成纤维细胞生长因子1对糖尿病小鼠下颌下腺增殖细胞核抗原表达的影响

Effect of fibroblast growth factor 1 on the proliferating cell nuclear antigen expression in submandibular gland of diabetic mice

目的 探讨成纤维细胞生长因子1（fibroblast growth factor 1,FGF-1）对糖尿病小鼠下颌下腺增殖细胞核抗原（proliferating cell nuclear antigen,PCNA）表达的影响及可能机制,为防治糖尿病性口干提供新思路.方法 选择8周龄db/db糖尿病型雄性小鼠16只,按随机数字表随机分为糖尿病组和给药组,每组8只;空白对照组为8周龄db/m小鼠8只.给药组连续腹腔注射FGF-1,共16周.分别于实验0、4、8、12、16周检测各组小鼠体质量及血糖.比较实验0、8、16周各组小鼠唾液流率.16周取下颌下腺组织,HE染色观察下颌下腺形态学改变;免疫组化染色检测PCNA表达变化.结果实验4周给药组小鼠血糖下降明显,接近空白对照组（P〉0.05）;之后,血糖趋于稳定.实验8周给药组小鼠体质量减轻明显,但仍显著高于空白对照组（P〈0.05）;之后,体质量趋于稳定.实验期间给药组小鼠唾液流率呈递增趋势,8和16周唾液流率[分别为（260.1±43.3）和（308.5±34.0）mg·min-1·kg-1]均显著高于同时间点糖尿病组[分别为（181.8±37.5）和（194.9±49.8）mg·min-1·kg-1]（P〈0.05）.与空白对照组相比,糖尿病组下颌下腺明显萎缩,而给药组腺体萎缩程度减轻.空白对照组、糖尿病组和给药组下颌下腺指数分别为（7.45±0.63）、（2.23±0.26）和（3.97±0.15）mg/g（P〈0.05）.HE染色示给药组下颌下腺组织结构较清晰,腺泡及导管萎缩程度均较糖尿病组减轻.免疫组化染色示空白对照组、糖尿病组和给药组PCNA细胞阳性率分别为（45.23±7.78）%、（11.50±1.69）%和（36.98±6.53）%（P〈0.05）.结论 FGF-1能上调糖尿病小鼠下颌下腺PCNA表达,这可能是FGF-1逆转糖尿病导致的下颌下腺结构萎缩及功能减退的机制之一.

Objective To examine the proliferating cell nuclear antigen （PCNA） expression in submandibular gland of diabetic mice and to investigate the influence of fibroblast growth factor 1 （FGF-1） on PCNA expression and its possible mechanism. Methods Sixteen db/db diabetic male mice were randomly divided into diabetic group and diabetic-FGF-1 group （n=8）. Eight age-matched db/m mice served as a control group. After FGF-1 was administered intraperitoneally to diabetic-FGF-1 group continuously for 16 weeks, blood glucose and body weight of each mouse in the three groups were detected at 0, 4, 8, 12, 16 weeks. Then the flow rate of saliva in three groups was compared at 0, 8, 16 weeks. At 16 week,bilateral submandibular glands were resected. Then HE staining was performed to observe the histologicalmorphology of submandibular gland and PCNA expression was examined by immunohistochemical staining. Results Four weeks after administration, the blood glucose in diabetic-FGF-1 group decreased markedly, close to the control group （P〉0.05）. Weight loss in diabetic-FGF-1 group was noticeable at 8 weeks after administration, but still higher than that in the control group （P〈0.05）. The flow rate of saliva in diabetic-FGF-1 group increased gradually after administration, which was higher at 8, 16 weeks （[260.1 ± 43.3], [308.5 ± 34.0] mg · min-1 · kg-1） respectively than that in the diabetic group at the same time point （[181.8 ± 37.5], [194.9 ± 49.8] mg · min-1 · kg-1） （P〈0.05）. Compared with the control group, submandibular glands in diabetic group significantly atrophied and the glandular atrophy in diabetic-FGF-1 group was alleviated. The submandibular gland index in the control group, diabetic group and diabetic-FGF-1 group were （7.45±0.63）, （2.23 ± 0.26）, （3.97 ± 0.15） mg/g, respectively （P〈0.05）. HE staining showed that the histological morphology of submandibular gland in diabetic-FGF-1 group was clearer, and acinar and ductal atrophy were less significant than diabetic group. Immunohistochemistry showed that the rate of PCNA-positive cells in the control group, diabetic group and diabetic-FGF-1 group were （45.23 ± 7.78）%, （11.50 ± 1.69）%, （36.98 ± 6.53）% respectively （P〈0.05）. Conclusions FGF-1 can up-regulate the expression of PCNA in submandibular gland of diabetic mice. This effect may be one of the important mechanisms of FGF-1 reversing the structural atrophy and dysfunction of submandibular gland caused by diabetes mellitus.