Mechanisms underlying mustard gas-induced conjunctival injury and use of lipid mediators as medical countermeasures

芥子气引起的结膜损伤的机制以及脂质介质作为医疗对策的使用

基本信息

批准号：
10882060
负责人：
Darlene A Dartt
金额：
$ 58.33万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10882060
关键词：
Acceleration Address Architecture Biological Assay CASP1 gene Cell Culture Techniques Cell Density Cell physiology Cell surface Chronic Clinical Management Clinical assessments Coculture Techniques Conjunctival Epithelium Conjunctivitis Cornea Dendritic Cells Enzyme-Linked Immunosorbent Assay Epithelial Cells Exposure to Eye Eye Injuries Flow Cytometry Fluorescein Goblet Cells Histologic Histopathology Homeostasis Human Immune In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Injections Injury Innate Immune Response Interleukin-1 beta Interleukin-6 Lipids Lymphocytic Infiltrate MUC5AC gene Maintenance Measurement Measures Mechlorethamine Mediating Mediator Medical Methods Molecular Mucins Mucous Membrane Mus Mustard Gas Neuropeptides Nociceptors Pathology Photophobia Property Proteins Regulation Regulatory T-Lymphocyte Reporting Resolution Reverse Transcriptase Polymerase Chain Reaction Secretory Cell Security Series Shapes Signal Transduction Signs and Symptoms Site Small Interfering RNA Source Stains Stimulus Structure of trigeminal ganglion Symptoms Therapeutic Thrombospondin 1 Tissues Topical application Toxic Actions Toxic effect Transcript Transforming Growth Factor beta Treatment Efficacy Vesicants Western Blotting acute symptom adaptive immune response cell injury conjunctiva eye dryness immunoregulation in vivo inhibitor insight lipid mediator lipoxin A4 medical countermeasure mouse model nerve supply novel novel strategies ocular pain ocular surface pharmacologic prevent response restoration retinal toxicity slit lamp imaging therapeutic target vascular abnormality

项目摘要

PROJECT SUMMARY Mustard gas (MG, most commonly sulfur and nitrogen mustard) is a highly toxic vesicant that causes ocular injuries in over 90% of exposed victims with symptoms lasting from minutes to years. These symptoms include conjunctivitis in addition to eye pain, photophobia and corneal epitheliopathy. Moderate to severe exposure to MG results in chronic or latent (delayed-onset) forms of symptoms that include changes in the conjunctiva such as vascular abnormalities and histopathology including reduced goblet cell (GC) density and lymphocytic infiltration. However, mechanisms of toxicity and therapeutic targets in the conjunctiva remain largely unknown. We reported that in addition to protective soluble mucin, MUC5AC,GCs are a source of pro-inflammatory IL-1β as well as immunomodulatory TGFβ and therefore play a role in shaping both local innate and adaptive immune responses. The contribution of GC secretory products to ocular mucosal homeostasis is further underscored by the observed chronic inflammation and related epitheliopathy associated with loss of GCs or GC-derived regulatory factors. Specialized pro-resolving mediators (SPM) like D-series resolvins RvD1 are endogenous lipid derivatives produced during inflammation are known to accelerate its resolution and restoration of tissue architecture. We reported that RvD1 can inhibit secretion of GC-derived IL-1β. In this proposal we will identify mechanisms underlying MG toxicity in the conjunctiva and its contribution to chronic pathology. We will determine if SPMs restore homeostasis in the conjunctiva to prevent chronic damage caused by MG and serve as effective medical counter measure (MCM) for ocular toxicity of MG. We hypothesize that SPMs promote resolution of MG-induced ocular damage by modulating secretory and homeostatic function of conjunctival GCs. To address this hypothesis, the following three specific aims are proposed. Aim 1: Identify nitrogen mustard (NM)-induced alteration in conjunctival epithelial GC function and the potential of SPMs to resolve NM toxicity and restore GC function in vitro; Aim 2: Determine if NM exposure disrupts immune homeostatic function of GCs in vitro and if SPMs can restore it; and Aim3: Determine therapeutic efficacy of RvD1 as a MCM, in vivo, using a mouse model of NM toxicity. Conjunctival and corneal damage as well as ocular surface innervation will be evaluated. Our anticipated results from these studies can reveal the potential of conjunctival GCs as a MG injury site and therefore a therapeutic target and provide critical insights into developing novel strategies to promote mucosal and immune homeostasis in clinical management of MG-induced ocular toxicity.

项目概要芥子气（MG，最常见的是硫芥子气和氮芥子气）是一种剧毒发泡剂，会导致眼部不适超过 90% 的暴露受害者受伤后症状持续数分钟至数年。结膜炎，此外还有眼痛、畏光和角膜上皮病变。中度至重度接触。 MG 会导致慢性或潜在（延迟发作）形式的症状，包括结膜的变化，例如血管异常和组织病理学，包括杯状细胞 (GC) 密度和淋巴细胞减少然而，结膜的毒性机制和治疗靶点仍然很大程度上未知。我们报道，除了保护性可溶性粘蛋白外，MUC5AC、GC 也是促炎性 IL-1β 的来源以及免疫调节性 TGFβ，因此在塑造局部先天性和适应性方面发挥作用 GC 分泌产物对眼粘膜稳态的贡献更大。观察到的慢性炎症和与 GC 丢失相关的相关上皮病强调了这一点 GC 衍生的调节因子（SPM）如 D 系列分解蛋白 RvD1 是众所周知，炎症过程中产生的内源性脂质衍生物可以加速其消退，我们报道了 RvD1 可以抑制 GC 衍生的 IL-1β 的分泌。我们将确定 MG 结膜毒性的潜在机制及其对慢性病的影响我们将确定 SPM 是否可以恢复结膜的稳态以防止慢性损伤。 MG 引起的，可作为 MG 眼毒性的有效医疗对策（MCM）。 SPM 通过调节分泌和分泌来促进 MG 引起的眼部损伤的解决结膜 GC 的稳态功能为了解决这一假设，有以下三个具体目标：目标 1：识别氮芥 (NM) 诱导的结膜上皮 GC 功能的改变和 SPM 在体外解决 NM 毒性和恢复 GC 功能的潜力；目标 2：确定 NM 是否暴露；体外破坏 GC 的免疫稳态功能，SPM 是否可以恢复它，目标 3：确定；使用 NM 毒性小鼠模型，观察 RvD1 作为 MCM 的体内治疗效果。我们可以评估这些研究的预期结果。揭示了结膜 GC 作为 MG 损伤部位的潜力，因此可以作为治疗靶点，并提供重要的见解发展成为临床中促进粘膜和免疫稳态的新策略 MG 引起的眼毒性的管理。