B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.12.2016; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Air flow; Alveoli; Analysis; Animal models; Animals; Biology and Life Sciences; Blotting, Western; Bronchus; Cell Line, Tumor; Cell lines; Chemokines; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarettes; Complications and side effects; Cytokines; Cytokines - metabolism; Development and progression; Disease control; Emphysema; Environmental stress; Epithelial cells; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Epithelium; Female; Gene Expression; Health aspects; HEK293 Cells; Humans; Inflammation; Inflammation Mediators - metabolism; Influenza A; Influenza A virus; Inhibition; Kinases; Lamina propria; Lung diseases; Macrophages; Macrophages - enzymology; Male; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Middle Aged; Molecular weight; Neutrophilia; Neutrophils; NF-kappa B - metabolism; NF-κB protein; Obstructive lung disease; Orthomyxoviridae; Osmotic stress; Oxidative stress; Parenchyma; Patients; Pneumonia - enzymology; Pneumonia - etiology; Pneumonia - genetics; Pulmonary Disease, Chronic Obstructive - enzymology; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Research and Analysis Methods; Respiratory function; Respiratory System - enzymology; Respiratory System - metabolism; Respiratory System - pathology; Respiratory tract; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; siRNA; Smoke; Smoking; Smoking - adverse effects; Tobacco smoke; Transcription; Viruses; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167169

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.