Peroxisome Proliferator-Activated Receptor-γ Agonist Attenuates Vocal Fold Fibrosis in Rats via Regulation of Macrophage Activation

Abstract

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.