Department of Psychology, University of British Columbia.
Psychol Bull. 2011 Nov;137(6):959-97. doi: 10.1037/a0024768.
Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.
在早期经历重大心理压力源的人群中,慢性病的发病率和死亡率较高。最有说服力的数据来自于在贫困或遭受父母虐待的环境中长大的儿童研究,这些儿童表现出对血管疾病、自身免疫性疾病和过早死亡的高度易感性。这些发现提出了具有挑战性的理论问题。童年压力如何在分子水平上“潜入”皮肤,从而影响以后疾病的风险?它又是如何在那里潜伏,导致几十年后出现疾病的?在这里,我们提出了一个生物嵌入模型,该模型试图通过综合几个行为和生物医学文献的知识来解决这些问题。该模型认为,童年压力通过表观遗传标记、翻译后修饰和组织重塑被“编程”到巨噬细胞中。因此,这些细胞具有促炎倾向,表现为对挑战的细胞因子反应过度和对抑制性激素信号的敏感性降低。该模型接着提出,在整个生命周期中,这些促炎倾向会因行为倾向和激素失调而加剧,而行为倾向和激素失调本身就是早期应激暴露的产物。在行为方面,该模型假设童年压力会导致过度的威胁警觉、对他人的不信任、不良的人际关系、自我调节受损和不健康的生活方式选择。在激素方面,早期压力会导致内分泌和自主神经放电模式的改变。这种环境放大了巨噬细胞已经存在的促炎环境。与其他暴露和遗传缺陷共同作用,由此产生的炎症推动了导致慢性疾病的发病机制。