Department of Histology and Cell Biology, Minia Faculty of Medicine, Minia University, Minia, Egypt.
Department of Histology and Cell Biology, Minia Faculty of Medicine, Minia University, Minia, Egypt.
Biochim Biophys Acta Mol Basis Dis. 2020 Oct 1;1866(10):165850. doi: 10.1016/j.bbadis.2020.165850. Epub 2020 Jun 1.
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.
异常的伤口愈合和过度的瘢痕形成是一个主要的健康问题，具有社会经济和心理影响。在人类中，慢性伤口和瘢痕与诱导型一氧化氮合酶（iNOS）的上调有关。最近，我们已经展示了伤口愈合过程中 iNOS 的生理调节。在这里，我们试图通过生化和免疫组织化学检测来研究 iNOS 在伤口愈合中的可能机制作用。我们发现：（a）iNOS 是伤口中一氧化氮（NO）的主要来源，（b）伤口中 NOS 的抑制作用下调了 iNOS 蛋白、mRNA 和酶活性，并减少了伤口中的 NO，（c）iNOS 的抑制作用导致在早期时间点愈合延迟，并在晚期时间点产生过多的瘢痕。此外，对伤口的分子和细胞分析表明，iNOS 的抑制作用显著（P < 0.05）增加了 TGF-β1 的 mRNA 和蛋白水平、成纤维细胞和胶原蛋白沉积。这些发现表明，iNOS 可能通过 TGF-β1 信号通路发挥作用，激活伤口成纤维细胞产生过多的胶原蛋白。我们目前的研究结果进一步表明，iNOS 对生理伤口愈合至关重要，并表明在炎症期 iNOS 的失调会损害愈合，并导致愈合后的瘢痕变形。因此，iNOS 和 TGF-β1 在基因、蛋白和功能水平上的相互反馈调节可能是 iNOS 调节愈合的机制。监测和维持伤口中 NO 的水平可能对愈合和避免易感人群（包括糖尿病伤口、静脉溃疡或瘢痕疙瘩患者）的长期并发症很重要。
