Role of corneal neuropeptides in the pathogenesis of herpetic stromal keratitis

角膜神经肽在疱疹性基质性角膜炎发病机制中的作用

• 批准号: 7875060
• 负责人: Susmit Suvas
• 金额: $ 21.8万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875060
• 关键词: Adrenal Cortex Hormones; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Blindness; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Cicatrix; Cornea; Corneal Opacity; Corneal Stroma; Development; Disease; Eye; Goals; Herpesvirus 1; Herpetic Keratitis; Immune; Immunity; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-10; Interleukin-2; Interleukin-6; Keratitis; Left; Lesion; Macrophage Inflammatory Protein-1; Mediating; Mus; Nerve Fibers; Neuropeptides; Ocular Pathology; Pathogenesis; Pharmaceutical Preparations; Pilot Projects; Reaction; Recombinants; Recurrence; Reporting; Role; Severities; Substance P; Testing; Tissues; Topical Corticosteroids; United States; Vascular Endothelial Growth Factors; Vasoactive Intestinal Peptide; Viral; Virus; angiogenesis; cell type; chemokine; cytokine; mouse model; neutrophil; novel strategies; novel therapeutic intervention; public health relevance

DESCRIPTION (provided by applicant): Herpes simplex virus-1 (HSV-1) recurrences can cause many ocular pathologies including, immune cell mediated chronic inflammation in the corneal stroma. If left untreated, the chronic immunoinflammatory reactions in the corneal stroma can give rise to herpetic stromal keratitis (HSK); a disease that results in permanent scarring of the cornea and is a leading cause of infection induced corneal blindness in the United States. The current therapies to manage the HSK lesions have significant downsides. Therefore, investigating novel approaches to control the severity of HSK lesions are urgently needed. In this study, we will explore the role of corneal neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), in the progression and severity of HSK lesions in a mouse model. Our long-term goal is to understand the role of neuropeptides in regulating the immunity to HSV-1 infection. Neuropeptides SP and VIP are reported to have differential roles in promoting or inhibiting the inflammation. Our pilot studies demonstrated higher amounts of SP but lower levels of VIP in the mice corneas with severe HSK lesions in comparison to those with mild HSK lesions. Therefore, we hypothesize that neuropeptides SP and VIP in the inflamed cornea regulate the progression and severity of HSK lesions. The development of HSK lesions is immune-mediated, with the involvement of pro-inflammatory cytokines (IL-1, IL-6, IL-2, IFN-3 and TNF-1), chemokines (MIP-1 and MIP-2), and immune cell types such as neutrophils and CD4 T cells. Therefore, we will test our hypothesis by demonstrating that corneal neuropeptides SP and VIP regulate the amounts of pro- and anti-inflammatory cytokines, and chemokines in HSV-1 infected corneas. We will also demonstrate that SP and VIP regulate the influx, survival and effector function of neutrophils and CD4 T cells in virus infected corneas. We anticipate that our findings will provide a novel approach to elucidate the pathogenesis of HSK and may significantly impact the management of this condition. PUBLIC HEALTH RELEVANCE: Recurrent herpes simplex virus type-1 (HSV-1) infection of the cornea results in the development of herpetic stromal keratitis (HSK), a disease that can cause permanent scarring and loss of vision. The current therapies to control HSK have significant drawbacks. In this study, we will investigate a novel approach to manage HSK in a mouse model by understanding the role of corneal neuropeptides in the progression and severity of HSK.

描述(申请人提供)：单纯疱疹病毒-1(HSV-1)复发可导致许多眼部病理，包括免疫细胞介导的角膜基质慢性炎症。如果不进行治疗，角膜基质中的慢性免疫炎症反应可能会导致疱疹间质角膜炎(HSK)；这是一种导致角膜永久疤痕的疾病，是美国感染导致角膜失明的主要原因。目前治疗HSK皮损的方法有很大的缺点。因此，迫切需要研究新的方法来控制HSK病变的严重程度。在本研究中，我们将探讨P物质(SP)和血管活性肠肽(VIP)这两种角膜神经肽在单纯疱疹病毒性角膜炎(HSK)小鼠病变进展和严重程度中的作用。我们的长期目标是了解神经肽在调节对HSV-1感染的免疫中的作用。据报道，神经肽SP和VIP在促进或抑制炎症方面具有不同的作用。我们的初步研究表明，与轻度HSK损害相比，严重HSK损害的小鼠角膜中SP含量更高，而VIP水平更低。因此，我们推测炎症角膜中的神经肽SP和VIP调节HSK病变的进展和严重程度。HSK病变的发展是免疫介导的，参与了促炎细胞因子(IL-1、IL-6、IL-2、干扰素-3和肿瘤坏死因子-1)、趋化因子(MIP-1和MIP-2)以及中性粒细胞和CD4T细胞等免疫细胞类型。因此，我们将通过证明角膜神经肽SP和VIP调节HSV-1感染的角膜中促炎症和抗炎细胞因子以及趋化因子的数量来检验我们的假设。我们还将展示SP和VIP调节病毒感染的角膜中性粒细胞和CD4T细胞的流入、存活和效应功能。我们预计，我们的发现将为阐明HSK的发病机制提供一种新的方法，并可能对这种疾病的治疗产生重大影响。 公共卫生相关性：反复感染角膜的单纯疱疹病毒1型(HSV-1)会导致疱疹间质角膜炎(HSK)，这是一种可导致永久性疤痕和失明的疾病。目前控制单纯疱疹病毒性角膜炎的治疗方法有明显的缺陷。在这项研究中，我们将通过了解角膜神经肽在HSK的进展和严重程度中的作用，来探索一种新的方法来处理小鼠模型中的HSK。