Tear hyperosmolarity, corneal nerves and dry eye disease

泪液渗透压过高、角膜神经和干眼病

• 批准号: 8700419
• 负责人: Harumitsu Hirata
• 金额: $ 41.53万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700419
• 关键词: Acute; Affect; Aftercare; American; Animals; Area; Behavioral; Blinking; Bradykinin; Calcium; Calcium Oscillations; Characteristics; Chronic; Chronic stress; Cornea; Dinoprostone; Disease; Dose; Dryness; Epithelial; Epithelial Cells; Epithelium; Esthesia; Eye; Eye diseases; Failure; Functional disorder; Human; Hypersensitivity; Inflammation Mediators; Ion Channel; Lead; Measurement; Measures; Membrane; Mental Depression; Molecular; Nerve; Nerve Endings; Neurons; Neurophysiology - biologic function; Nociceptors; Pain; Painless; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Potassium; Process; Rattus; Reporting; Research; Role; Signs and Symptoms; Societies; Sodium Channel; Staging; Stimulus; Sting Injury; Stress; Substance P; Swelling; Testing; Tissues; base; biological adaptation to stress; cell injury; corneal epithelium; cytokine; design; experience; eye dryness; in vivo; insight; irritation; ocular pain; ocular surface; public health relevance; relating to nervous system; repaired; response

DESCRIPTION (provided by applicant): Millions worldwide suffer from the ocular pain and diminished tearing of dry eye disease. Although great advances have been made in many aspects of dry eye research, one area of studies that of corneal nerves has lagged behind. Tear hyperosmolarity is ubiquitously present in dry eye disease and dysfunction of the corneal nerve contributes significantly to the initiation and/or perpetuation of dry eye disease. However, these two subjects have never been studied together. Thus, the proposed research will investigate the effect of tear hyperosmolarity on the corneal nerves responsible for tearing and pain sensation. We recently discovered in rats that special types of corneal nerves displayed many of the response characteristics that are consistent with these nerves serving the functions of tearing and pain sensation. We also discovered that these corneal nerves altered their sensitivities when the eyes were treated with the amounts of hyperosmolar tears found in dry eye patients. Thus, after the corneal nerves were treated with hyperosmolar tears, the nerves began to be excited by a gentle cooling (~1oC) of the cornea, indicating that the normally non-painful stimulus (mild cooling) now activated these neurons presumably giving rise to ocular pain. On the other hand, after the treatment with hyperosmolar tears these neurons began to be less excited by the stimulus thought to be critical for tearing (i.e., drying of the cornea). Therefore, the effects of tear hyperosmolarity on these nerves could explain the exaggerated eye pain and the diminished tearing that DE patients report. We propose to study the following questions in more detail: 1) what is the minimum amount of tear hyperosmolarity necessary to change the neural sensitivity; 2) how long does the tear hyperosmolarity have to remain on the cornea for the nerves to change sensitivity, and does the longer tear hyperosmolarity necessarily lead to more or less activation of these neurons (i.e., more pain and fewer tears?); 3) does the hyperosmolar tear-induced change become permanent, and if so, when? We have also discovered that these neurons show abnormal activity under extended hyperosmolar tear conditions (2 days). What are the mechanisms responsible for these sudden changes in activity? The answers to these questions could identify hyperosmolar tears as being a crucial determinant of the ocular pain and diminished tears found in DE patients. A variety of drugs such as antagonists for inflammatory mediators and membrane ion channels in corneal nerves and epithelia will be tested to block these sensitivity changes and the abnormal activities seen in these nerves. These pharmacological determinations of the changes in corneal nerve functions may lead to better understanding of the pathogenesis of dry eye diseases and offer new avenues of treatment for one of the most common and yet challenging diseases in our society.

描述（由申请人提供）：全世界有数百万人患有干眼症引起的眼痛和流泪减少。尽管干眼研究的许多方面都取得了巨大进展，但角膜神经的研究领域却相对滞后。泪液渗透压过高普遍存在于干眼病中，并且角膜神经功能障碍显着促进干眼病的发生和/或持续。然而，这两个主题从未被一起研究过。因此，拟议的研究将调查泪液高渗透压对负责流泪和痛觉的角膜神经的影响。我们最近在大鼠中发现，特殊类型的角膜神经表现出许多与这些神经服务于撕裂和痛觉功能一致的反应特征。我们还发现，当用干眼患者的高渗性眼泪治疗眼睛时，这些角膜神经的敏感性会发生变化。因此，在用高渗性眼泪治疗角膜神经后，神经开始因角膜的温和冷却（~1oC）而兴奋，表明通常无痛的刺激（温和冷却）现在激活了这些神经元，可能会引起眼部疼痛。另一方面，在用高渗性眼泪治疗后，这些神经元开始对被认为对眼泪至关重要的刺激（即角膜干燥）不再那么兴奋。所以， 泪液渗透压过高对这些神经的影响可以解释 DE 患者报告的过度眼部疼痛和泪液减少。我们建议更详细地研究以下问题：1）改变神经敏感性所需的最小泪液高渗透压量是多少？ 2）泪液高渗透压必须在角膜上保留多长时间才能使神经改变敏感性，较长的泪液高渗透压是否一定会导致这些神经元更多或更少的激活（即更多的疼痛和更少的眼泪？）； 3）高渗性眼泪引起的变化是否会成为永久性的，如果是的话，什么时候？我们还发现这些神经元在长时间的高渗性撕裂条件下（2天）表现出异常活动。导致这些活动突然变化的机制是什么？这些问题的答案可以确定高渗性泪液是 DE 患者眼部疼痛和泪液减少的关键决定因素。将测试多种药物，例如炎症介质拮抗剂以及角膜神经和上皮细胞膜离子通道的拮抗剂，以阻止这些敏感性变化以及角膜中出现的异常活动。 这些神经。这些对角膜神经功能变化的药理学测定可能有助于更好地了解干眼病的发病机制，并为我们社会中最常见但最具挑战性的疾病之一提供新的治疗途径。