Karran E H, Dodgson K, Harris S J, Markwell R E, Harper G P
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Inflamm Res. 1995 Jan;44(1):36-46. doi: 10.1007/BF01630486.
A simple in vivo model of collagen degradation has been developed, and the effects of various agents have been tested. Type I collagen was prepared from rat skin and acetylated with either [3H]- or [14C] acetic anhydride. The radiolabelled collagen was added to sterile cotton buds and incubated at 37 degrees C to allow the collagen to form native fibrils that were firmly adsorbed to the cotton matrix. After subcutaneous implantation of the collagen-gelled cotton buds into rats, the radiolabelled collagen was progressively removed over a period of weeks by an infiltrating granuloma. Of the agents that were administered directly into the cotton buds using subcutaneously implanted osmotic mini-pumps, only the synthetic collagenase inhibitors CI-A (containing a hydroxamate moiety as a zinc ligand) and CI-C (containing a thiol moiety as a zinc ligand) were able to prevent the removal of collagen: their efficacy correlated with the level of collagenase inhibitory activity assayed in the exudate fluid sequestered within the cotton bud granuloma. Of the agents that were administered systemically, including anti-inflammatory drugs and other compounds used as therapies for arthritis, only hydrocortisone was able to inhibit the removal of radiolabelled collagen. These results suggest that, in this model, interstitial collagenase, a member of the matrix metalloproteinase family, comprised the major degradative pathway for collagen. The collagen-gelled cotton bud model is a useful test system for delineating those processes that result in collagen catabolism. In addition, the model can be used for testing agents, including those of limited or unknown systemic bioavailability, in order to discover novel therapeutic agents for preventing collagen degradation in connective tissue diseases such as arthritis.
已建立了一种简单的体内胶原蛋白降解模型，并测试了各种药物的作用。I型胶原蛋白从大鼠皮肤中制备，并用[3H] - 或[14C]乙酸酐进行乙酰化。将放射性标记的胶原蛋白添加到无菌棉签中，并在37℃下孵育，以使胶原蛋白形成牢固吸附在棉基质上的天然纤维。将胶原蛋白凝胶化的棉签皮下植入大鼠后，放射性标记的胶原蛋白在数周内通过浸润性肉芽肿逐渐被清除。使用皮下植入的渗透微型泵直接注入棉签中的药物中，只有合成的胶原酶抑制剂CI - A（含有异羟肟酸部分作为锌配体）和CI - C（含有硫醇部分作为锌配体）能够阻止胶原蛋白的清除：它们的功效与在棉签肉芽肿中隔离的渗出液中测定的胶原酶抑制活性水平相关。在全身给药的药物中，包括抗炎药和用作关节炎治疗的其他化合物，只有氢化可的松能够抑制放射性标记胶原蛋白的清除。这些结果表明，在该模型中，基质金属蛋白酶家族的成员间质胶原酶构成了胶原蛋白的主要降解途径。胶原蛋白凝胶化棉签模型是一种有用的测试系统，用于描绘导致胶原蛋白分解代谢的那些过程。此外，该模型可用于测试药物，包括那些全身生物利用度有限或未知的药物，以发现用于预防结缔组织疾病如关节炎中胶原蛋白降解的新型治疗药物。
