The role of adenosine in the pathogenesis of influenza

腺苷在流感发病机制中的作用

• 批准号: 8080241
• 负责人: IAN CHRISTOPHER DAVIS
• 金额: $ 38.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080241
• 关键词: 5' -Nucleotidase; ATP Synthesis Pathway; Acute; Acute Lung Injury; Adenosine; Adenosine A1 Receptor; Award; Biochemical; Biological Assay; Bone Marrow; C57BL/6 Mouse; Catabolism; Cell physiology; Cells; Cessation of life; Data; Development; Disease; Epithelial Cells; Extracellular Signal Regulated Kinases; Functional disorder; Funding; Generations; Health; Human; Hypoxemia; Inbred BALB C Mice; Infection; Inflammatory; Influenza; Influenza A virus; Injury; Ion Transport; Knockout Mice; Lead; Life; Liquid substance; Lung; Lung diseases; Measures; Mediating; Mediator of activation protein; Methodology; Modeling; Mus; NF-kappa B; National Center for Research Resources; Nucleotides; Outcome; Pathogenesis; Patients; Play; Publications; Pulmonary Edema; Purinergic P1 Receptors; Receptor Signaling; Research; Respiratory Syncytial Virus Infections; Respiratory physiology; Respiratory syncytial virus; Role; Signal Transduction; Sorting - Cell Movement; Symptoms; Testing; Therapeutic Intervention; Translating; Viral; Virus; Virus Diseases; Work; adenosine receptor activation; alveolar type II cell; base; career; combat; extracellular; improved; infancy; influenza epidemic; influenzavirus; innovation; lung development; lung injury; man; neutrophil; novel; nucleotide metabolism; pandemic disease; public health relevance; purine metabolism; receptor expression; respiratory; seasonal influenza; therapeutic target; tool; virology

DESCRIPTION (provided by applicant): Influenza A viruses cause a highly contagious acute respiratory disease. Seasonal influenza epidemics cause >300,000 deaths/yr worldwide, while pandemics elicited devastating loss of life in the 20th century, and may do so in the 21st. Currently, however, essential mechanisms underlying development of lung dysfunction and injury in influenza or any other pulmonary viral infection are poorly defined. Both respiratory syncytial virus (RSV) and influenza virus infection of BALB/c mice induce increased channel-mediated release of the nucleotides UTP and ATP into the bronchoalveolar lining fluid (BALF), and, in both infections, elevated BALF UTP contributes to development of lung edema and hypoxemia. RSV infection in BALB/c mice causes only mild disease while influenza causes more severe disease with many of the pathophysiologic features of acute lung injury, which is also seen in lethal pandemic or epidemic influenza in man. Importantly, following influenza, but not RSV, infection, elevated ATP release into BALF is accompanied by increased activation of A1-subtype adenosine receptors (AdoR) by the ATP degradation product adenosine. Adenosine stimulation of neutrophil A1-AdoR plays a significant role in the initiation and promotion of acute lung injury. The central hypothesis of this proposal is that influenza stimulates de novo ATP synthesis and release from infected ATII cells, that released ATP is metabolized to adenosine at an accelerated rate (due to increased ectonucleotidase CD73 activity), and that, by its effects on A1-AdoR, adenosine in the BALF plays a pivotal role in inducing lung injury in influenza. This hypothesis will be tested in 3 Specific Aims: 1) To determine temporal effects of influenza infection on pulmonary nucleotide metabolism, changes in nucleotide metabolism following influenza infection of MLE-12 cells and purified alveolar type II (ATII) cells, as well as FACS-sorted ATII cells from C57Bl/6 or SP- C/GFP mice will be measured, together with the impact of influenza infection on the BALF nucleotide profile, and the role of ERK MAP kinase in inducing nucleotide synthesis after influenza infection. 2) To determine the role of CD73 in influenza pathogenesis, effects of influenza infection on respiratory epithelial cell CD73 expression and activity will be measured; the impact of pharmacologic blockade of CD73 on influenza pathogenesis in C57BL/6 mice will be determined; and the outcome of influenza infection in CD73-knockout mice will be investigated. 3) To determine the role of adenosine/A1-AdoR receptor signaling in influenza pathogenesis, the effect of influenza-induced NF-kB activation on A1-AdoR expression in ATII cells and neutrophils will be measured; the impact of pharmacologic A1-AdoR blockade on influenza pathogenesis in C57BL/6 mice will be determined; and the outcome of influenza infection in A1-AdoR-/- knockout mice, or in A1- AdoR-/- bone marrow-chimeric mice will be investigated. Completion of these objectives will lead to increased understanding of the role of adenosine in the pathogenesis of influenza-associated lung injury, and permit determination of its potential as a target for therapeutic intervention to combat influenza-induced lung damage. PUBLIC HEALTH RELEVANCE: Influenza A virus causes a highly contagious acute respiratory disease. Seasonal influenza epidemics cause >300,000 deaths/yr worldwide, while pandemics elicited devastating loss of life in the 20th century, and may do so in the 21st. The proposed studies are aimed at improving our understanding of the mechanisms underlying lung dysfunction in influenza, and identifying a novel potential target for influenza therapy.

描述（由申请人提供）：流感病毒引起高度传染性的急性呼吸道疾病。季节性流感流行病在全球范围内导致300,000人死亡，而大流行病会导致20世纪毁灭性的生命丧失，并可能在21世纪造成。然而，目前，流感或任何其他肺部病毒感染的肺功能障碍和损伤的基本机制的定义很差。 BALB/c小鼠的呼吸道合胞病毒（RSV）和流感病毒感染诱导了核苷酸UTP和ATP的通道介导的释放增加，使支气管肺泡内膜液（BALF）（BALF）释放，在这两种感染中，BALF UTP均有助于升高的BALF UTP。 BALB/C小鼠中的RSV感染仅引起轻度疾病，而流感疾病会引起更严重的疾病，急性肺损伤的许多病理生理特征，这在人类的致死性大流行或流行流行性流行中也可以看到。重要的是，随着流感（而不是RSV）感染，ATP释放到BALF中，伴随着ATP降解产物腺苷增加了A1-抑制腺苷受体（ADOR）的激活。腺苷刺激中性粒细胞A1粘结剂在急性肺损伤的启动和促进中起着重要作用。该提议的中心假设是，流感刺激从头ATP的合成并从感染的ATII细胞中释放，释放的ATP以加速速率代谢为腺苷（由于其对A1-Ador，Ad-Ador，Adensine and lunde in Pla in the Piv的影响，PIV的影响。该假设将在3个特定目的中进行检验：1）确定流感感染对肺核苷酸代谢的时间影响，MLE-12细胞流感感染后核苷酸代谢的变化以及纯化的肺泡II型（ATII）细胞的纯化肺泡型细胞，以及与facs at Atii artim at aTi at a at Atii con-Spored C57Bl/6bl/6bl/6bl/6bl/6bl/6bl/gf。 BALF核苷酸谱的流感感染以及ERK MAP激酶在诱导流感感染后核苷酸合成中的作用。 2）确定CD73在流感发病机理中的作用，将测量流感感染对呼吸性上皮细胞CD73表达和活性的影响；将确定CD73的药理阻滞对C57BL/6小鼠流感发病机理的影响；将研究CD73-敲除小鼠中流感感染的结果。 3）确定腺苷/A1-ador受体信号传导在流感发病机理中的作用，将测量流感诱导的NF-KB激活对ATII细胞和中性粒细胞中A1-辅助表达的影响；将确定药理学A1-ador封锁对C57BL/6小鼠流感发病机理的影响；将研究A1-ADOR - / - 基因敲除小鼠或A1- ADOR - / - 骨髓 - 智中小鼠中流感感染的结果。这些目标的完成将导致人们对腺苷在与流感相关的肺损伤的发病机理中的作用增加了解，并允许确定其潜力作为治疗干预措施以对抗流感诱发的肺损伤的靶标。 公共卫生相关性：流感病毒会引起高度传染性的急性呼吸道疾病。季节性流感流行病在全球范围内导致300,000人死亡，而大流行病会导致20世纪毁灭性的生命丧失，并可能在21世纪造成。拟议的研究旨在提高我们对流感肺功能障碍的机制的理解，并确定流感疗法的新型潜在靶标。