Rhinovirus Induced Airway Inflammation in Na

Rhinovirus INduced Exacerbations of Asthma;Physiology;Science;Molecular and Integrative Physiology

Nagarkar, Deepti RavindraPeters-Golden, Marc ;

University of Michigan

关键词: Rhinovirus INduced Exacerbations of Asthma;    Physiology;    Science;    Molecular and Integrative Physiology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/77817/deepti_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Respiratory viruses, including rhinovirus (RV), are responsible for 80% of asthma exacerbations in children and roughly 50% of exacerbations in adults.However mechanisms by which RV causes exacerbation of lower airways disease in asthmatic, compared to simple upper respiratory tract infections in normals, are poorly understood.Progress in this area has been hampered in part by the lack of an appropriate animal model.Here we compare airway responses of normal (naïve) mice with those undergoing allergen sensitization and challenge, a model of allergic asthma. RV infection of naïve C57BL/6 mice increases production of murine IL-8 homologs KC/CXCL-1, and MIP-2/CXCL-2, neutrophil infiltration, and airway hyperreactivity up to 4 days post infection.We hypothesized that RV induction of C-X-C chemokines is required for neutrophil inflammation and hyperresponsiveness in naïve mice.Here we show that Balb/c mice deficient in the CXCR2 receptor have reductions in airway neutrophils, C-X-C chemokine expression, and TNF- production.RV treated CXCR2 -/- mice have significantly lower airway hyperreactivity 24 hours post infection.Similar results were obtained with a neutrophil depleting antibody.We demonstrate that TNFR1 is required for RV induced neutrophil inflammation and airway hyperreactivity.We conclude that in naïve mice, C-X-C chemokines and neutrophils are required for maximal airway responses 24 hours after RV infection and this effect is partly mediated by TNF-.RV infection of ovalbumin (OVA) treated mice shifts the primarily neutrophilic response in naïve mice to a T (helper)-h-2 cell driven response which is characterized by increased numbers of eosinophils and macrophages and increased airway hyperresponsiveness day 4 post infection which partly mediated by eosinophil specific chemokine eotaxin-1/CCL11.RV co-localizes with eotaxin and IL-4 in CD68+ macrophages.RV infection of OVA sensitized macrophages ex vivo increased expression of IL-4, IL-13, eotaxin and IL-10, indicating a shift from a classically activated (M1) to an alternatively activated phenotype (M2). Macrophage depletion abrogates OVA/RV induced expression of eotaxin, IL-13, infiltration of eosinophils, and cholinergic responsiveness.We conclude that RV induces exacerbations of allergic airways disease by infecting alternatively-activated lung macrophages, leading to increased eosinophilic inflammation.These observations provide a new paradigm to explain RV-induced asthma exacerbations.