Abnormal wound healing with excessive scarring is a major health problem with socioeconomic and psychological impacts. In human, chronic wounds and scarring are associated with upregulation of the inducible nitric oxide synthase (iNOS). Recently, we have shown physiological regulation of iNOS in wound healing. Here, we sought to investigate the possible mechanistic role of iNOS in wound healing using biochemical and immunohistochemical assays. We found: (a) iNOS is the main source of wound nitric oxide (NO), (b) NOS inhibition in the wound, downregulated iNOS protein, mRNA and enzymatic activity, and reduced wound NO, and (c) iNOS inhibition resulted in delayed healing at early time points, and excessive scarring at late time points. Furthermore, molecular and cellular analysis of the wound showed that iNOS inhibition significantly (P < 0.05) increased TGF-β1 mRNA and protein levels, fibroblasts and collagen deposition. These latter findings suggest that iNOS might be exerting its action in the wound by signaling through TGF-β1 that activates wound fibroblasts to produce excessive collagen. Our current findings provide further support that iNOS is crucial for physiological wound healing, and suggest that dysregulation of iNOS during the inflammatory phase impairs healing, and results in disfiguring post-healing scarring. Thus, the mutual feedback regulation between iNOS and TGF-β1 at the gene, protein and functional levels might be the mechanism through which iNOS regulates the healing. Monitoring and maintenance of wound NO levels might be important for healing and avoiding long-term complications in susceptible people including patients with diabetic wounds, venous ulcers or keloid prone.

具有过多疤痕的异常伤口愈合是具有社会经济和心理影响的主要健康问题。在人类中，慢性伤口和疤痕与诱导型一氧化氮合酶（iNOS）的上调有关。最近，我们显示了伤口愈合中iNOS的生理调节。在这里，我们试图使用生物化学和免疫组织化学方法研究iNOS在伤口愈合中的可能机制。我们发现：（a）iNOS是伤口一氧化氮（NO）的主要来源，（b）伤口中NOS的抑制，iNOS蛋白，mRNA和酶活性的下调以及伤口NO的减少，以及（c）iNOS抑制导致在早期时间点延迟愈合，在晚期时间点过度瘢痕形成。此外，伤口的分子和细胞分析表明iNOS抑制显着（P <0。05）TGF-β1mRNA和蛋白水平，成纤维细胞和胶原沉积增加。这些后面的发现表明，iNOS可能通过激活伤口成纤维细胞以产生过量胶原的TGF-β1发出信号，从而在伤口中发挥其作用。我们当前的发现进一步提供了iNOS对于生理性伤口愈合至关重要的支持，并表明在炎症阶段iNOS的失调会损害愈合，并导致愈合后瘢痕的外观消失。因此，iNOS和TGF-β1在基因，蛋白质和功能水平上的相互反馈调节可能是iNOS调节愈合的机制。监测和维持伤口NO的水平可能对包括糖尿病伤口患者在内的易感人群的康复和避免长期并发症很重要，