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Mechanisms of Inflammation Resolution in Bacterial Endophthalmitis

细菌性眼内炎的炎症消退机制

基本信息

批准号：
10231125
负责人：
Ashok Kumar
金额：
$ 37.35万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231125
关键词：
Adrenal Cortex Hormones Anti-Inflammatory Agents Antibiotics Arachidonate 15-Lipoxygenase Arachidonate 5-Lipoxygenase Attenuated Blindness Bone Marrow CD59 Antigen Cataract Extraction Cells Co-Immunoprecipitations Communicable Diseases Complication Data Development Disease Docosahexaenoic Acids Dopamine D1 Receptor Endophthalmitis Enzymes Eye Eye Infections Eye Injuries FPR2 gene Gene Silencing Generations Genus staphylococcus Goals Homeostasis Human Immune Immune response Immunomodulators Incidence Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune Response Invaded Knockout Mice Ligands Mediating Mediator of activation protein Mus Myeloid Cells Nature Older Population Omega-3 Fatty Acids Operative Surgical Procedures Pathway interactions Penetrating Eye Injuries Pharmaceutical Preparations Pharmacology Procedures Production Property Receptor Signaling Resolution Retina Role Route Severities Signal Pathway Signal Transduction Staphylococcus aureus Staphylococcus aureus infection Structure TLR2 gene Testing Therapeutic Tissues Toll-like receptors Transgenic Mice Treatment Efficacy Virulence Factors Vision Visual aging population bacterial endophthalmitis base design disability efficacy testing experimental study immunomodulatory therapies improved outcome inhibitor/antagonist insight intravitreal injection lipid mediator lipidomics lipoxin A4 microbial mouse model novel overexpression pathogen pre-clinical preservation prevent programmed cell death protein 1 protective effect receptor response restoration retinal damage tissue injury trauma surgery treatment strategy

项目摘要

Project Summary Inflammation is generally considered a beneficial host response towards invading pathogens or tissue injury. Prolonged inflammation, however, can be destructive and maladaptive, leading to irreversible damage to delicate tissues. Thus, the ideal treatment approach when dealing with inflammation-sensitive tissues, such as the retina, should include immunomodulatory therapies to promote the rapid resolution of inflammation and the restoration of tissue homeostasis to minimize secondary host-mediated damage. Recently, pro-resolution- based strategies using specialized pro-resolving mediators (SPMs) have shown great potential for the treatment of multiple inflammatory diseases. We show that the intravitreal administration of resolvin D1 (RvD1), a type of SPM, in bacterial (S. aureus)-infected mouse eyes attenuated the development of endophthalmitis, with drastically reduced inflammation and tissue damage and preserved retinal function, underline the importance of RvD1-mediated pro-resolving signaling in endophthalmitis. However, unexpectedly, we discovered that RvD1 treatment failed to protect the eyes of Toll-like receptor 2 (TLR2) knockout mice from staphylococcal endophthalmitis. Moreover, we observed a direct interaction of TLR2 with the RvD1 receptor, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2, referred as FPR2). This raises an interesting fundamental question, whether the molecule or signaling pathways that induce the resolution of inflammation interact with other pathways such as the TLRs, which promote the induction of inflammation. Thus, based on prior studies and our preliminary data, we hypothesize that RvD1-mediated protective innate responses in bacterial endophthalmitis are dependent on TLR2 signaling. This will be tested with three specific aims. Aim-1 will decipher the mechanisms underlying RvD1-induced protective innate responses in bacterial endophthalmitis. This will be accomplished by using pharmacological inhibitors of RvD1-mediated FPR2 signaling, as well as the use of FPR2 overexpressing transgenic (Tg) mice and FPR2 KO mice. Bone marrow chimeric studies will be performed to determine the relative contribution of FPR2 on residential vs. myeloid cells. Aim-2 will investigate the interplay of the RvD1 and TLR2 signaling pathways in promoting inflammation resolution in endophthalmitis. These studies will elucidate this novel cross-talk by determining 1) whether TLR2 deficiency alters the generation of RvD1, 2) under which conditions TLR2 and FPR2 interact physically, and 3) the consequences of this interaction on downstream signaling. Aim-3 is designed to test the efficacy of RvD1 as an adjunct therapeutic in mitigating endophthalmitis-associated vision loss. Proposed experiments include the co- administration of RvD1 with conventional antibiotics and the determination of the optimal route of delivery (topical vs. intravitreal) and a comparison of its efficacy with that of corticosteroids. Together, we believe that the mechanistic insights and the treatment strategies developed in this proposal could have a major impact on the field, not only with regards to endophthalmitis but other ocular and non-ocular infectious diseases as well.

项目总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systemic diseases and the cornea.

DOI：
10.1016/j.exer.2021.108455
发表时间：
2021-03
期刊：
Experimental eye research
影响因子：
3.4
作者：
Shah R;Amador C;Tormanen K;Ghiam S;Saghizadeh M;Arumugaswami V;Kumar A;Kramerov AA;Ljubimov AV
通讯作者：
Ljubimov AV

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier.