title: A modeling-derived hypothesis on chronicity in respiratory diseases: desensitized pathogen recognition secondary to hyperactive IRAK/TRAF6 signaling.
abstract: Several chronic respiratory diseases exhibit hyperactive immune responses in the lung: abundant inflammatory mediators; infiltrating neutrophils, macrophages, lymphocytes and other immune cells; and increased level of proteases. Such diseases include cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and severe/neutrophilic asthma. Paradoxically, patients with these diseases are also susceptible to detrimental bacterial infection and colonization. In this paper, we seek to explain how a positive feedback mechanism via IL-8 could lead to desensitization of epithelial cells to pathogen recognition thus perpetuating bacterial colonization and chronic disease states in the lung. Such insight was obtained from mathematical modeling of the IRAK/TRAF6 signaling module, and is consistent with existing clinical evidence. The potential implications for targeted treatment regimes for these persistent respiratory diseases are explored.
authors.affiliation: Roche Palo Alto LLC, Palo Alto, California, United States of America. tingting.zhang@roche.com
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Kyung W
authors.initials: KW
authors.lastname: Song
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hekmat-Nejad
authors.forename: David G
authors.initials: DG
authors.lastname: Morris
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
mesh_terms: D001249:Asthma / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000276:immunology; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology; D012120:Respiration Disorders / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; D048029:TNF Receptor-Associated Factor 6; D053592:Interleukin-1 Receptor-Associated Kinases