Darabniya Ali, Darabniya Mahdi, Rezaei Shahrzad Jalilpour, Davoodi AmirReza, Azarmehr Elham, Shokrpoor Sara, Falahatipour Sakineh Khanamani
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Inflammopharmacology. 2025 Jul 22. doi: 10.1007/s10787-025-01863-2.
This study evaluated the therapeutic potential of fosfomycin on surgical wound healing in a sterile rat model, emphasizing its immunomodulatory and regenerative effects beyond antimicrobial activity. Thirty male Sprague Dawley rats were randomly assigned to five groups: negative control, positive control (dexamethasone 1 mg/kg), and three fosfomycin-treated groups (75, 150, and 300 mg/kg, intraperitoneally). A standardized full-thickness dorsal wound was surgically induced, and treatments were administered over a 14-day period. Macroscopic healing was assessed using a validated Wound Healing Score (WHS) on days 1, 3, 5, 7, 9, 12, and 14. Histological analyses using H&E and Masson's trichrome staining were performed on days 7 and 14. Additionally, ELISA was used to quantify pro- and anti-inflammatory cytokines (TNF-α, IL-6, IL-10) and VEGF levels, while western blotting assessed the expression of NF-κB, p-NF-κB, NLRP3, and caspase-3 proteins. Fosfomycin at 150 mg/kg significantly accelerated wound closure, enhanced collagen deposition, improved re-epithelialization, and increased neovascularization compared to control groups. ELISA results showed reduced TNF-α and IL-6 levels and elevated IL-10 and VEGF levels, indicating an anti-inflammatory and a pro-angiogenic profile. Western blot analyses confirmed the downregulation of NF-κB, p-NF-κB, caspase-3, and NLRP3, suggesting suppressed inflammatory signaling and apoptosis. These results support the hypothesis that fosfomycin facilitates wound healing through modulation of immune responses and tissue regeneration pathways. 150 mg/kg dose emerged as the most effective, highlighting a potential therapeutic window. Collectively, the findings suggest that fosfomycin may serve as a dual-function agent in surgical wound care, warranting further investigations in clinical and infected wound models.
本研究在无菌大鼠模型中评估了磷霉素对手术伤口愈合的治疗潜力，重点关注其抗菌活性之外的免疫调节和再生作用。30只雄性Sprague Dawley大鼠被随机分为五组：阴性对照组、阳性对照组（地塞米松1 mg/kg）以及三个磷霉素治疗组（75、150和300 mg/kg，腹腔注射）。通过手术造成标准化的全层背部伤口，并在14天内进行治疗。在第1、3、5、7、9、12和14天，使用经过验证的伤口愈合评分（WHS）评估宏观愈合情况。在第7天和第14天进行苏木精-伊红（H&E）染色和Masson三色染色的组织学分析。此外，酶联免疫吸附测定（ELISA）用于定量促炎和抗炎细胞因子（肿瘤坏死因子-α、白细胞介素-6、白细胞介素-10）以及血管内皮生长因子（VEGF）水平，而蛋白质免疫印迹法检测核因子-κB（NF-κB）、磷酸化核因子-κB（p-NF-κB）、NLRP3炎性小体和半胱天冬酶-3蛋白的表达。与对照组相比，150 mg/kg的磷霉素显著加速了伤口闭合，增强了胶原蛋白沉积，改善了上皮再形成，并增加了新血管形成。ELISA结果显示肿瘤坏死因子-α和白细胞介素-6水平降低以及白细胞介素-10和血管内皮生长因子水平升高，表明具有抗炎和促血管生成的特征。蛋白质免疫印迹分析证实了NF-κB、p-NF-κB、半胱天冬酶-3和NLRP3的下调，提示炎症信号传导和细胞凋亡受到抑制。这些结果支持了磷霉素通过调节免疫反应和组织再生途径促进伤口愈合的假说。150 mg/kg剂量显示出最有效，突出了一个潜在的治疗窗。总体而言，研究结果表明磷霉素可能作为手术伤口护理中的一种双功能药物，值得在临床和感染伤口模型中进一步研究。
