Cornea and Ocular Surface Disease Unit, Eye Repair Lab, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Invest Ophthalmol Vis Sci. 2018 Nov 1;59(13):5329-5335. doi: 10.1167/iovs.18-24707.
Aging impairs corneal nerve density and sensitivity. Substance P (SP), a neuropeptide secreted by sensory nerves, regulates nerve morphology and nociception. Here, we investigate the relationship between aging, nerve morphology, and SP expression in mouse and human corneas.
SP levels in mouse corneas (wild type and substance P-knockout) and human corneas and tears were quantified with an ELISA assay. Corneal total nerve length (TNL) was measured with whole-mount β3-tubulin immunofluorescence in mouse and in vivo laser corneal confocal microscopy in humans. SP and β3-tubulin stained cross-sections were used to assess the colocalization of SP and nerves in human and mouse corneas. Ocular surface nociception was assessed with a wiping test in mice.
SP colocalizes with sub-basal neurons in mice and humans. In WT mice, SP levels decrease with age (P = 0.0045, 8 vs. 52 weeks; P = 0.004, 26 vs. 52 weeks) as well as TNL (P = 0.018, 8 vs. 26 weeks; P = 0.0001, 8 vs. 52 weeks). Knockout mice show a greater TNL reduction (8 vs. 26 weeks, P = 0.0016) than WT mice. In the oldest WT and age-matched KO mice, nociception is impaired (P = 0.007 and P < 0.0001, respectively), and KO mice sensitivity is restored by topical SP treatment. In humans, SP levels are reduced in old subject corneas and correlate, in tears, with age (P = 0.0368); TNL also decreases in older patients (P = 0.0002).
Age-associated corneal nerve loss is paralleled by reduction of SP expression in mice and humans. SP promotes the maintenance of normal nerve morphology in the long term and modulates nociception in the cornea.
衰老会损害角膜神经密度和敏感性。P 物质（SP）是一种由感觉神经分泌的神经肽，可调节神经形态和痛觉。本研究旨在探讨衰老、神经形态和 SP 表达在小鼠和人角膜中的关系。
采用 ELISA 法检测小鼠（野生型和 P 物质敲除型）和人角膜及泪液中的 SP 水平。采用全角膜 β3-微管蛋白免疫荧光法检测小鼠角膜总神经长度（TNL），采用活体激光角膜共聚焦显微镜法检测人角膜。用 SP 和 β3-微管蛋白染色的角膜横截面评估 SP 和神经在人及小鼠角膜中的共定位。采用擦眼试验评估小鼠眼表痛觉。
SP 与小鼠和人角膜下神经元共定位。在 WT 小鼠中，SP 水平随年龄下降（8 周 vs. 52 周，P = 0.0045；26 周 vs. 52 周，P = 0.004），TNL 也下降（8 周 vs. 26 周，P = 0.018；8 周 vs. 52 周，P = 0.0001）。与 WT 小鼠相比，KO 小鼠的 TNL 下降更明显（8 周 vs. 26 周，P = 0.0016）。在最老的 WT 和年龄匹配的 KO 小鼠中，痛觉受损（P = 0.007 和 P < 0.0001），而 KO 小鼠的敏感性可通过局部 SP 治疗恢复。在人类中，老年患者的角膜中 SP 水平降低，且在泪液中与年龄相关（P = 0.0368）；TNL 也随年龄增加而降低（P = 0.0002）。
与年龄相关的角膜神经丢失与小鼠和人类 SP 表达减少相平行。SP 可促进长期正常神经形态的维持，并调节角膜的痛觉。
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