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.

外科手术伤口愈合不良是急性后遗症慢性伤口护理的第二大原因。 根据联邦医疗保险的数据，每年约为70亿美元。最佳的治疗需要协调和信号传递 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个问题的焦点。 求婚。而释放促炎神经肽的肽能感觉传入物质(即， 降钙素基因相关肽(CGRP)和P物质(SubP)在损伤反应中一直表现良好 研究了非肽能传入物质在伤口修复中的作用。 还没有得到很好的定义。我的初步研究表明，非肽能传入物质对 免疫信号。我的研究计划的一个目标是进一步定义这些神经元的作用，特别是在 手术切开和伤口修复过程中引起的炎症反应。我的初步研究和 已发表的转录学研究发现髓系分化1(MD-1，由LY86基因编码)，a 先天免疫系统的分子，主要在非肽能神经元表达，表达 Mas相关的G蛋白D(MRGprD)受体。我们的初步数据使用的是Mr gprDcre LY86-/-基因敲除 (MCKO)小鼠的研究表明，由非肽能感觉神经元产生的MD-1起着调节作用 具有神经免疫通讯功能，具有抗炎作用。非肽能传入，通过MD-1， 也可以促进正常的愈合。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 神经元型MD-1的缺失改变炎症和增殖性免疫细胞的募集和激活 治疗阶段。我们将研究组织结构作为愈合和疼痛行为变化的指标 与炎症状态的关系。神经细胞表达的MD-1调节免疫的研究 对损伤的反应是新颖的，为优化伤口修复提供了一个潜在的新靶点。 区域麻醉被用来控制与手术相关的围手术期疼痛，也已被 证明通过降低交感神经张力和其不利免疫来保护免疫细胞 效果。然而，周围神经阻滞(PNBs)在手术中的神经免疫交流中的作用 地点尚未划定。我的研究计划的另一个目标是描述PNBs的作用 对手术切开的免疫反应。这些研究将使用足底切开模型和坐骨神经 在小鼠中进行神经阻断，以确定PNBs对损伤和愈合的免疫反应的影响。我们会 确定局部麻醉剂的类型和浓度以及神经阻滞时间如何影响免疫功能 回应。最后，利用MCKO小鼠，我们将确定PNBs对神经元MD-1作用的影响 外科手术伤口炎症和愈合的信号传导。