Neuroimmune signaling in surgical wound healing and modulation by regional anesthesia

手术伤口愈合中的神经免疫信号传导和区域麻醉的调节

• 批准号: 10711153
• 负责人: Marsha Elizabeth Ritter Jones
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711153
• 关键词: Acute; Affect; Afferent Neurons; Antiinflammatory Effect; Architecture; Calcitonin Gene-Related Peptide; Cells; Communication; Conduction Anesthesia; Cutaneous; Data; GTP-Binding Proteins; Genes; Goals; Immune; Immune response; Immune signaling; Immune system; Impaired healing; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Invaded; Knockout Mice; Local Anesthetics; Medicare; Modeling; Mus; Myelogenous; Nerve Block; Neuroimmune; Neurons; Neuropeptides; Operative Surgical Procedures; Pain; Patient Care; Perioperative; Perioperative Care; Peripheral Nerves; Phase; Publishing; Research; Role; Sensory; Signal Transduction; Site; Skin; Substance P; Surgical incisions; Surgical wound; Tissues; Work; chronic wound; healing; improved; neural; neuron loss; novel; pain behavior; pathogen; peptide P; programs; receptor; recruit; response to injury; sciatic nerve; tool; transcriptomics; wound care; wound healing

Impaired healing of surgical incisions is the second leading cause of chronic wound care in the post-acute setting, about $7 billion annually, according to Medicare. Optimal healing requires coordination and signaling between sensory neurons and the immune system. These neural immune interactions are the focus of this proposal. While the role of peptidergic sensory afferents, which release proinflammatory neuropeptides (i.e., calcitonin gene related peptide (CGRP) and Substance P (Sub P)) in response to injury, have been well studied, the function of nonpeptidergic afferents, those afferents that are neuropeptide-poor, in wound repair have not been well defined. My initial studies suggest nonpeptidergic afferents have a suppressive action on immune signaling. One goal of my research program is to further define the role of these neurons specifically in the inflammatory response evoked by surgical incision and during wound repair. My preliminary studies and published transcriptomic studies have identified myeloid differentiation 1 (MD-1, encoded by gene Ly86), a molecule of the innate immune system, to be expressed predominantly in nonpeptidergic neurons expressing the Mas-related G protein D (MrgprD) receptor. Our preliminary data using MrgprDcre Ly86-/- knockout (MCKO) mice, suggest that MD-1, produced by nonpeptidergic sensory neurons, functions as a regulator of neural-immune communication and has anti-inflammatory effects. Nonpeptidergic afferents, via MD-1, may also promote normal healing. We propose to determine the role of MD-1 in these neurons with regard to the cutaneous inflammatory response, wound healing and resolution of incisional pain. We will determine if loss of neuronal MD-1 alters immune cell recruitment and activation during inflammatory and proliferative healing phases. We will examine tissue architecture as a metric of healing and changes in pain behaviors in relation to the inflammatory state. The finding that MD-1 expressed by neurons regulates the immune response to injury is novel and offers a potential new target for optimizing wound repair. Regional anesthesia is used to manage perioperative pain associated with surgery and has also been demonstrated to be protective of immune cells by decreasing sympathetic tone and its adverse immune effects. However, the role of peripheral nerve blocks (PNBs) in neural immune communication at the surgical site have not been delineated. Another goal of my research program is to characterize the role of PNBs in the immune response to surgical incision. These studies will use the plantar incision model and sciatic nerve blocks in mice to define the effects of PNBs on the immune response to injury and on healing. We will define how type and concentration of local anesthetic and duration of nerve block affects the immune response. Finally, using the MCKO mice, we will determine the effect of PNBs on the role of neuronal MD-1 signaling in surgical incision inflammation and healing.

手术切口愈合不良是急性创伤后慢性伤口护理的第二大原因。 根据医疗保险的数据，每年约有70亿美元。最佳愈合需要协调和信号 感觉神经元和免疫系统之间的联系这些神经免疫相互作用是这方面的重点 提议而肽能感觉传入神经的作用，释放促炎神经肽（即， 降钙素基因相关肽（CGRP）和P物质（Sub P））在损伤反应中的作用， 研究表明，非肽能传入神经，即缺乏神经肽的传入神经，在创伤修复中的作用 还没有很好的定义。我的初步研究表明，非肽能传入神经对 免疫信号我的研究计划的一个目标是进一步确定这些神经元的作用，特别是在 由手术切口和伤口修复引起的炎症反应。我的初步研究和 已发表的转录组学研究已经鉴定出髓样分化1（MD-1，由基因Ly 86编码）， 先天免疫系统的分子，主要在表达非肽能神经元中表达， Mas-related G protein D（MrgprD）receptor。我们使用MrgprDcre Ly 86-/-敲除的初步数据 （MCKO）小鼠的研究表明，MD-1由非肽能感觉神经元产生， 神经免疫通讯的重要组成部分，并具有抗炎作用。非肽能传入，通过MD-1， 也可以促进正常愈合。我们建议确定MD-1在这些神经元中的作用， 皮肤炎症反应、伤口愈合和切口疼痛的缓解。我们将确定是否 神经元MD-1的缺失改变了炎症和增殖过程中免疫细胞的募集和活化 愈合阶段我们将研究组织结构作为愈合和疼痛行为变化的指标， 与炎症状态有关。神经元表达的MD-1调节免疫的发现， 对损伤的反应是新颖的，并为优化伤口修复提供了潜在的新靶点。 区域麻醉用于管理与手术相关的围手术期疼痛， 证明通过降低交感神经紧张和其不利的免疫细胞保护免疫细胞 方面的影响.然而，周围神经阻滞（PNB）在手术中神经免疫通讯中的作用 地点尚未划定。我的研究计划的另一个目标是描述PNB的作用 对手术切口的免疫反应。这些研究将使用足底切口模型和坐骨神经 神经阻滞，以确定PNB对损伤的免疫应答和愈合的影响。我们将 确定局麻药的类型和浓度以及神经阻滞的持续时间如何影响免疫 反应最后，使用MCKO小鼠，我们将确定PNB对神经元MD-1的作用的影响。 手术切口炎症和愈合中的信号传导。