Abstract
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 (1.5×1.5 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 μg or 10 ng/kg b.w. intraperitoneally (i.p.) by injection or alternatively, topically, at the burn, as a thin layer of cream (50 μg 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 μg, 5 μg, 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.
Introduction
Deep partial skin thickness burns may be used in a reproducible animal model to study burn wound healing and attenuation of acute gastric mucosal lesions in response to antiulcer agent therapy [1], [2], [3]. An essential failure of healing is a common problem in both mucosal ulcer and skin wound therapy (for review see Ref. [4]). This study aimed to investigate the effects on burn wound healing and thermal injury-gastric lesions of the gastric pentadecapeptide BPC 157 (GEPPPGKPADDALV M.W. 1419 [4]). BPC 157 is known to have a beneficial effect in a variety of gastrointestinal lesion models [5], [6], [7], [8], [9], including stress-ulcer [10], [11], and a healing effect in different wound models [12], [13], [14]. BPC 157 also stimulates healing of segmental osteoperiosteal bone defects when given locally either percutaneously into the bone defect, or applied intramuscularly [15]. BPC 157 solution was shown to stimulate corneal wound healing [16].
Conditions of healing in burns are complex as a result of vascular damage caused by burn. Dermal vascular changes following thermal trauma result in fibrin deposition and vascular occlusion at the site directly destroyed by thermal energy and changes in dermal haemodynamics and blood vessel morphology in the areas of dermis surrounding the burn area [17]. In addition, a particular problem for peptide application is to find a carrier that does not limit their efficacy at the wound site (i.e. EGF, TGF-β) [18], [19], [20]. In previous experiments [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], BPC 157 was effective without a special carrier. Its particular property of stability (i.e. not degraded in human gastric juice for 24 h [21]) may be a relevant point. BPC 157 may be suitably stable in a simple commercial vehicle (i.e. neutral cream) providing a suitable presence at the defect site and able to influence the potential upregulation of the growth factors, as well as other local factors, acting to promote burn healing.
This study as a first step in burn wound therapy and burn injury-gastric lesion-studies also used topical application of BPC 157 at the site of the burn, administration at a concentration 1 μg/1 g of vehicle, once daily. Pentadecapeptide BPC 157 as an intraperitoneal (i.p.) application was also used. Silver sulfadiazine cream 1% was used as a standard agent acting locally [22]. The next step was the analysis of the influence of this local medication on thermal injury-induced gastric lesions and the healing of the burn wounds itself if given daily topically at the site of the stronger burn wounds also in lower concentrations.
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Section snippets
Drugs
BPC 157 (manufactured by Diagen, d.o.o., Ljubljana, Slovenia) is a partial sequence of human gastric juice protein BPC, freely soluble in water at pH 7.0 and in saline. It was prepared as described before [5], [6], [11], [12], [13], [14], [15], [16]. Peptide with 99% (HPLC) purity (1-des-Gly peptide as impurity), dissolved in saline [5], [6], [11], [12], [13], [14], [15], [16] was used in all of the experiments. Silver sulfadiazine cream 1% (Dermazin, Lek, Slovenia), and neutral commercial
Microscope assessment of BPC 157 regimens and silver sulfadiazine cream in mice exposed to direct flame for 5 s
A consistent damage was induced in controls which received an equal volume of saline (5.0 ml/kg i.p.) or mice with no medication. Since these were not different, they are shown together (control). Mice treated with only cream vehicle (Belobaza) showed no difference with respect to controls, and the same poor re-epithelization ratio was observed in the untreated controls or in mice treated with only cream vehicle. Compared with the controls, the BPC 157 cream-treated mice showed improvement in
Discussion
The benefit of creams containing BPC 157 on burn wound and burn-induced stress gastric ulcers may be considered from both local (i.e. healing of the burn-wound) [3], [23], [24] and systemic (i.e. interruption of the negative chain of events that otherwise inevitably lead to stress stomach lesions) [1], [2] points of view. The gastric pentadecapeptide BPC 157 appears to have a special relationship to bone morphogenetic protein-6 precursor (BMP-6), a molecule known to be involved in keratinocyte
Conclusion
In summary, when compared with the control values, the activity of the pentadecapeptide BPC 157 on inflammatory cells, edema, reticulin, collagen, necrosis, blood vessel formation, number of preserved follicles, re-epithelization and stress-gastric lesion attenuation, tensile breaking strength, and water content in burned skin, suggests that this substance may act to give a more accelerated healing in burns of treated mice. In addition, BPC 157 appears to attenuate stress-induced gastric
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