BRD4 Is A Novel Therapeutic Target For Hypertropic Scar

Background and ObjectiveWound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue.There are two commonly clinical types of excessive scaring,hypertrophic and keloid scar secondary to burn injuries,traumatic injuries and surgical procedures.Hypertropic scar represent the most common complication of skin injury and are caused by excessive cutaneous wound healing characterized by hypervascularity and pathological deposition of extracellular matrix(ECM)components.Hypertrophic scars are also associated with contractures and hypervascularity that may lead to considerably reduced functional performance and erythematous appearances in patients.Consequently,hypertrophic scars cause significant abnormality in aesthetic and functional symptoms.Scar produces significant morbidity through pruritis,compression,anatomic deformity and decreased joint mobility for which few effective treatments are available.Consequently,there is a need to understand molecular mechanisms involved in scar formation to modify the repair process and prevent these adverse outcomes.BRD4(bromodomain containing protein 4),the principal readers of acetylation marks on histones,is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways,where BRD4 is colocalized with profibrotic transcription factors.JQ1,a small molecule inhibitor of BRD4,not only inhibits tumor growth but prevents fibrotic diseases.Pharmacological intervention however,has not been discovered for hypertropic scar.To investigate the effect of BRD4 inhibitor JQ-1 on hypertropic scar and relevant mechanisms.Methods 1.The experiments in vitro to assess the effects of JQ-1 on fibroblasts from human hypertrophic scar development: Primary fibroblasts were isolated from human hypertrophic tissue and treated by JQ-1 of different concentrations(0,0.1,0.5,1,2,2.5,12.5?mol/l)for 48 hours to the third passage.Then CCK-8 and wound healing assay were used to measure the proliferation and migration of the fibroblasts.ELISA was adopted to detect the secretion of collagen of type I and III of fibroblasts treated by JQ-1 at different time points(6,12,24,48h).Concentration TGF-?1 in fibroblasts treated by JQ-1 was detected by ELISA.2.The experiments in vivo to assess the effects of JQ-1 on hypertrophic scar development: Thirty-two nude mice were used for hypertrophic scar models.Human hypertrophic scar(1.0cm*1.0cm*0.5cm)was grafted at dorsa of Thirty-six nude mice to establish scar animal models.Then random allocation was taken to averagely divided those nude mice into two groups:JQ-1(injected with 0.5?mol/l JQ-1 after the model successfully for three weeks)and DMSO(injected with 0.1%DMSO as indicated).Collagen of type ? ? and ?-SMA were examined by immunohistoche-michemical method.Results JQ-1 dramatically inhibited fibroblasts dose-dependent proliferation and the cell migration;0.5 ?mol/l JQ-1 induced secretion and concentration of Collagen of type I ?III and TGF-?1 of fibroblasts;In vivo,concentration of Collagen of type ??? and ?-SMA in groups of JQ-1 were induced by immunohistochemichemical method.Conclusion JQ-1,inhibitor of BRD4,can inhibit the proliferation and migration of the scar fibroblasts;JQ-1 inhibit the function and secretion of scar fibroblasts;BRD4 is a novel therapeutic target for hypertrophic scar.