Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

急性炎症的消退机制：消退药理学

• 批准号: 9906229
• 负责人: Charles Nicholas Serhan
• 金额: $ 160.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906229
• 关键词: Acute; Address; Anabolism; Animal Disease Models; Anti-Inflammatory Agents; Back; Biological Models; CD59 Antigen; Cell Communication; Chemicals; Chemotactic Factors; Clinic; Coupled; Critical Pathways; Epithelial Cells; Exudate; Family; Goals; Healthcare; Histology; Homeostasis; Host Defense; Human; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Invaded; Knowledge; Leukocytes; Leukotrienes; Lipoxins; Mediator of activation protein; Mission; Molecular; Natural regeneration; Nosocomial Infections; Operative Surgical Procedures; Organ; Organic Synthesis; Organism; Outcome; Pathway interactions; Patient Care; Peptides; Phagocytes; Pharmacology; Phase; Process; Prostaglandins; Public Health; Recovery; Resolution; Role; Severities; Signal Transduction; Strategic Planning; Structure; Surgical Injuries; Testing; Time; Tissues; Trauma; clinical practice; counterregulation; human disease; human tissue; improved; indexing; instrument; interdisciplinary approach; lipid mediator; metabolome; microbial; multidisciplinary; novel; novel therapeutic intervention; programs; public health relevance; tissue injury; tissue regeneration; tool

 DESCRIPTION (provided by applicant): When uncontrolled, infectious inflammation compromises organ function and is associated with many widely occurring human diseases of major public health concern. Surgery, trauma, and tissue injury can enable invading organisms to cause infections and inflammation that, if unresolved, can be fatal. These barrier breaks and microbial invasion evoke acute inflammation that is ideally protective and self-resolving. Resolution of inflammation was believed to occur via passive dilution of chemical mediators and pro-inflammatory molecules. From this Program Project, evidence emerged indicating resolution is an active molecular process orchestrated by new families of specialized pro-resolving mediators (SPM). These structurally distinct families include resolvins (Rv), protectins (PD), maresins (MaR) and their newly discovered potent SPM-sulfido-conjugates (SC) that resolve inflammation and stimulate tissue regeneration (Conjugates in Tissue Regeneration; CTR). Our overall mission in this renewal is to systematically elucidate the structures and functions of nove mediators in resolution and tissue regeneration. Our strategic plan includes lipid mediator (LM)-SPM-metabolipidomics with resolution and regeneration indices to interrogate inflammatory exudates and tissues coupled with total organic synthesis of SPM and SPM-SC standards to validate structure-function. The overarching novel hypothesis to be addressed by each project of this renewal requires a highly multi-disciplinary team and approach. Together, we shall test the following: Infectious inflammatory exudates evoked by tissue injury, surgical trauma and infection emit potent soluble chemical mediators locally such as SPM and their newly identified sulfido- conjugates that actively orchestrate resolution of inflammation, enhance microbial killing and clearance, as well as tissue regeneration. These new molecular resolution programs are essential for host defense and dictate severity and recovery intervals. This program project team is configured to address these unmet challenges and consists of 3 highly interactive projects, 2 scientific cores and an administrative core with expert advisory panels focused on establishing lipid mediator-resolution functional metabolome, stereo-controlled synthesis of SPM, SPM-SC and their specific mechanisms in resolution of infectious inflammation and clearance pathways. Our broad goal is to harness these molecules and pathways to bring forth resolution pharmacology for new treatments to control infectious inflammation and related tissue damage.

 描述（由申请人提供）：如果不加以控制，感染性炎症会损害器官功能，并与许多广泛发生的重大公共卫生问题的人类疾病相关。手术、创伤和组织损伤可能会使入侵的生物体引起感染和炎症，如果不解决这些感染和炎症。这些屏障破坏和微生物入侵会引起急性炎症，炎症的消退被认为是通过化学介质和促炎症分子的被动稀释来实现的。表明解析是由新的专门促解析介体 (SPM) 家族精心策划的主动分子过程，这些结构不同的家族包括解析素 (Rv)、保护素 (PD)、maresins (MaR) 及其新发现的有效 SPM-硫醚缀合物。 (SC) 能够解决炎症并刺激组织再生（组织再生中的结合物；CTR）。我们的战略计划包括脂质介质（LM）-SPM-代谢脂质组学，具有解析度和再生指数，可检测炎症渗出物和组织，并结合 SPM 和 SPM-SC 标准的总有机合成，以验证结构功能的总体新假设。此次更新的每个项目都需要一个高度多学科的团队和方法来解决，我们将共同测试以下内容：组织损伤、手术创伤和感染引起的感染性炎症渗出物释放出强效的可溶性化学物质。局部介质，如 SPM 及其新发现的硫代结合物，可积极协调炎症的解决，增强微生物杀灭 这些新的分子解决方案对于宿主防御和处方严重性和恢复间隔至关重要，该项目团队旨在解决这些未解决的挑战，由 3 个高度互动的项目、2 个科学核心和一个项目组成。行政核心与专家咨询小组专注于建立脂质介质解析功能代谢组、SPM、SPM-SC 的立体控制合成及其解决感染性炎症和清除途径的具体机制。提出解决药理学控制感染性炎症和相关组织损伤的新疗法。

项目成果

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.

• DOI: 10.1016/j.jvs.2018.05.206
• 发表时间: 2018-12
• 期刊: Journal of vascular surgery
• 影响因子: 4.3
• 作者: Wu B;Werlin EC;Chen M;Mottola G;Chatterjee A;Lance KD;Bernards DA;Sansbury BE;Spite M;Desai TA;Conte MS
• 通讯作者: Conte MS

Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents.

保护素 D1 类似物的合成：新型促解析剂和放射性示踪剂。

• DOI: 10.1039/c8ob01232f
• 发表时间: 2018
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Tungen,JE;Aursnes,M;Ramon,S;Colas,RA;Serhan,CN;Olberg,DE;Nuruddin,S;Willoch,F;Hansen,TV
• 通讯作者: Hansen,TV

Proresolving receptor tames inflammation in atherosclerosis.

促解受体可抑制动脉粥样硬化中的炎症。

• DOI: 10.1172/jci155240
• 发表时间: 2021
• 期刊: The Journal of clinical investigation
• 作者: Mena,HebeAgustina;Spite,Matthew
• 通讯作者: Spite,Matthew

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1n-3 DPA.

解决炎症：RvD1n-3→DPA 的合成、构型分配和生物学评估。

• DOI: 10.1002/chem.201806029
• 发表时间: 2019
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Tungen,JørnEivind;Gerstmann,Lisa;Vik,Anders;DeMatteis,Roberta;Colas,RomainAlexandre;Dalli,Jesmond;Chiang,Nan;Serhan,CharlesNicholas;Kalesse,Markus;Hansen,TrondVidar
• 通讯作者: Hansen,TrondVidar

Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue.

• DOI: 10.4049/jimmunol.1502522
• 发表时间: 2016-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Titos E;Rius B;López-Vicario C;Alcaraz-Quiles J;García-Alonso V;Lopategi A;Dalli J;Lozano JJ;Arroyo V;Delgado S;Serhan CN;Clària J
• 通讯作者: Clària J