Jhawer Ashwin, Frampton Gabriel, Bhattarai Shadikchhya Maya, DeMorrow Sharon, McMillin Matthew
Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Metab Brain Dis. 2024 Dec 10;40(1):57. doi: 10.1007/s11011-024-01493-7.
Acute liver failure results from severe hepatic injury and can lead to neurological dysfunction known as hepatic encephalopathy (HE). Thrombospondin-1 can contribute to HE by increasing cerebral edema and microglia activation in the azoxymethane (AOM) mouse model. CD47 is a receptor for TSP1 and can directly modulate inflammation in numerous disease states. However, the role of CD47 in the progression of HE is currently unknown. Therefore, the aim of this study was to assess the role of CD47 in liver and brain pathology in the AOM mouse model of HE. C57Bl/6 or CD47 knockout (CD47) were administered AOM to induce acute liver failure and HE. Liver damage was evaluated by measuring serum transaminases and histological assessment. Neurological function was determined by evaluating the time taken to reach coma (loss of all reflexes), cerebral edema, and microglia activation. CD47 signaling, and downstream signaling pathways, were assessed by real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. AOM-treated mice had increased expression of CD47 in the liver, cortex, hippocampus, and cerebellum when compared to vehicle-treated mice. CD47 AOM-treated mice had reduced liver injury and apoptosis when compared to wildtype AOM-treated mice. A slower degree of neurological decline and less cerebral edema were observed in CD47 mice compared to wildtype AOM-treated mice. This was associated with decreased microglia proliferation and increased SOD1 expression in CD47 mice compared to wildtype AOM-treated mice. These findings support that CD47 signaling exacerbates AOM-induced acute liver failure and HE by inducing hepatic cell death, cerebral edema, and microglia activation.
急性肝衰竭由严重肝损伤引起，可导致称为肝性脑病（HE）的神经功能障碍。在氧化偶氮甲烷（AOM）小鼠模型中，血小板反应蛋白-1可通过增加脑水肿和小胶质细胞活化促进肝性脑病。CD47是TSP1的受体，可在多种疾病状态下直接调节炎症。然而，CD47在肝性脑病进展中的作用目前尚不清楚。因此，本研究的目的是评估CD47在AOM肝性脑病小鼠模型的肝脏和脑病理中的作用。给C57Bl/6或CD47基因敲除（CD47-/-）小鼠注射AOM以诱导急性肝衰竭和肝性脑病。通过测量血清转氨酶和组织学评估来评价肝损伤。通过评估达到昏迷（所有反射消失）的时间、脑水肿和小胶质细胞活化来确定神经功能。通过实时PCR、蛋白质印迹、免疫荧光和免疫组织化学评估CD47信号传导及其下游信号通路。与给予赋形剂处理的小鼠相比，给予AOM处理的小鼠肝脏、皮质、海马和小脑中CD47的表达增加。与野生型AOM处理的小鼠相比，给予CD47-/- AOM处理小鼠的肝损伤和细胞凋亡减少。与野生型AOM处理的小鼠相比，CD47-/-小鼠的神经功能衰退程度较慢，脑水肿较轻。与野生型AOM处理的小鼠相比，CD47-/-小鼠的小胶质细胞增殖减少，SOD1表达增加。这些发现支持CD47信号传导通过诱导肝细胞死亡、脑水肿和小胶质细胞活化加重AOM诱导的急性肝衰竭和肝性脑病。
