Lundvig Ditte M S, Immenschuh Stephan, Wagener Frank A D T G
Department of Orthodontics and Craniofacial Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre Nijmegen, Netherlands.
Front Pharmacol. 2012 May 7;3:81. doi: 10.3389/fphar.2012.00081. eCollection 2012.
Upon injury, prolonged inflammation and oxidative stress may cause pathological wound healing and fibrosis, leading to formation of excessive scar tissue. Fibrogenesis can occur in most organs and tissues and may ultimately lead to organ dysfunction and failure. The underlying mechanisms of pathological wound healing still remain unclear, and are considered to be multifactorial, but so far, no efficient anti-fibrotic therapies exist. Extra- and intracellular levels of free heme may be increased in a variety of pathological conditions due to release from hemoproteins. Free heme possesses pro-inflammatory and oxidative properties, and may act as a danger signal. Effects of free heme may be counteracted by heme-binding proteins or by heme degradation. Heme is degraded by heme oxygenase (HO) that exists as two isoforms: inducible HO-1 and constitutively expressed HO-2. HO generates the effector molecules biliverdin/bilirubin, carbon monoxide, and free iron/ferritin. HO deficiency in mouse and man leads to exaggerated inflammation following mild insults, and accumulating epidemiological and preclinical studies support the widely recognized notion of the cytoprotective, anti-oxidative, and anti-inflammatory effects of the activity of the HO system and its effector molecules. In this review, we address the potential effects of targeted HO-1 induction or administration of HO-effector molecules as therapeutic targets in fibrotic conditions to counteract inflammatory and oxidative insults. This is exemplified by various clinically relevant conditions, such as hypertrophic scarring, chronic inflammatory liver disease, chronic pancreatitis, and chronic graft rejection in transplantation.
受伤后，长期的炎症和氧化应激可能导致病理性伤口愈合和纤维化，进而形成过多的瘢痕组织。纤维化可发生于大多数器官和组织，最终可能导致器官功能障碍和衰竭。病理性伤口愈合的潜在机制仍不清楚，被认为是多因素的，但到目前为止，尚无有效的抗纤维化治疗方法。在各种病理状态下，由于血红蛋白释放，细胞外和细胞内的游离血红素水平可能会升高。游离血红素具有促炎和氧化特性，可能作为一种危险信号。游离血红素的作用可能被血红素结合蛋白或血红素降解所抵消。血红素由血红素加氧酶（HO）降解，该酶有两种同工型：诱导型HO-1和组成型表达的HO-2。HO产生效应分子胆绿素/胆红素、一氧化碳和游离铁/铁蛋白。小鼠和人类中HO缺乏会导致轻度损伤后炎症反应加剧，越来越多的流行病学和临床前研究支持了HO系统及其效应分子活性具有细胞保护、抗氧化和抗炎作用这一广泛认可的观点。在本综述中，我们探讨了靶向诱导HO-1或给予HO效应分子作为纤维化疾病治疗靶点以对抗炎症和氧化损伤的潜在作用。这通过各种临床相关疾病得以例证，如肥厚性瘢痕、慢性炎症性肝病、慢性胰腺炎和移植中的慢性移植物排斥反应。
