Pirfenidone suppresses keloid fibroblast-embedded collagen gel contraction

Abstract

Keloid is a clinically intractable disease that causes disfigurement, itching, and pain due to abnormal proliferation of fibroblasts and production of collagen. Pirfenidone is a novel anti-fibrotic agent that inhibits the progression of fibrosis occurring in the keloid lesions of the lung and kidney. In order to examine whether pirfenidone has a therapeutic effect on keloid lesions, we prepared an in vitro wound contraction model with keloid fibroblasts. The gel contractility of a mixture of keloid fibroblasts and an acid-soluble collagen solution was examined with/without transforming growth factor (TGF)-β1 in the presence or absence of pirfenidone. Real time RT-PCR was performed to detect mRNA expression of TGFB1, CTGF, aSMA, and Col1A1 quantitatively in keloid fibroblasts incubated with/without TGF-β1 in the presence or absence of pirfenidone. The contractility of keloid fibroblast-embedded collagen gel was increased after the addition of TGF-β1. Pirfenidone suppressed gel contraction with TGF-β1 dose dependently. TGF-β1 stimulated mRNA expression of TGFB1, CTGF, aSMA, and Col1A1 in keloid fibroblasts, while pirfenidone significantly inhibited mRNA expression of CTGF and aSMA in the identical cells. These findings suggest that pirfenidone suppresses the contraction of keloid-derived fibroblasts by inhibiting the down-stream pathway of TGF-β1, thus demonstrating its therapeutic utility for the treatment of keloid lesions.

Anti-Fibrotic Actions of Interleukin-10 against Hypertrophic Scarring by Activation of PI3K/AKT and STAT3 Signaling Pathways in Scar-Forming Fibroblasts

“…Currently, there is no effective therapy for HS, largely because the underlying mechanisms of HS development are poorly understood [7], [8]. IL-10 has recently been identified as a promising new therapeutic agent that can reduce HS [16]–[19].…”

“…The incidence of HS ranges from 40–70% following surgery, and up to 91% following burn injury [7]. However, there is currently no effective therapy for HS, in part because the underlying mechanisms of HS progression are poorly understood [7], [8].…”

Strategy for treatment of fibrosis in systemic sclerosis: Present and future

“…Pirfenidone, a pyridine with a simple chemical structure, is an antifibrotic agent, and has been approved for the treatment of idiopathic pulmonary fibrosis worldwide . Pirfenidone inhibits the production of profibrotic cytokines, including TGF‐β1 and platelet‐derived growth factor, leading to attenuated collagen deposition . Moreover, pirfenidone has also been shown to suppress pro‐inflammatory cytokine production, such as that of tumor necrosis factor‐α, IL‐1β and IL‐6 .…”

“…85 Pirfenidone inhibits the production of profibrotic cytokines, including TGF-b1 and platelet-derived growth factor, leading to attenuated collagen deposition. 85,86 Moreover, pirfenidone has also been shown to suppress pro-inflammatory cytokine production, such as that of tumor necrosis factor-a, IL-1b and IL-6. 85 In experimental models, pirfenidone has been shown to inhibit the progression of fibrosis in the lung 87,88 and liver.…”

Effect of pirfenidone injection on ferret vocal fold scars: A preliminary in vivo study

“…Earlier studies describing TGF-β blockade by PFD, inhibiting fibroblast-to-myofibroblast differentiation, may support this suggestion. [30][31][32] The positive effects of PFD on the scarred LP reflect effective delivery, a long duration of action, and drug migration into tissue layers between the LP and muscle, as demonstrated (using ink) in our previous article. 17 The localization of PFD to, and drug duration in, the targeted layer (that between the deep LP and muscle adjunct to scar tissue) are critical.…”