Irmina Jastrzębska-Miazga, Bartosz Machna, Dorota Wyględowska-Promieńska, Adrian Smędowski
Department of Ophthalmology, Kornel Gibinski University Clinical Center, Medical University of Silesia, 40-514 Katowice, Poland.
Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland.
Biomolecules. 2025 May 16;15(5):729. doi: 10.3390/biom15050729.
The cornea, a highly innervated and avascular ocular tissue, relies on intricate neuro-immune interactions to maintain homeostasis. Among key neuromediators, substance P (SP)-a neuropeptide belonging to the tachykinin family-plays a dual role in corneal physiology and pathology. This review synthesizes current knowledge on SP's involvement in corneal innervation, epithelial homeostasis, immune regulation, neovascularization, and wound healing, while highlighting its dichotomous effects in both promoting tissue repair and exacerbating inflammation. SP, primarily signaling through the neurokinin-1 receptor (NK1R), influences corneal epithelial proliferation, barrier function, and wound healing by modulating cytokines, chemokines, and growth factors. However, its overexpression is linked to pain sensitization, inflammatory keratitis, and corneal neovascularization, driven by interactions with immune cells (e.g., mast cells, neutrophils) and pro-angiogenic factors (e.g., VEGF). Clinical studies demonstrate altered SP levels in dry eye disease, neurotrophic keratitis, and post-refractive surgery, correlating with nerve damage and ocular surface dysfunction. Emerging therapies targeting SP pathways- such as NK1R antagonists (e.g., fosaprepitant) and SP-IGF-1 combinations-show promise for treating neurotrophic ulcers but face challenges due to SP's context-dependent actions. Future research should clarify the roles of NK2R/NK3R receptors and optimize SP-based interventions to balance its reparative and inflammatory effects. Understanding SP's multifaceted mechanisms could advance the development of therapies for corneal diseases, particularly those involving sensory neuropathy and immune dysregulation.
角膜是一种神经高度密集且无血管的眼组织，依靠复杂的神经免疫相互作用来维持体内平衡。在关键的神经介质中，P物质（SP）——一种属于速激肽家族的神经肽——在角膜生理和病理过程中发挥双重作用。本综述综合了当前关于SP参与角膜神经支配、上皮稳态、免疫调节、新生血管形成和伤口愈合的知识，同时强调了其在促进组织修复和加剧炎症方面的二分效应。SP主要通过神经激肽-1受体（NK1R）发出信号，通过调节细胞因子、趋化因子和生长因子来影响角膜上皮增殖、屏障功能和伤口愈合。然而，其过度表达与疼痛敏化、炎性角膜炎和角膜新生血管形成有关，这是由与免疫细胞（如肥大细胞、中性粒细胞）和促血管生成因子（如血管内皮生长因子）的相互作用驱动的。临床研究表明，在干眼病、神经营养性角膜炎和屈光手术后，SP水平会发生改变，这与神经损伤和眼表功能障碍相关。针对SP途径的新兴疗法——如NK1R拮抗剂（如磷丙泊酚）和SP-胰岛素样生长因子-1组合——在治疗神经营养性溃疡方面显示出前景，但由于SP的作用依赖于具体情况而面临挑战。未来的研究应阐明NK2R/NK3R受体的作用，并优化基于SP的干预措施，以平衡其修复和炎症作用。了解SP的多方面机制可能会推动角膜疾病治疗方法的发展，特别是那些涉及感觉神经病变和免疫失调的疾病。
