Mendenhall C L, Roselle G A, Gartside P, Grossman C J
Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Alcohol Clin Exp Res. 1997 Feb;21(1):1-10.
Patients with severe alcoholic liver injury exhibit very low serum insulin-like growth factor-1 (IGF-1) concentrations, along with many of the symptoms that might occur with an IGF-1 deficiency state (including severe protein calorie malnutrition and immunosuppression). This study was performed to assess the effects of recombinant human (rh) IGF-1 and/or rh growth hormone (rhGH) on anabolism and immunity in the calorie-restricted, immunosuppressed alcoholic rat.
Undernutrition was induced by calorie restriction such that each animal consumed 40% of ad libitum-fed controls. Alcohol was administered orally in the diet such that the mean daily intake was 9.4 g/kg/day. rhIGF-1 was administered by continuous subcutaneous infusion (380 micrograms/day) using a 14-day miniosmotic pump; rhGH was given by subcutaneous injections (400 micrograms/day). Matching placebo groups were also studied.
On this regimen, ad libitum-fed controls were well nourished and increased body weight 34%, whereas Restricted controls lost 7.7% and Restricted alcohol-fed rats lost 15.2%. Significant but incomplete reversal of undernutrition was achieved with hormone therapy. Best improvement was obtained with combined therapy: rhIGF-1 + rhGH (p < 0.005; placebo versus active treatments). Immunologic impairment was observed to be severe in both thymus and spleen. The most severe changes were seen in thymi of the calorie-restricted, alcohol-fed rats, wherein 98% of the T lymphocytes were lost. rhIGF-1 treatment, but not rhGH, produced significant improvements in thymus. This was most pronounced in control rats (p < 0.005). Splenic T lymphocytes were less impaired and were more responsive to rhIGF-1 treatment; there was a maximum loss of 71% of T cells in Restricted, alcohol-fed rats. rhIGF-1 treatment completely restored splenic cellularity, as well as each of the T lymphocytes studied: CD5, CD4, and CD8. Functional status of splenic T lymphocytes was assessed by blast transformation after concanavalin A stimulation. Calorie restriction did not impair significantly this function in controls [Lieber-DeCarli control diet (LCD)]. However, it was significantly impaired in the Restricted, alcohol-fed rats (p = 0.003). In the presence of continued calorie restriction and alcohol, this function was not restored with either hormone (rhIGF-1 and/or rhGH). Their role in facilitating functional recovery after calories is restored, and alcohol is discontinued is under investigation.
重度酒精性肝损伤患者血清胰岛素样生长因子-1（IGF-1）浓度极低，伴有许多可能在IGF-1缺乏状态下出现的症状（包括严重蛋白质热量营养不良和免疫抑制）。本研究旨在评估重组人（rh）IGF-1和/或rh生长激素（rhGH）对热量受限、免疫抑制的酒精性大鼠合成代谢和免疫的影响。
通过限制热量诱导营养不良，使每只动物摄入的热量为自由进食对照组的40%。在饮食中口服给予酒精，使平均每日摄入量为9.4 g/kg/天。使用14天的微型渗透泵通过持续皮下输注给予rhIGF-1（380微克/天）；通过皮下注射给予rhGH（400微克/天）。还研究了匹配的安慰剂组。
在该方案下，自由进食对照组营养良好，体重增加34%，而限制饮食对照组体重下降7.7%，限制饮食且给予酒精的大鼠体重下降15.2%。激素治疗实现了营养不良的显著但不完全逆转。联合治疗（rhIGF-1 + rhGH）取得了最佳改善（p < 0.005；安慰剂与活性治疗组相比）。观察到胸腺和脾脏的免疫功能均严重受损。在限制热量、给予酒精的大鼠胸腺中观察到最严重的变化，其中98%的T淋巴细胞丢失。rhIGF-1治疗而非rhGH治疗使胸腺有显著改善。在对照大鼠中最为明显（p < 0.005）。脾脏T淋巴细胞受损较轻，对rhIGF-1治疗反应更敏感；在限制饮食、给予酒精的大鼠中，T细胞最多丢失71%。rhIGF-1治疗完全恢复了脾脏细胞数量以及所研究的每种T淋巴细胞：CD5、CD4和CD8。通过刀豆蛋白A刺激后的增殖转化评估脾脏T淋巴细胞的功能状态。在对照组[Lieber-DeCarli对照饮食（LCD）]中，热量限制并未显著损害该功能。然而，在限制饮食、给予酒精的大鼠中该功能显著受损（p = 0.003）。在持续存在热量限制和酒精的情况下，两种激素（rhIGF-1和/或rhGH）均未恢复该功能。它们在热量恢复且停止给予酒精后促进功能恢复中的作用正在研究中。
