Specialized Pro-Resolving Mediators in Asthma

哮喘专业解决调解员

• 批准号: 10625837
• 负责人: Bruce D Levy
• 金额: $ 73.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625837
• 关键词: Acute; Adverse effects; Agonist; Allergic; Anabolism; Anti-Inflammatory Agents; Arachidonic Acids; Asthma; Biological Products; Biopsy; CD59 Antigen; Cell Communication; Cell membrane; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Dependence; Disease; Docosahexaenoic Acids; Dose; Drug Design; Enzymes; Epithelial Cells; Epithelium; Essential Fatty Acids; Experimental Models; Family; Fatty Acids; Funding; Gene Expression; Generations; Head; Health; Homeostasis; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Leukocytes; Lipids; Lipoxins; Lung; Macrophage; Measures; Mediator; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Pharmaceutical Preparations; Play; Process; Production; Publishing; Pulmonary Inflammation; Regulation; Resolution; Respiratory Mucosa; Role; Severities; Signal Transduction; Sorting; Stimulus; Structure of parenchyma of lung; Testing; Therapeutic; Thinking; Tissues; Translations; Validation; Work; airway hyperresponsiveness; airway inflammation; asthma exacerbation; asthma model; asthmatic; asthmatic airway; candidate identification; cell type; cellular transduction; cysteinyl-leukotriene; design; eosinophil; experimental study; granulocyte; high dimensionality; in vivo; insight; lipid mediator; molecular imaging; mouse model; novel; pre-clinical; prevent; programs; receptor; response; spatiotemporal; stem; translation to humans; volunteer

Abstract The proposed experiments will test the hypothesis that specialized pro-resolving mediators (SPMs) and cysteinyl-containing SPMs (CysSPMs) are produced in the lung to counter-regulate pro-phlogistic responses and to promote resolution of lung inflammation, in part via activation of a pro-resolving subset of eosinophils. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness in asthma as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including in eosinophil subsets that are relevant in asthma. With several drugs already developed to block CysLT formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head and identify CysSPMs as natural pro-resolving mediators and novel templates for drug design. To test our hypothesis, we propose three specific aims to:  Determine lung SPM and CysSPM production in acute and chronic allergic lung inflammation,  Establish SPM and CysSPM actions in the resolution of lung inflammatory responses, and  Define roles for lung eosinophil subsets in promoting inflammation resolution. This proposal’s specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.

摘要 拟议的实验将测试的假设，专门的亲解决调解人（SPM）和 含半胱氨酰的SPM（CysSPM）在肺中产生以反调节促炎反应 并且部分地通过激活嗜酸性粒细胞的促消退亚群来促进肺部炎症的消退。 虽然我们习惯于观察气道炎症和高反应性的增加， 哮喘是由于过度的促炎刺激，哮喘的严重程度和持续时间 恶化也可由内源性抗炎效应物不足引起。半胱氨酰白三烯 在哮喘中发挥促炎作用，但并非所有脂质介质都引发炎症。 现在有几个家庭的专门亲解决调解员（SPM）已被确定， 以急性炎症为特征。这些保护介质是酶促衍生自必需脂肪酸， 酸，并作为激动剂在特定的受体，以促进细胞类型的特异性功能反应，包括 与哮喘相关的嗜酸性粒细胞亚群已经开发了几种药物来阻断CysLT 形成或作用的概念，选择内源性脂质衍生的介质产生促进 哮喘气道反应的解析将颠覆传统思维， 作为天然的前拆分介质和药物设计的新模板。 为了验证我们的假设，我们提出了三个具体目标： 确定急性和慢性过敏性肺部炎症中肺SPM和CysSPM的产生， 建立SPM和CysSPM在解决肺部炎症反应中的作用， 明确肺嗜酸性粒细胞亚群在促进炎症消退中的作用。 本提案的具体目标是揭示解决这些问题的基本机制， 健康和疾病中的过敏性气道反应。

项目成果

Lipoxin B₄ promotes the resolution of allergic inflammation in the upper and lower airways of mice.

• DOI: 10.1038/mi.2014.116
• 发表时间: 2015-07
• 期刊: Mucosal immunology
• 影响因子: 8

Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation.

• DOI: 10.4049/jimmunol.1402534
• 发表时间: 2015-02-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Krishnamoorthy N;Burkett PR;Dalli J;Abdulnour RE;Colas R;Ramon S;Phipps RP;Petasis NA;Kuchroo VK;Serhan CN;Levy BD
• 通讯作者: Levy BD

Mast cells contribute to the resolution of allergic inflammation by releasing resolvin D1.

肥大细胞通过释放 resolvin D1 有助于解决过敏性炎症。

• DOI: 10.1016/j.phrs.2023.106691
• 发表时间: 2023
• 期刊: Pharmacological research
• 影响因子: 9.3
• 作者: Puzzovio,PierGiorgio;Pahima,Hadas;George,Tresa;Mankuta,David;Eliashar,Ron;Tiligada,Ekaterini;Levy,BruceD;Levi-Schaffer,Francesca
• 通讯作者: Levi-Schaffer,Francesca

Activation of CD8+ T Cells in Chronic Obstructive Pulmonary Disease Lung.

慢性阻塞性肺疾病肺中 CD8 T 细胞的激活。

• DOI: 10.1164/rccm.202305-0924oc
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Villaseñor-Altamirano,AnaB;Jain,Dhawal;Jeong,Yunju;Menon,JaivardhanA;Kamiya,Mari;Haider,Hibah;Manandhar,Reshmi;Sheikh,MuhammadDawoodAmir;Athar,Humra;Merriam,LouisT;Ryu,MinHyung;Sasaki,Takanori;Castaldi,PeterJ;Rao,DeepakA
• 通讯作者: Rao,DeepakA

FcεR1-expressing nociceptors trigger allergic airway inflammation.

• DOI: 10.1016/j.jaci.2020.12.644
• 发表时间: 2021-06
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Crosson, Theo;Wang, Jo-Chiao;Doyle, Benjamin;Merrison, Hannah;Balood, Mohammad;Parrin, Alexandre;Pascal, Maud;Mindt, Barbara C.;Seehus, Corey R.;Ozcan, Alp;Huang, Xuan;Semenara, Elise;Lai, Nicole Y. Y.;Majdoubi, Abdelilah;Abdulnour, Raja-Elie E.;Rajchgot, Trevor;Rafei, Moutih;Foster, Simmie L.;Thibodeau, Jacques;Fritz, Joerg H.;Levy, Bruce D.;Woolf, Clifford J.;Talbot, Sebastien
• 通讯作者: Talbot, Sebastien