Campbell S J, Carare-Nnadi R O, Losey P H, Anthony D C
Experimental Neuropathology, Department of Pharmacology, University of Oxford, Mansfield Road, Oxfordshire, UK.
Neuropathol Appl Neurobiol. 2007 Feb;33(1):108-20. doi: 10.1111/j.1365-2990.2006.00773.x.
Epidemiological evidence indicates that the severity of many human neuropathologies is often age-related, and this also appears true in rodent models of human disease. In this study, we examined the inflammatory response within the brain to the archetypal pro-inflammatory cytokines interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF-alpha). We assessed how the cerebral vasculature changes with age and whether any structural alterations are associated with altered cytokine sensitivities. Six hours after equivalent microinjections of IL-1beta or TNF-alpha, 3-week-old juvenile and 18-month-old aged rats displayed increased leucocyte recruitment, blood-brain barrier (BBB) breakdown, and a loss of specificity in the populations of leucocytes recruited when compared with the restricted profile observed in 2-month-old young adult rat brain. The expression of the tight junction protein claudin-1 was absent in those vessels where neutrophils were being actively recruited. To determine whether changes in the structure of the BBB might be responsible for the increased susceptibility observed at either end of the age spectrum, we compared the number of claudin-1 positive vessels in the unchallenged brain to the total number of vessels. Virtually all vessels in the young adult brain express claudin-1, but a significant proportion of vessels are claudin-1 negative in the juvenile rat brain. In the aged rat brain, the overall number of vessels is markedly reduced, but the majority of these still appear to be claudin-1 positive. The pattern of claudin-1 expression together with the change in vessel density indicates that the properties of the BBB change with age, and, despite similarities, the underlying cause of the heightened inflammatory response in the juvenile and in the aged brain is likely to differ. Indeed, the spatial characteristics of the cytokine-induced BBB breakdown are different at either end of the age spectrum. These studies identify two periods within the lifespan of a rat where susceptibility to pro-inflammatory mediators is dramatically increased.
流行病学证据表明，许多人类神经病理学的严重程度通常与年龄相关，在人类疾病的啮齿动物模型中似乎也是如此。在本研究中，我们检测了大脑对典型促炎细胞因子白细胞介素-1β（IL-1β）或肿瘤坏死因子-α（TNF-α）的炎症反应。我们评估了脑脉管系统如何随年龄变化，以及是否有任何结构改变与细胞因子敏感性改变相关。在等量微量注射IL-1β或TNF-α 6小时后，与2个月大的年轻成年大鼠脑中观察到的受限分布相比，3周大的幼年大鼠和18个月大的老年大鼠表现出白细胞募集增加、血脑屏障（BBB）破坏以及募集的白细胞群体特异性丧失。在中性粒细胞被积极募集的血管中，紧密连接蛋白claudin-1的表达缺失。为了确定BBB结构的变化是否可能是在年龄谱两端观察到的易感性增加的原因，我们将未受刺激的大脑中claudin-1阳性血管的数量与血管总数进行了比较。年轻成年大鼠脑中几乎所有血管都表达claudin-1，但幼年大鼠脑中相当一部分血管是claudin-1阴性。在老年大鼠脑中，血管总数明显减少，但其中大多数似乎仍是claudin-1阳性。claudin-1的表达模式以及血管密度的变化表明BBB的特性随年龄而变化，并且，尽管有相似之处，但幼年和老年大脑中炎症反应增强的潜在原因可能不同。事实上，细胞因子诱导的BBB破坏的空间特征在年龄谱两端是不同的。这些研究确定了大鼠寿命中的两个时期，在这两个时期对促炎介质的易感性显著增加。
