Yamaguchi Taizo, Kihara Yasuyuki, Taguchi Masashi, Nagashio Yoshikuni, Tashiro Mitsuo, Nakamura Hayato, Otsuki Makoto
Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu 807-8555, Japan.
Pancreas. 2005 Nov;31(4):365-72. doi: 10.1097/01.mpa.0000179729.61457.e5.
The imbalance between synthesis and degradation of extracellular matrix (ECM) proteins is a characteristic feature in chronic pancreatitis. We evaluated the relationship between type IV collagen structure in the basement membrane (BM) and the development of acinar atrophy or the regeneration from acinar injury.
Three different models of pancreatitis were induced in rats by repetitive intraperitoneal injections of 500 mg/100 g body weight of arginine (Arg) or 20 microg/kg body weight of caerulein (Cn) or a single retrograde intraductal infusion of 40 microL/100 g body weight of 3% sodium taurocholate (NaTc). We examined the changes in type IV collagen structure by immunostaining, and the serial changes in the gelatinolytic activity of pro- and active matrix metalloproteinase-2 by zymography in these models of pancreatitis.
The pancreas appeared to be histologically normal on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc, whereas 85% to 90% of acinar tissue was replaced by fatty tissue and dilated pancreatic ducts on day 54 after the first intraperitoneal Arg injection. Immunoreactivity for type IV collagen appeared as a discontinuous line along the BM of ducts, vessels, tubular complexes, and acinar cells on day 40 in Arg-induced pancreatitis, whereas it was detected as a continuous line along the BM on day 35 in Cn-induced pancreatitis and on day 42 in NaTc-induced pancreatitits. Gelatinolytic activity of active MMP-2 increased significantly from day 13 to day 40 after the first intraperitoneal Arg injection, whereas it decreased to the baseline level on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc.
Our findings indicate that a long-term increase in gelatinolytic activity of active MMP-2 in Arg-induced pancreatitis causes continuous disorganization of type IV collagen in the BM and progressive acinar atrophy, whereas a transient increase in gelatinolytic activity of active MMP-2 is involved in the regeneration of type IV collagen structure in the BM and recovery from acinar injury.
细胞外基质（ECM）蛋白合成与降解之间的失衡是慢性胰腺炎的一个特征性表现。我们评估了基底膜（BM）中IV型胶原结构与腺泡萎缩的发展或腺泡损伤后再生之间的关系。
通过重复腹腔注射500mg/100g体重的精氨酸（Arg）或20μg/kg体重的雨蛙素（Cn），或单次逆行胰管内注入40μL/100g体重的3%牛磺胆酸钠（NaTc），在大鼠中诱导三种不同的胰腺炎模型。我们通过免疫染色检查IV型胶原结构的变化，并通过酶谱法检测这些胰腺炎模型中前基质金属蛋白酶-2和活性基质金属蛋白酶-2的明胶酶活性的系列变化。
在首次腹腔注射Cn后第35天以及胰管内注入NaTc后第42天，胰腺在组织学上似乎正常，而在首次腹腔注射Arg后第54天，85%至90%的腺泡组织被脂肪组织和扩张的胰管取代。在Arg诱导的胰腺炎中，第40天IV型胶原的免疫反应性沿导管、血管、管状复合体和腺泡细胞的BM呈不连续线，而在Cn诱导的胰腺炎中第35天以及NaTc诱导的胰腺炎中第42天，其沿BM被检测为连续线。首次腹腔注射Arg后第13天至第40天，活性MMP-2的明胶酶活性显著增加，而在首次腹腔注射Cn后第35天以及胰管内注入NaTc后第42天，其降至基线水平。
我们的研究结果表明，在Arg诱导的胰腺炎中，活性MMP-2的明胶酶活性长期增加会导致BM中IV型胶原持续紊乱和进行性腺泡萎缩，而活性MMP-2明胶酶活性的短暂增加参与了BM中IV型胶原结构的再生和腺泡损伤后的恢复。
