Kumar Suneel, Tan Yuying, Berthiaume Francois
Department of Biomedical Engineering, Rutgers, State University of New Jersey, 599 Taylor Road, Piscataway, NJ 08854, USA.
Biomedicines. 2021 Feb 22;9(2):222. doi: 10.3390/biomedicines9020222.
Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing of PUs may be dysfunction of the local neurovascular system including deficiency of essential neuropeptides, such as substance P (SP). Previous studies indicate that disturbance in cutaneous sensory innervation leads to a defect in all stages of wound healing, as is the case after SCI. It is hypothesized that nerve fibers enhance wound healing by promoting initial inflammation via the releasing of neuropeptides such as SP. Therefore, we investigated whether exogenous SP improves skin wound healing using in vitro and in vivo models. For in vitro studies, the effects of SP on keratinocyte proliferation and wound closure after a scratch injury were studied under normoxia (pO ~21%) or hypoxia (pO ~1%) and in presence of normal serum (10% /) or low serum (1% /) concentrations. Hypoxia and low serum both significantly slowed cell proliferation and wound closure. Under combined low serum and hypoxia, used to mimic the nutrient- and oxygen-poor environment of chronic wounds, SP (10 M) significantly enhanced cell proliferation and wound closure rate. For in vivo studies, two full-thickness excisional wounds were created with a 5 mm biopsy punch on the dorsum on either side of the midline of 15-week-old C57BL/6J male and female mice. Immediately, wounds were treated topically with one dose of 0.5 μg SP or PBS vehicle. The data suggest a beneficial role in wound closure and reepithelization, and thus enhanced wound healing, in male and female mice. Taken together, exogenously applied neuropeptide SP enhanced wound healing via cell proliferation and migration in vitro and in vivo. Thus, exogenous SP may be a useful strategy to explore further for treating PUs in SCI and diabetic patients.
压疮（PUs）或褥疮是糖尿病性神经病变和创伤性脊髓损伤（SCI）的继发性并发症。压疮往往发生在骨隆突周围的软组织中，愈合可能缓慢或根本无法愈合。压疮愈合受损的一个常见潜在机制可能是局部神经血管系统功能障碍，包括必需神经肽（如P物质（SP））缺乏。先前的研究表明，皮肤感觉神经支配紊乱会导致伤口愈合各阶段出现缺陷，脊髓损伤后就是这种情况。据推测，神经纤维通过释放SP等神经肽促进初始炎症反应，从而促进伤口愈合。因此，我们使用体外和体内模型研究外源性SP是否能改善皮肤伤口愈合。对于体外研究，在常氧（pO₂21%）或低氧（pO₂1%）以及正常血清（10% /）或低血清（1% /）浓度存在的情况下，研究了SP对划痕损伤后角质形成细胞增殖和伤口闭合的影响。低氧和低血清均显著减慢细胞增殖和伤口闭合。在联合低血清和低氧条件下，用于模拟慢性伤口营养和氧气匮乏的环境，SP（10 μM）显著提高细胞增殖和伤口闭合率。对于体内研究，用5毫米活检打孔器在15周龄C57BL/6J雄性和雌性小鼠中线两侧的背部创建两个全层切除伤口。立即用一剂0.5 μg SP或PBS载体对伤口进行局部处理。数据表明，外源性SP对雄性和雌性小鼠的伤口闭合和再上皮化具有有益作用，从而促进伤口愈合。综上所述，外源性应用神经肽SP通过体外和体内的细胞增殖和迁移促进伤口愈合。因此，外源性SP可能是进一步探索治疗脊髓损伤和糖尿病患者压疮的有用策略。
