Suñer Ivan J, Espinosa-Heidmann Diego G, Marin-Castano Maria E, Hernandez Eleut P, Pereira-Simon Simone, Cousins Scott W
Department of Ophthalmology, Miami Veterans Affairs Medical Center, Miami, Florida, USA.
Invest Ophthalmol Vis Sci. 2004 Jan;45(1):311-7. doi: 10.1167/iovs.03-0733.
Cigarette smoking is the strongest environmental risk factor for all forms of age-related macular degeneration (AMD). In the present study, the influence of nicotine on the severity of choroidal neovascularization (CNV) in a mouse model of neovascular AMD and its effects on vascular smooth muscle cells derived from mouse choroid were investigated.
A mouse model for CNV was used to study the effects of nicotine in young and middle-aged mice. Nicotine was administered orally in the drinking water to achieve serum levels consistent with those of chronic smokers. Hexamethonium, a nonspecific nicotinic receptor antagonist, was injected subconjunctivally to counteract the effects of nicotine. A mouse choroidal vascular smooth muscle cell line was exposed to nicotine, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), or a combination of one of the factors and nicotine. Cell growth was determined by cell counts, and the activity of matrix metalloproteinase (MMP)-2 and -9 was quantified by gel zymography.
Nicotine administration resulted in increased size and vascularity of CNV, and older mice developed a greater relative increase than younger mice. This effect was blocked by subconjunctival hexamethonium. Choroidal vascular smooth muscle cells demonstrated a statistically significant increase in growth after exposure to a combination of PDGF and nicotine. Nicotine also reversed VEGF-induced suppression of MMP-2 activity.
Nicotine increases size and severity of experimental CNV in the present mouse model, possibly by potentiating PDGF-mediated upregulation of proliferation of choroidal smooth muscle cells or by other mechanisms. These results suggest that non-neuronal nicotinic receptor activation probably mediates some of the harmful effects of cigarette smoking in wet AMD.
吸烟是所有形式的年龄相关性黄斑变性（AMD）最强的环境危险因素。在本研究中，研究了尼古丁对新生血管性AMD小鼠模型中脉络膜新生血管（CNV）严重程度的影响及其对源自小鼠脉络膜的血管平滑肌细胞的作用。
使用CNV小鼠模型研究尼古丁在年轻和中年小鼠中的作用。通过在饮用水中口服给予尼古丁，以达到与慢性吸烟者一致的血清水平。非特异性烟碱受体拮抗剂六甲双铵结膜下注射以抵消尼古丁的作用。将小鼠脉络膜血管平滑肌细胞系暴露于尼古丁、血管内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）或其中一种因子与尼古丁的组合。通过细胞计数确定细胞生长，并通过凝胶酶谱法对基质金属蛋白酶（MMP）-2和-9的活性进行定量。
给予尼古丁导致CNV的大小和血管化增加，老年小鼠的相对增加比年轻小鼠更大。这种作用被结膜下注射六甲双铵阻断。脉络膜血管平滑肌细胞在暴露于PDGF和尼古丁的组合后显示出生长的统计学显著增加。尼古丁还逆转了VEGF诱导的MMP-2活性抑制。
在本小鼠模型中，尼古丁增加了实验性CNV的大小和严重程度，可能是通过增强PDGF介导的脉络膜平滑肌细胞增殖上调或通过其他机制。这些结果表明，非神经元烟碱受体激活可能介导了吸烟在湿性AMD中的一些有害作用。
