Hodges R R, Li D, Shatos M A, Bair J A, Lippestad M, Serhan C N, Dartt D A
Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Mucosal Immunol. 2017 Jan;10(1):46-57. doi: 10.1038/mi.2016.33. Epub 2016 Apr 13.
Conjunctival goblet cells play a major role in maintaining the mucus layer of the tear film under physiological conditions as well as in inflammatory diseases like dry eye and allergic conjunctivitis. Resolution of inflammation is mediated by proresolution agonists such as lipoxin A (LXA) that can also function under physiological conditions. The purpose of this study was to determine the actions of LXA on cultured rat conjunctival goblet cell mucin secretion, intracellular [Ca] ([Ca]), and identify signaling pathways activated by LXA. ALX/FPR2 (formyl peptide receptor2) was localized to goblet cells in rat conjunctiva and in cultured goblet cells. LXA significantly increased mucin secretion, [Ca], and extracellular regulated kinase 1/2 (ERK 1/2) activation. These functions were inhibited by ALX/FPR2 inhibitors. Stable analogs of LXA increased [Ca] to the same extent as LXA. Sequential addition of either LXA or resolvin D1 followed by the second compound decreased [Ca] of the second compound compared with its initial response. LXA activated phospholipases C, D, and A and downstream molecules protein kinase C, ERK 1/2, and Ca/calmodulin-dependent kinase to increase mucin secretion and [Ca]. We conclude that conjunctival goblet cells respond to LXA to maintain the homeostasis of the ocular surface and could be a novel treatment for dry eye diseases.
结膜杯状细胞在生理条件下以及在诸如干眼症和过敏性结膜炎等炎症性疾病中，对维持泪膜的黏液层起着主要作用。炎症的消退是由促消退激动剂介导的，如脂氧素A（LXA），其在生理条件下也能发挥作用。本研究的目的是确定LXA对培养的大鼠结膜杯状细胞黏蛋白分泌、细胞内[Ca]（[Ca]）的作用，并鉴定LXA激活的信号通路。ALX/FPR2（甲酰肽受体2）定位于大鼠结膜和培养的杯状细胞中的杯状细胞。LXA显著增加黏蛋白分泌、[Ca]以及细胞外调节激酶1/2（ERK 1/2）的激活。这些功能被ALX/FPR2抑制剂抑制。LXA的稳定类似物使[Ca]升高的程度与LXA相同。先加入LXA或消退素D1，再加入第二种化合物，与第二种化合物的初始反应相比，其[Ca]降低。LXA激活磷脂酶C、D和A以及下游分子蛋白激酶C、ERK 1/2和钙/钙调蛋白依赖性激酶，以增加黏蛋白分泌和[Ca]。我们得出结论，结膜杯状细胞对LXA有反应，以维持眼表的稳态，并且可能是干眼症的一种新的治疗方法。
