Kaba Shinji, Kawai Yoshitaka, Tanigami Yuki, Ohnishi Hiroe, Kita Tomoko, Yoshimatsu Masayoshi, Omori Koichi, Kishimoto Yo
Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Otolaryngology, Kyoto Katsura Hospital, Kyoto, Japan.
Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Am J Pathol. 2022 May;192(5):771-782. doi: 10.1016/j.ajpath.2022.02.002. Epub 2022 Feb 19.
Macrophages aid in wound healing by changing their phenotype and can be a key driver of fibrosis. However, the contribution of macrophage phenotype to fibrosis following vocal fold injury remains unclear. Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed mainly by macrophages during early wound healing and regulates the macrophage phenotype. This study aimed to evaluate the effects of pioglitazone (PIO), a PPARγ agonist, on the macrophage phenotype and fibrosis following vocal fold injury in rats. PIO was injected into the rat vocal folds on days 1, 3, 5, and 7 after injury, and the vocal fold lamina propria was evaluated on days 4 and 56 after injury. Moreover, THP-1-derived macrophages were treated with PIO, and the expression of proinflammatory cytokines under lipopolysaccharide/interferon-γ stimulation was analyzed. PIO reduced the expression of Ccl2 both in vivo and in vitro. Furthermore, PIO decreased the density of inducible nitric oxide synthase CD68 macrophages and inhibited the expression of fibrosis-related factors on day 4 after injury. On day 56 after injury, PIO inhibited fibrosis, tissue contracture, and hyaluronic acid loss in a PPARγ-dependent manner. These results indicate that PPARγ activation could inhibit accumulation of inflammatory macrophages and improve tissue repair. Taken together, these findings imply that inflammatory macrophages play a key role in vocal fold fibrosis.
巨噬细胞通过改变其表型来协助伤口愈合，并且可能是纤维化的关键驱动因素。然而，巨噬细胞表型对声带损伤后纤维化的作用仍不清楚。过氧化物酶体增殖物激活受体γ（PPARγ）在伤口愈合早期主要由巨噬细胞表达，并调节巨噬细胞表型。本研究旨在评估PPARγ激动剂吡格列酮（PIO）对大鼠声带损伤后巨噬细胞表型和纤维化的影响。在损伤后第1、3、5和7天向大鼠声带注射PIO，并在损伤后第4天和第56天评估声带固有层。此外，用PIO处理THP-1衍生的巨噬细胞，并分析脂多糖/干扰素-γ刺激下促炎细胞因子的表达。PIO在体内和体外均降低了Ccl2的表达。此外，PIO在损伤后第4天降低了诱导型一氧化氮合酶CD68巨噬细胞的密度，并抑制了纤维化相关因子的表达。在损伤后第56天，PIO以PPARγ依赖的方式抑制纤维化、组织挛缩和透明质酸丢失。这些结果表明，PPARγ激活可抑制炎性巨噬细胞的积累并改善组织修复。综上所述，这些发现意味着炎性巨噬细胞在声带纤维化中起关键作用。
