Gosain Ankush, Muthu Kuzhali, Gamelli Richard L, DiPietro Luisa A
Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, Ill, USA.
Surgery. 2007 Aug;142(2):170-9. doi: 10.1016/j.surg.2007.04.015.
The systemic response to injury is characterized by massive release of norepinephrine (NE) into the circulation as a result of global sympathetic activation. We have recently demonstrated that NE modulates the recruitment of macrophages to the cutaneous wound. We hypothesized that NE suppresses wound macrophage phagocytic function through canonical adrenergic signaling pathways.
Murine wound macrophages were harvested at 5 days after injury and treated with physiologic and pharmacologic dose norepinephrine. Phagocytosis of green fluorescent protein-labeled Escherichia coli was assayed by flow cytometry. The signaling pathways mediating NE modulation of wound macrophage phagocytosis were interrogated by pharmacologic manipulation of alpha- and beta-adrenoreceptors (ARs), intracellular cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). Tissue specificity was determined by comparison of wound macrophages to splenic macrophages.
Both physiologic and pharmacologic dose NE suppressed wound macrophage phagocytic efficiency. This effect was mediated by alpha- and beta-ARs in a dose-dependent fashion. Direct stimulation of cAMP-suppressed phagocytic efficiency and blockade of PKA signaling prevented NE-mediated suppression of phagocytic efficiency. Splenic macrophage phagocytic efficiency was less than that of wound macrophages and was not altered by NE.
NE has a profound immunosuppressive effect on wound macrophage function that is tissue specific and appears to be mediated through adrenergic receptors and their canonical downstream signaling pathway. Attenuation of post-injury immunosuppression represents another potential mechanism by which beta-AR blockade may reduce morbidity and mortality after severe injury.
机体对损伤的全身反应特征是由于全身交感神经激活导致去甲肾上腺素（NE）大量释放入循环系统。我们最近证明NE可调节巨噬细胞向皮肤伤口的募集。我们推测NE通过经典的肾上腺素能信号通路抑制伤口巨噬细胞的吞噬功能。
在损伤后5天收集小鼠伤口巨噬细胞，并用生理剂量和药理剂量的去甲肾上腺素进行处理。通过流式细胞术检测绿色荧光蛋白标记的大肠杆菌的吞噬作用。通过对α和β肾上腺素能受体（ARs）、细胞内环磷酸腺苷（cAMP）和蛋白激酶A（PKA）进行药理操作，探究介导NE对伤口巨噬细胞吞噬作用调节的信号通路。通过将伤口巨噬细胞与脾巨噬细胞进行比较来确定组织特异性。
生理剂量和药理剂量的NE均抑制伤口巨噬细胞的吞噬效率。这种作用由α和β肾上腺素能受体以剂量依赖的方式介导。直接刺激cAMP可抑制吞噬效率，而阻断PKA信号传导可防止NE介导的吞噬效率抑制。脾巨噬细胞的吞噬效率低于伤口巨噬细胞，且不受NE影响。
NE对伤口巨噬细胞功能具有深远的免疫抑制作用，这种作用具有组织特异性，并且似乎是通过肾上腺素能受体及其经典的下游信号通路介导的。减轻损伤后的免疫抑制是β肾上腺素能受体阻断可能降低严重损伤后发病率和死亡率的另一种潜在机制。
