Mikus D, Sikiric P, Seiwerth S, Petricevic A, Aralica G, Druzijancic N, Rucman R, Petek M, Pigac B, Perovic D, Kolombo M, Kokic N, Mikus S, Duplancic B, Fattorini I, Turkovic B, Rotkvic I, Mise S, Prkacin I, Konjevoda P, Stambuk N, Anic T
Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia.
Burns. 2001 Dec;27(8):817-27. doi: 10.1016/s0305-4179(01)00055-9.
The effects of the gastric pentadecapeptide BPC 157 were investigated when administered topically or systemically in burned mice. This agent is known to have a beneficial effect in a variety of models of gastrointestinal lesions, as well as on wound or fracture healing. Deep partial skin thickness burns (1.5x1.5 cm) covering 20% of total body area, were induced under anesthesia on the back of mice by controlled burning and gastric lesions were assessed 1, 2, 3, 7, 14 and 21 days following injury. The first application of BPC 157 was immediately following burning, and thereafter, once daily, until 24 h before sacrifice. In the initial experiments, exposure to direct flame for 5 s, the BPC 157 was applied at 10 microg or 10 ng/kg b.w. intraperitoneally (i.p.) by injection or alternatively, topically, at the burn, as a thin layer of cream (50 microg of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream (also used as local vehicle-control)), while silver sulfadiazine 1% cream was a standard agent acting locally. Others received no local medication: they were treated i.p. by injection of distilled water (distilled water-control) or left without any medication (control). In subsequent experiments involving deeper burns (direct flame for 7 s), BPC 157 creams (50 microg, 5 microg, 500 ng, 50 ng or 5 ng of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream), or vehicle as a thin layer of cream, were applied topically, at the burn. Compared with untreated controls, in both experiments, in the BPC 157 cream-treated mice all parameters of burn healing were improved throughout the experiment: less edema was observed and inflammatory cell numbers decreased. Less necrosis was seen with an increased number of capillaries along with an advanced formation of dermal reticulin and collagen fibers. An increased number of preserved follicles were observed. Two weeks after injury, BPC 157 cream-treated mice completely reversed the otherwise poor re-epithelization ratio noted in the untreated control or mice treated with vehicle only. Tensiometry investigation showed an increased breaking strength and relative elongation of burned skin, while water content in burned skin decreased. This was, however, not the case with the vehicle or silver sulfadiazine. Relative to the control values, in silver sulfadiazine cream-treated mice, only collagen fiber formation was increased, in addition to a decreased inflammatory cell number. Relative to control values, BPC 157 given i.p. decreased the number of inflammatory cells, lowered water content in burned skin, and raised breaking strength and relative elongation of burned skin during tensiometry. Through the experimental period, gastric lesions were continuously noted in all thermally injured mice left without local medication and they were consistently attenuated only by BPC 157 treatments: either given i.p. (at either dose), or given locally (at either concentration). Other treatments (i.e. local treatment with silver sulfadiazine cream or neutral cream in mice subjected for 5 s to direct flame), led to only poor, if any attenuation. This stable gastric pentadecapeptide appears to be active and gives a stimulation to burn healing at the defect site. The agent may act by causing an upregulation of the growth factors, as well as influencing other local factors.
研究了胃十五肽BPC 157局部或全身给药对烧伤小鼠的影响。已知该药物在多种胃肠道损伤模型以及伤口或骨折愈合方面具有有益作用。在小鼠背部麻醉下通过控制烧伤诱导占全身面积20%的深度部分皮肤厚度烧伤(1.5×1.5厘米),并在受伤后1、2、3、7、14和21天评估胃部损伤。BPC 157在烧伤后立即首次应用,此后每天一次,直至处死前24小时。在最初的实验中,暴露于直接火焰5秒后,BPC 157以10微克或10纳克/千克体重腹腔内注射,或者作为薄层乳膏局部应用于烧伤处(将50微克BPC 157溶解于2毫升蒸馏水中与50克市售中性乳膏混合,该中性乳膏也用作局部赋形剂对照),而1%磺胺嘧啶银乳膏是局部起作用的标准药物。其他小鼠未接受局部用药:它们通过注射蒸馏水腹腔内给药(蒸馏水对照)或不接受任何药物治疗(对照)。在随后涉及更深烧伤(直接火焰7秒)的实验中,将BPC 157乳膏(50微克、5微克、500纳克、50纳克或5纳克BPC 157溶解于2毫升蒸馏水中与50克市售中性乳膏混合)或作为薄层乳膏的赋形剂局部应用于烧伤处。与未治疗的对照相比,在两个实验中,BPC 157乳膏治疗的小鼠在整个实验过程中烧伤愈合的所有参数均得到改善:观察到水肿减轻,炎症细胞数量减少。坏死减少,毛细血管数量增加,同时真皮网状纤维和胶原纤维形成提前。观察到保留毛囊的数量增加。受伤两周后,BPC 157乳膏治疗的小鼠完全逆转了未治疗对照或仅用赋形剂治疗的小鼠中原本较差的再上皮化率。张力测定研究表明烧伤皮肤的抗张强度和相对伸长率增加,而烧伤皮肤中的含水量降低。然而,赋形剂或磺胺嘧啶银并非如此。相对于对照值,在磺胺嘧啶银乳膏治疗的小鼠中,除了炎症细胞数量减少外,仅胶原纤维形成增加。相对于对照值,腹腔内给予BPC 157可减少炎症细胞数量,降低烧伤皮肤中的含水量,并在张力测定时提高烧伤皮肤的抗张强度和相对伸长率。在整个实验期间,未接受局部用药的所有热损伤小鼠持续出现胃部损伤,并且仅通过BPC 157治疗(腹腔内给药(任一剂量)或局部给药(任一浓度))持续减轻。其他治疗(即对暴露于直接火焰5秒的小鼠局部用磺胺嘧啶银乳膏或中性乳膏治疗),即使有减轻作用也很微弱。这种稳定的胃十五肽似乎具有活性,并对缺损部位的烧伤愈合有刺激作用。该药物可能通过上调生长因子以及影响其他局部因素起作用。