Disruptive and Deterrence Technologies Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, New Delhi 110054, India.
Delhi Pharmaceutical Science and Research University, Pushp Vihar, New Delhi 110017, India.
ACS Appl Bio Mater. 2024 May 20;7(5):2836-2850. doi: 10.1021/acsabm.3c01197. Epub 2024 May 8.
High-altitude regions, cold deserts, permafrost regions, and the polar region have some of the severest cold conditions on earth and pose immense perils of cold injuries to exposed individuals. Accidental and unintended exposures to severe cold, either unintentionally or due to occupational risks, can greatly increase the risk of serious conditions including hypothermia, trench foot, and cold injuries like frostbite. Cold-induced vasoconstriction and intracellular/intravascular ice crystal formation lead to hypoxic conditions at the cellular level. The condition is exacerbated in individuals having inadequate and proper covering and layering, particularly when large area of the body are exposed to extremely cold environments. There is a paucity of preventive and therapeutic pharmacological modalities that have been explored for managing and treating cold injuries. Given this, an efficient modality that can potentiate the healing of frostbite was investigated by studying various complex pathophysiological changes that occur during severe cold injuries. In the current research, we report the effectiveness and healing properties of a standardized formulation, ., a herbosomal-loaded PEG-poloxamer topical formulation (-HPTF), on frostbite. The intricate mechanistic pathways modulated by the novel formulation have been elucidated by studying the pathophysiological sequelae that occur following severe cold exposures leading to frostbite. The results indicate that -HPTF ameliorates the outcome of frostbite, as it activates positive sensory nerves widely distributed in the epidermis transient receptor potential vanilloid 1 (TRPV1), significantly ( < 0.05) upregulates cytokeratin-14, promotes angiogenesis (VEGF-A), prominently represses the expression of thromboxane formation (TXA2), and significantly ( < 0.05) restores levels of enzymatic (glutathione reductase, superoxide dismutase, and catalase) and nonenzymatic antioxidants (glutathione). Additionally, -HPTF attenuates oxidative stress and the expression of inflammatory proteins PGF-2α, NFκB-p65, TNF-α, IL-6, IL-1β, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and protein carbonylation (PCO). Masson's Trichrome staining showed that -HPTF stimulates cellular proliferation, and increases collagen fiber deposition, which significantly ( < 0.05) promotes the healing of frostbitten tissue, as compared to control. We conclude that protection against severe cold injuries by -HPTF is mediated modulation of pathways involving TRPV1, VEGF-A, TXA2, redox homeostasis, and inflammatory cascades. The study is likely to have widespread implications for the prophylaxis and management of moderate-to-severe frostbite conditions.
高海拔地区、寒冷沙漠、永久冻土层地区和极地地区拥有地球上一些最恶劣的寒冷条件，对暴露在外的个体构成了巨大的冷伤危险。意外和非故意暴露于严寒中，无论是无意的还是由于职业风险，都会大大增加发生严重情况的风险，包括体温过低、战壕足和冻伤等冷伤。寒冷引起的血管收缩和细胞内/血管内冰晶形成导致细胞水平缺氧。当身体的大面积暴露在极冷环境中时，这种情况会因个体的覆盖物和分层不足而加剧。目前，已经探索了一些预防和治疗冷伤的药物治疗方法，但效果有限。有鉴于此，通过研究严重冷伤期间发生的各种复杂病理生理变化，我们研究了一种能够增强冻伤愈合的有效治疗方法。在目前的研究中，我们报告了一种标准化配方的有效性和愈合特性，该配方为一种载有 Herbosome 的 PEG-泊洛沙姆 topical 制剂（-HPTF），用于治疗冻伤。通过研究导致冻伤的严重寒冷暴露后的病理生理后果，阐明了该新型制剂调节的复杂机制途径。结果表明，-HPTF 改善了冻伤的结果，因为它激活了广泛分布在表皮瞬时受体电位香草素 1（TRPV1）中的阳性感觉神经，显著（<0.05）上调细胞角蛋白-14，促进血管生成（VEGF-A），显著抑制血栓素形成（TXA2）的表达，并显著（<0.05）恢复酶（谷胱甘肽还原酶、超氧化物歧化酶和过氧化氢酶）和非酶抗氧化剂（谷胱甘肽）的水平。此外，-HPTF 可减轻氧化应激和炎症蛋白 PGF-2α、NFκB-p65、TNF-α、IL-6、IL-1β、丙二醛（MDA）、高级氧化蛋白产物（AOPP）和蛋白羰基化（PCO）的表达。Masson's Trichrome 染色显示，-HPTF 刺激细胞增殖，增加胶原蛋白纤维沉积，与对照组相比，这显著（<0.05）促进了冻伤组织的愈合。我们得出结论，-HPTF 通过调节涉及 TRPV1、VEGF-A、TXA2、氧化还原平衡和炎症级联的途径来防止严重冷伤。这项研究可能对中度至重度冻伤情况的预防和管理具有广泛的意义。
