Kang Yu-Ming, Zhang Zhi-Hua, Xue Baojian, Weiss Robert M, Felder Robert B
Univ. of Iowa College of Medicine, Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H227-36. doi: 10.1152/ajpheart.01157.2007. Epub 2008 May 16.
The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 microg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E(2)) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1beta, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1beta, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.
心力衰竭（HF）大鼠下丘脑促炎细胞因子的表达增加。这一观察结果的病理生理意义尚不清楚。我们假设下丘脑促炎细胞因子上调中枢神经系统的活性，这有助于HF中交感神经活动增加，具体而言，是脑肾素-血管紧张素系统（RAS）和下丘脑-垂体-肾上腺（HPA）轴。通过冠状动脉结扎诱导HF的大鼠和假手术对照组（SHAM）连续4周经脑室内输注细胞因子合成抑制剂己酮可可碱（PTX，10微克/小时）或人工脑脊液（VEH）进行治疗。在接受VEH治疗的HF大鼠中，与接受VEH治疗的SHAM大鼠相比，促炎细胞因子的下丘脑表达增加，同时脑RAS的关键成分（肾素、血管紧张素转换酶、血管紧张素1型受体）以及促肾上腺皮质激素释放激素（HPA轴激活的中枢指标）在下丘脑室旁核（PVN）中的表达也增加。其他炎症/兴奋性介质（超氧化物、前列腺素E2）的表达也增加，同时PVN中存在慢性神经元兴奋的证据。接受VEH治疗的HF大鼠血浆去甲肾上腺素、血管紧张素II、白细胞介素（IL）-1β和促肾上腺皮质激素水平较高，左心室舒张末期压力增加，肺湿重与体重比增加。除了作为外周促炎细胞因子活性指标的血浆IL-1β外，经脑室内PTX治疗的HF大鼠所有神经体液兴奋指标均显著降低。这些发现表明，在缺血性HF大鼠中观察到的脑促炎细胞因子增加具有功能意义，通过激活脑RAS和HPA轴导致神经体液兴奋。
