Carbamazepine mitigates parenteral nutrition-associated liver disease in a novel ambulatory piglet model.
Carbamazepine mitigates parenteral nutrition-associated liver disease in a novel ambulatory piglet model.
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DOI：
10.1002/jpen.2330
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发表时间：
2022-08
影响因子：
3.4
通讯作者：
Jain, Ajay K.
中科院分区：
文献类型：
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作者：
Song, Eric;Nagarapu, Aakash;van Nispen, Johan;Armstrong, Austin;Manithody, Chandrashekhara;Murali, Vidul;Voigt, Marcus;Samaddar, Ashish;Hutchinson, Chelsea;Jain, Sonali;Roenker, Jeremy;Krebs, Joseph;Jain, Ajay K.
对于不能耐受肠内喂养的患者，完全肠外营养(TPN)仍然是一种关键的治疗选择。然而，在挽救生命的同时，TPN也与包括肝损伤在内的重大副作用有关，其病因是多因素的。卡马西平(CBZ)是一种抗癫痫药物，已知在多种肝病中调节肝纤维化和肝细胞损伤。我们假设CBZ可以预防肠外营养相关性肝病(PNALD)，我们使用我们新的非卧床TPN仔猪模型进行了测试。给仔猪配备颈静脉导管和输液泵进行TPN，随机分为3组，EN组7只，TPN组6只，TPN+CBZ组6只，持续2周。采用光镜、血清肝损伤标志物定量、Ki67、CK-7、RT-qPCR等方法对血清和肝组织进行分析。在我们的模型中，与EN组相比，饲喂TPN的仔猪出现了PNALD的表现，特别是血清胆红素、γ-谷氨酰转移酶、肝脏胆汁淤积和Ki67的表达(p<；0.03)。在服用TPN的动物中，CBZ治疗导致这些损伤标志物的显著降低(p<；0.05)。对这些疗效机制的研究显示，服用卡马西平的全胃肠外营养喂养的动物中SREBP-1、PPAR-α和FABP的表达增加(p<；0.03)。进一步研究发现，CBZ治疗增加了LC3的表达，降低了LAMP1的表达(p<；0.03)。CBZ给药减轻了PNALD的严重程度，提示了一种针对TPN相关副作用的新治疗策略，并可能代表着当前治疗方案的范式变化。
Total parenteral nutrition (TPN) remains a critical therapeutic option in patients who cannot tolerate enteral feeding. However, while lifesaving, TPN is associated with significant side effects including liver injury, the etiology of which is multifactorial. Carbamazepine (CBZ), an anti-epileptic medication, is known to modulate hepatic fibrosis and hepatocellular injury in a variety of liver diseases. We hypothesized that CBZ could prevent parenteral nutrition associated liver disease (PNALD), which we tested using our novel ambulatory TPN piglet model. Piglets were fitted with jugular catheters and infusion pumps for TPN and randomized to enteral milk feeding (EN, n=7), TPN (TPN, n=6), or TPN with parenteral CBZ (CBZ, n=6) for 2 weeks. Serum and liver tissue were analyzed via light microscopy, quantification of serum liver injury markers, Ki67 and CK-7 indexing, and RT-qPCR. TPN-fed piglets in our model developed manifestations of PNALD, particularly increased serum bilirubin, γ-glutamyl transferase, liver cholestasis, and Ki67 expression compared to EN animals (p<0.03). CBZ therapy in TPN-fed animals led to significant reduction in these markers of injury (p<0.05). Investigation into the mechanism of these therapeutic effects revealed increased expression of SREBP-1, PPAR-α, and FABP in TPN-fed animals receiving CBZ (p<0.03). Further investigation revealed increased LC3 expression and decreased LAMP1 expression with CBZ therapy (p<0.03). CBZ administration mitigates PNALD severity, suggesting a novel therapeutic strategy targeting TPN associated side effects, and may present a paradigm change to current treatment options.
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影响因子：
3.4
作者：
Jain, Ajay Kumar;Wen, Joy X.;Teckman, Jeffery H.
通讯作者：
Teckman, Jeffery H.
影响因子：
3.4
作者：
Lavallee, Celeste M.;Wizzard, Pamela R.;Turner, Justine M.
通讯作者：
Turner, Justine M.
影响因子：
24.5
作者：
MIURA, S;TANAKA, S;TSUCHIYA, M
通讯作者：
TSUCHIYA, M
影响因子：
2.2
作者：
Price, Amber;Blomenkamp, Keith;Jain, Ajay Kumar
通讯作者：
Jain, Ajay Kumar
DOI：
10.4103/1319-3767.141688
发表时间：
2014-09
期刊：
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association
影响因子：
--
作者：
Alkharfy TM;Ba-Abbad R;Hadi A;Sobaih BH;AlFaleh KM
通讯作者：
AlFaleh KM