Flierl Michael A, Rittirsch Daniel, Nadeau Brian A, Sarma J Vidya, Day Danielle E, Lentsch Alex B, Huber-Lang Markus S, Ward Peter A
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
PLoS One. 2009;4(2):e4414. doi: 10.1371/journal.pone.0004414. Epub 2009 Feb 12.
Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFkappaB in macrophages, causing enhanced release of proinflammatory cytokines (TNFalpha, IL-1beta, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-beta-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to alpha(2)-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of alpha(2)-adrenoceptors.
继我们最近报道吞噬细胞（中性粒细胞、多形核白细胞和巨噬细胞）是新发现的儿茶酚胺来源之后，我们现在表明肾上腺素和去甲肾上腺素均可直接激活巨噬细胞中的核因子κB，导致促炎细胞因子（肿瘤坏死因子α、白细胞介素-1β、白细胞介素-6）释放增加。本研究使用了肾上腺完整（AD+）和肾上腺切除（ADX）的啮齿动物，因为ADX动物吞噬细胞释放的儿茶酚胺大大增加，这有助于我们了解吞噬细胞释放的儿茶酚胺的作用。从肾上腺切除大鼠分离的吞噬细胞显示酪氨酸羟化酶和多巴胺-β-羟化酶表达增强，这两种酶是儿茶酚胺产生的关键酶，并且去甲肾上腺素和肾上腺素的基础分泌更高。在两种急性肺损伤（ALI）模型中研究了吞噬细胞衍生的儿茶酚胺上调的影响。吞噬细胞衍生的儿茶酚胺水平升高与急性炎症反应加剧相关，这通过白蛋白血浆渗漏增加、肺中髓过氧化物酶含量增加、支气管肺泡灌洗液中促炎介质水平升高以及肺细胞间黏附分子-1和血管细胞黏附分子-1表达升高来评估。在肾上腺切除的大鼠中，ALI的发展增强，并且与α₂-肾上腺素能受体参与有关，而与盐皮质激素或糖皮质激素受体无关。总体而言，这些数据表明儿茶酚胺是巨噬细胞的强效炎症激活剂，可上调核因子κB以及这些细胞下游的细胞因子产生。在用于进一步评估儿茶酚胺作用的肾上腺切除动物中，巨噬细胞中儿茶酚胺生成酶和儿茶酚胺似乎有代偿性增加，导致通过α₂-肾上腺素能受体参与放大急性炎症反应。
