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.