Rhinovirus and Airway Epithelial Cell Responses

鼻病毒和气道上皮细胞反应

• 批准号: 7783827
• 负责人: Marc B. Hershenson
• 金额: $ 36.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2010-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783827
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accident and Emergency department; Accounting; Acute; Adult; Air; Allergic inflammation; Asthma; Biochemical; Bronchial Lavages; CXC Chemokines; Cell Culture Techniques; Cells; Child; Common Cold; Data; Disease; Enhancers; Epithelial; Epithelial Cells; Event; Extracellular Signal Regulated Kinases; Family Picornaviridae; Growth; Human; ICAM1 gene; Infection; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interleukin-13; Interleukin-8; Lead; Life Cycle Stages; Ligation; Liquid substance; Mediating; Membrane Microdomains; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Mus; NADPH Oxidase; Nose; Oncogenes; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Pilot Projects; Production; RNA Viruses; Research Personnel; Rhinovirus; Signal Pathway; Signal Transduction; Site; Testing; Transactivation; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral; Virus Diseases; airway inflammation; base; chemokine; chemokine receptor; cytokine; in vivo; leucylarginine; macrophage inflammatory protein 2; neutrophil; p65; programs; promoter; response

Rhinovirus (RV) infection accounts for a large fraction of asthma exacerbations. Airway neutrophils and IL-8 levels are increased in RV-induced exacerbations, suggesting that RV stimulates exacerbations by inducing epithelial cell expression of (El_R)+ C-X-C chemokines, leading to an exaggerated inflammatory response. In pilot studies, we have shown that RV39 induces IL-8, ENA-78 and GRO-ct expression in primary, mu- cociliary-differentiated human tracheal epithelial cells. In 16HBE14o- cells, RV39 infection activates Src, PI 3-kinase, Akt and ERK minutes after infection, and activation of these kinases is required for IL-8 expression. RV increases C-X-C chemokine expression induced by two pro-asthmatic cytokines, IL-13 and TNFa. Fi- nally, RV1B infection of C57/BL6 mice increases airway neutrophils and levels of MIP-2, a murine ELR(+) C- X-C chemokine. Wetherefore hypothesize that RV is sufficient to activate biochemical signalingpathways involved in the asthmatic response, providing a mechanism for RV-induced asthma exacerbations. Specific Aim 1: Characterize upstream activators and downstream effectors of PI 3-kinase required for RV-induced ELR(+) C-X-C chemokine expression. We hypothesize that: 1) RV colocalizes with Src, PI 3- kinase, Akt and Grb2 in lipid rafts; 2) Src is required for activation of the PI 3-kinase/Akt pathway; 3) Class IA, II and III PI 3-kinases are required for maximal RV-induced expression of IL-8, ENA-78 and GROot; and 4) maximal NF-KB activation requires PI 3-kinase-dependent activation of NADPH oxidase. Specific Aim 2: Determine the biochemical signaling mechanisms responsible for cooperative effects of RV and pro-asthmatic cytokines on airway epithelial cell IL-8 expression. We hypothesize that: 1) ERKand JNK regulate IL-8 expression via activation of the AP-1 promoter site, which functions as a basal level en- hancer; 2) additive effects of RV39 and TNFa are mediated by increased p65 RelA phosphorylation and NF- transactivation; 3) synergistic effects of RV39 and IL-13 are mediated by increased AP-1 transactivation. Specific Aim 3: Determine the steps in the viral life cycle required or sufficient for RV-induced signaling and chemokine responses and, conversely, determine the requirement of host cell signal transduction for viralinfection. We hypothesize that: 1) ICAM1 ligation is required and sufficient for activation of Src, PI 3- kinase, Akt, ERK and JNK; 2) viral replication is not required for activation of these signaling intermediates; and 3) PI 3-kinase activation is required for RV39 internalization. Specific Aim 4: Determine the requirements of PI 3-kinase signaling and ELR(+) C-X-C chemokines for RV-inducedresponses in vivo. We hypothesize that: 1) RV1B infection is sufficient for airway inflammation and epithelial cell signaling in vivo; 2) PI 3-kinase is required for RV1B-induced airway inflammation in vivo; and 3) C-X-C chemokine receptor (CXCR)-2 regulates RV1B-induced airway inflammation in vivo. Understandina RV-induced asthma exacerbations will lead to improvements in the treatment of this disease.

鼻病毒（RV）感染占哮喘加重的很大一部分。气道中性粒细胞和IL-8