Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury
Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury
复制标题
DOI：
10.1016/j.ajpath.2011.03.029
复制
发表时间：
2011-07-01
影响因子：
6
通讯作者：
Sadis, Seth
中科院分区：
文献类型：
--
作者：
Radi, Zaher A.;Koza-Taylor, Petra H.;Sadis, Seth
巨噬细胞集落刺激因子（M-CSF）是一种造血生长因子，负责单核细胞的存活和增殖以及单核细胞分化为巨噬细胞，包括肝脏中的枯否细胞（KC）。KC在清除几种血清酶（包括天冬氨酸转氨酶和肌酸激酶）中起重要作用，这些酶通常因肝脏或骨骼肌损伤而升高。我们使用了三种不同的动物模型来研究这一假设，即在明显没有肝或骨骼肌损伤的情况下，KCs的减少可能是KCs水平升高的结果。具体而言，通过一种新型人单克隆抗体中和M-CSF活性可减少食蟹猴中的CD 14（+）CD 16（+）单核细胞群，消耗KC，并增加天冬氨酸转氨酶和肌酸激酶血清酶水平。此外，用氯膦酸盐脂质体治疗大鼠耗尽了KC，导致血清酶水平升高，同样没有组织损伤的证据。最后，在缺乏功能性M-CSF且KC水平降低的骨硬化（Csf（1 oP）/Ccf（1 oP））小鼠中，血清酶水平高于野生型同窝仔。总之，这些发现支持通过M-CSF调节组织巨噬细胞稳态而增加血清酶水平的机制，而不伴随肝脏或骨骼系统的组织病理学变化。(Ann J Pathol 2011，179：240-247; DOI：10.1016/j.ajpath.2011.03.029）
Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of scrum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury. Specifically, neutralizing M-CSF activity via a novel human monoclonal antibody reduced the CD14(+)CD16(+) monocyte population, depleted KCs, and increased aspartate aminotransferase and creatine kinase serum enzyme levels in cynomolgus macaques. In addition, the treatment of rats with clodronate liposomes depleted KCs and led to increased serum enzyme levels, again without evidence of tissue injury. Finally, in the osteopetrotic (Csf(1oP)/Ccf(1oP)) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes are higher than in wild-type littermates. Together, these findings support a mechanism for increases in serum enzyme levels through M-CSF regulation of tissue macrophage homeostasis without concomitant histopadtological changes in either the hepatic or skeletal system. (Ann J Pathol 2011, 179:240-247; DOI: 10.1016/j.ajpath.2011.03.029)