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.

手术切口的治愈受损是急性后慢性伤口护理的第二主要原因 根据Medicare的说法，每年的设置约为70亿美元。最佳愈合需要协调和信号传导 在感觉神经元和免疫系统之间。这些神经免疫相互作用是其中的重点 提议。虽然抑制了促炎性神经肽的肽能感觉传入的作用（即 降钙素基因相关的肽（CGRP）和物质P（sub p）响应损伤，已经很好 研究了非肽性传入的功能，这些传入是神经肽弱的传入，在伤口修复中 尚未得到很好的定义。我的最初研究表明，非肽性传入对 免疫信号传导。我的研究计划的目标之一是进一步定义这些神经元的作用 手术切口和伤口修复期间引起的炎症反应引起了。我的初步研究和 已发表的转录组研究确定了髓样分化1（MD-1，由Gene Ly86编码），A 先天免疫系统的分子，主要在表达非肽神经元中表达 MAS相关的G蛋白D（MRGPRD）受体。我们使用MRGPRDCRE LY86 - / - 敲除的初步数据 （McKO）小鼠，建议由非肽性感觉神经元产生的MD-1充当调节剂 神经免疫通信的抗炎作用。通过MD-1，非肽性传入， 也可能促进正常愈合。我们建议确定MD-1在这些神经元中的作用 皮肤炎症反应，伤口愈合和切开疼痛的分辨率。我们将确定是否 神经元MD-1的丧失在炎症和增生过程中改变免疫细胞的募集和激活 治愈阶段。我们将研究组织结构是治愈的指标和疼痛行为的变化 与炎症状态有关。神经元表达的MD-1调节免疫的发现 对伤害的反应是新颖的，为优化伤口修复提供了潜在的新目标。 区域麻醉用于管理与手术相关的围手术期疼痛，也一直是 证明可以通过降低交感神经及其不良免疫来保护免疫细胞 效果。但是，外周神经阻滞（PNB）在外科手术中的神经免疫通信中的作用 网站尚未划定。我的研究计划的另一个目标是表征PNB的角色 在对手术切口的免疫反应中。这些研究将使用足底切口模型和坐骨神经痛 小鼠中的神经阻滞，以定义PNB对损伤和愈合的免疫反应的影响。我们将 定义局部麻醉和持续时间神经阻滞的类型和浓度如何影响免疫 回复。最后，使用MCKO小鼠，我们将确定PNB对神经元MD-1作用的影响 手术切口炎症和愈合中的信号传导。