Epithelial-Immune Cell Interactions for Drug Discovery in Chronic Obstructive Pulmonary Disease

• Published in: Annals of the American Thoracic Society Vol. 15; no. Suppl 4; pp. S260 - S265
• Main Authors: Keeler, Shamus P, Gerovac, Benjamin J, Wu, Kangyun, Wang, Xinyu, Chartock, Joshua R, Byers, Derek E, Romero, Arthur G, Holtzman, Michael J
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2018
• Subjects: Animals; Cell Communication; Chronic obstructive pulmonary disease; Drug Discovery; Endothelial Progenitor Cells - cytology; Gene Expression; Humans; Immunity, Innate; Inflammation - complications; Inflammation - immunology; Interleukin-13 - immunology; Kinases; Marvin I. Schwarz Lecture; Mitogen-Activated Protein Kinase 13 - immunology; Mucin 5AC - genetics; Mucin 5AC - metabolism; Mucous membrane; Pulmonary Disease, Chronic Obstructive - immunology; Pulmonary Disease, Chronic Obstructive - pathology; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Signal Transduction; Viral infections; airway disease; drug discovery; innate immune cells; airway epithelial cells; chronic obstructive pulmonary disease
• ISSN: 2329-6933; 2325-6621
• DOI: 10.1513/AnnalsATS.201808-531MG

New studies of chronic obstructive pulmonary disease (COPD) are revealing the key role of airway epithelial cells and innate immune cells in the initiation, exacerbation, and progression of airway disease. An emerging scheme focuses on expansion of airway progenitor epithelial cells that feed forward for a type 2 immune response and consequent IL-13-driven mucus production that is linked to the morbidity and mortality of COPD. Analysis of human airway progenitor epithelial cells and airway tissue shows that IL-13 signaling to MUC5AC mucin gene expression relies on specific activation of mitogen-activated protein kinase 13, providing a druggable target for attenuating mucus production in the setting of viral infection and other inhaled stimuli of airway inflammation. Moreover, structure-based drug design is delivering highly potent, selective, and nontoxic small-molecule kinase inhibitors of mitogen-activated protein kinase 13 that offer a therapeutic strategy to downregulate excess mucus production to a physiological level and thereby achieve a precision medicine solution to the major health care problem of COPD and related airway diseases.