Cigarette smoking, a powerful mixture of chemical oxidants, is the strongest environmental risk factor for developing age-related macular degeneration (AMD), the most common cause of blindness among the elderly in western societies. Despite intensive study, the full impact of smoking on the retinal pigment epithelium (RPE), a central cell type involved in AMD pathobiology, remains unknown. The relative contribution of the known dysfunctional pathways to AMD, at what stage they are most pathogenic, or whether other processes are relevant, is poorly understood, and furthermore, whether smoking activates them, is unknown. We performed global RNA-sequencing of the RPE from C57BL/6J mice exposed to chronic cigarette smoke for 6 months to identify potential pathogenic and cytoprotective pathways. The RPE transcriptome induced by chronic cigarette smoking exhibited a mixed response of marked suppression of the innate immune response including type I and II interferons and upregulation of cell differentiation and morphogenic gene clusters, suggesting an attempt by the RPE to maintain its differentiated state despite smoke-induced injury. Given that mice exposed to chronic smoke develop early features of AMD, these novel findings are potentially relevant to the transition from aging to AMD.

吸烟是一种强大的化学氧化剂混合物，是发展与年龄相关的黄斑变性 (AMD) 的最强环境风险因素，这是西方社会老年人失明的最常见原因。尽管进行了深入研究，但吸烟对视网膜色素上皮 (RPE)（一种参与 AMD 病理学的中央细胞类型）的全面影响仍然未知。已知的功能障碍途径对 AMD 的相对贡献、它们在哪个阶段最具致病性，或者其他过程是否相关，我们知之甚少，此外，吸烟是否激活它们也是未知的。我们对暴露于慢性香烟烟雾 6 个月的 C57BL/6J 小鼠的 RPE 进行了全局 RNA 测序，以确定潜在的致病和细胞保护途径。慢性吸烟诱导的 RPE 转录组表现出明显抑制先天免疫反应的混合反应，包括 I 型和 II 型干扰素以及细胞分化和形态发生基因簇的上调，表明 RPE 试图在吸烟的情况下维持其分化状态诱发伤害。鉴于暴露于慢性烟雾的小鼠会出现 AMD 的早期特征，这些新发现可能与从衰老到 AMD 的转变有关。