Editorial [Hot Topic: Therapeutic Applications of the Heme Oxygenase System (Guest Editor:Stephan Immenschuh)]

The heme oxygenase (HO) enzyme reaction has initially been described more that 40 years ago [1]. HO catalyzes the degradation of the redox-reactive molecule heme into equimolar amounts of bilirubin, carbon monoxide (CO) and iron. Two genetically distinct isozymes of HO, HO-1 and HO-2, have been identified and exhibit distinct patterns of cell- and tissue- specific gene expression. In contrast to the constitutive isoform HO-2, which is mainly found in brain and testis [2], the inducible isoform HO-1 is expressed in almost all cells and tissues and is up-regulated by its substrate heme and a wide variety of oxidative stress stimuli. Up-regulation of HO-1 has therefore been considered for many years as a general antioxidant protective response against unfavourable cellular conditions including, but not limited to oxidative stress. Major advances in understanding the wide-ranging physiological functions of HO-1 have been made in studies on HO-1 knockout mouse models [3]. Such studies not only confirmed the antioxidant cytoprotective role of HO-1, but also provided evidence that HO-1 has major anti-inflammatory and immunomodulatory effects. Importantly, phenotypical alterations in the so far only known human case of genetic HO-1 deficiency were highly similar to those observed in HO-1 knockout mice [4]. Further insights into the cell type- and cell context-specific functions of HO-1 have recently been given in a mouse model, in which the HO-1 gene has been specifically deleted in myeloid cells. Animals with myeloid HO-1 deficiency exhibited a defect of the early innate immune response and an exacerbated phenotype of an experimental autoimmune disease [5]. Future experimental approaches along this line might help to further elucidate the anti-inflammatory functions of HO-1, as HO-1 appears to be crucially involved in the regulatory mechanisms that link various forms of cellular stress (endoplasmic reticulum stress and oxidative stress) with the pathogenesis of inflammatory diseases [6, 7]. In addition to the advances in understanding principal biological functions of HO-1, this enzyme has attracted major attention in recent years as a therapeutic target [8]. A rapidly growing body of evidence has demonstrated that specific induction of HO-1 may provide novel therapeutic options for the treatment of multiple experimental disease models ranging from inflammatory disorders to transplantation and cancer. This Special Issue Edition of Current Drug Targets on Therapeutic Applications of the Heme Oxygenase System deals with pertinent aspects on the basic physiological functions of HO-1, in particular how the HO system and its products are specifically involved in controlling the physiological homeostasis of different organs and organ systems (e.g. lung, liver, cardiovascular system and central nervous system). Moreover, current concepts will be discussed that show how targeted modulation of HO-1 may be applicable for specific therapeutic interventions in various disease entities (e.g. neurodegenerative disease, atherosclerosis, sepsis, cancer and wound healing). Finally, emerging roles of the bilirubin producing enzyme biliverdin reductase and that of synthetic CO-releasing molecules (CORMs), which may release the gaseous HO product CO for therapeutic purposes, are addressed in more detail. In conclusion, although HO-1 and its products have raised many expectations for the development of novel pharmacological compounds, critical questions remain to be answered before targeted interventions might be available for clinical applications.