Pirfenidone (PFD) is a synthetic small molecule inhibitor with demonstrated anti-inflammatory and antifibrotic properties in vitro and in vivo. The exact mechanism(s) of PFD action remain unclear, due in part to the broad effects of this drug on the complex processes involved in inflammation and fibrosis. While PFD is FDA-approved for the treatment of idiopathic pulmonary fibrosis, the efficacy of this compound for the treatment of dermal fibrosis has not yet been fully characterized. Dermal fibrosis is the pathological formation of excess fibrous connective tissue of the skin, usually the result of traumatic cutaneous injury. Fibroproliferative scarring, caused by delayed wound healing and prolonged inflammation, remains a major clinical concern with considerable morbidity. Despite efforts to identify a therapeutic that targets the fibrotic pathways involved in wound healing to mitigate scar formation, no satisfactory dermal antifibrotic has yet been identified. We aim to better elucidate the antifibrotic mechanism(s) of PFD activity using an in vitro model of dermal fibrosis. Briefly, cultured human dermal fibroblasts were stimulated with TGF-β1 to induce differentiation into profibrotic myofibroblast cells. A dose-dependent reduction in cellular proliferation and migration was observed in TGF-β1-stimulated cells when treated with PFD. We observed a clear inhibition in the development of essential myofibroblast mechanoregulatory machinery, including contractile F-actin stress fibers containing α-SMA and large super-mature focal adhesions. PFD treatment significantly reduced protein levels of major ECM components type I and type III collagen. PFD targeted the p38 MAPK signaling pathway and mitigated profibrotic gene expression profiles. This in vitro data promotes PFD as a potential therapeutic agent for the treatment of dermal fibrosis.

Burn injuries are a pervasive clinical problem. Extensive thermal trauma can be life-threatening or result in long-lasting complications, generating a significant impact on quality of life for patients as well as a cost burden to the healthcare system. The importance of addressing global or systemic issues such as resuscitation and management of inhalation injuries is not disputed but is beyond the scope of this review, which focuses on cutaneous pathophysiologic mechanisms for current treatments, both in the acute and long-term settings. Pathophysiological mechanisms of burn progression and wound healing are mediated by highly complex cascades of cellular and biochemical events, which become dysregulated in slow-healing wounds such as burns. Burns can result in fibroproliferative scarring, skin contractures, or chronic wounds that take weeks or months to heal. Burn injuries are highly individualized owing to wound-specific differences such as burn depth and surface area, in addition to patient-specific factors including genetics, immune competency, and age. Other extrinsic complications such as microbial infection can complicate wound healing, resulting in prolonged inflammation and delayed re-epithelialization. Although mortality is decreasing with advancements in burn care, morbidity from postburn deformities continues to be a challenge. Optimizing specialized acute care and late burn outcome intervention on a patient-by-patient basis is critical for successful management of burn wounds and the associated pathological scar outcome. Understanding the fundamentals of integument physiology and the cellular processes involved in wound healing is essential for designing effective treatment strategies for burn wound care as well as development of future therapies. Published 2018. Compr Physiol 8:371-405, 2018.