Canbay Ali, Guicciardi Maria Eugenia, Higuchi Hajime, Feldstein Ariel, Bronk Steven F, Rydzewski Robert, Taniai Makiko, Gores Gregory J
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
J Clin Invest. 2003 Jul;112(2):152-9. doi: 10.1172/JCI17740.
Although a lysosomal, cathepsin B-dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb-/- versus Ctsb+/+ animals. Likewise, R-3032 (a Ctsb inhibitor) also reduced these parameters in BDL WT mice. Both genetic and pharmacologic inhibition of Ctsb in the BDL mouse reduced (a). hepatic inflammation, as assessed by transcripts for CXC chemokines and neutrophil infiltration, and (b). fibrogenesis, as assessed by transcripts for stellate cell activation and sirius red staining for hepatic collagen deposition. These differences could not be ascribed to alterations in cholestasis. These findings support a prominent role for the lysosomal pathway of apoptosis in tissue injury and link apoptosis to inflammation and fibrogenesis. Ctsb inhibition may be therapeutic in liver diseases.
尽管已经描述了一种溶酶体依赖性、组织蛋白酶B依赖性（Ctsb依赖性）的凋亡途径，但该途径对组织损伤的作用仍不清楚。我们的目的是确定Ctsb失活是否能减轻胆管结扎（BDL）后的肝损伤、炎症和纤维化。在BDL 3天的小鼠中，与Ctsb+/+动物相比，Ctsb-/-小鼠的肝细胞凋亡、线粒体细胞色素c释放和血清丙氨酸转氨酶（ALT）值均降低。同样，R-3032（一种Ctsb抑制剂）也降低了BDL野生型小鼠的这些参数。BDL小鼠中Ctsb的基因和药物抑制均降低了：（a）肝炎症，通过CXC趋化因子转录本和中性粒细胞浸润评估；（b）纤维化，通过星状细胞激活转录本和肝胶原沉积的天狼星红染色评估。这些差异不能归因于胆汁淤积的改变。这些发现支持凋亡的溶酶体途径在组织损伤中起重要作用，并将凋亡与炎症和纤维化联系起来。抑制Ctsb可能对肝脏疾病具有治疗作用。
