Heme Oxygenase, Inflammation, and Fibrosis: The Good, the Bad, and the Ugly?

Abstract

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.

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

“…The protective role of the HO/CO system has been reported in several disease conditions, including diabetes, heart disease, hypertension, neurological disorders (Alzheimer's disease) and endotoxemia as well as organ transplantation, fibrosis and inflammation [11,36,37]. There have also been some studies that support a protective role of HO-1 against the development of some types of cancers, i.e.…”

“…Thus, HO-1 appears to play a critical role in normal cellular function in both laboratory animals and humans, largely due to conversion of a toxic molecule, heme, to cytoprotective molecules. The pro-oxidative, pro-inflammatory effects of excess free heme, which lead to fibrotic events, can be countered by its degradation by the HO system as well as the cytoprotective and anti-inflammatory effects of its by-products-namely CO, biliverdin (bilirubin) and Fe 2þ -making them novel targets to alleviate tissue inflammation, oxidative stress and fibrosis (reviewed in [11]). Endogenously formed CO, of which the HO system produces approximately 85 per cent, has been shown to be an important gasotransmitter, with a regulatory role in a variety of cellular functions, including anti-inflammatory, & 2012 The Author(s) Published by the Royal Society.…”

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

“…Its role in preventing excessive and prolonged inflammation after wounding has already been studied (20,(89)(90)(91). Although the HO-1 system has been shown to prevent inflammation in the liver under several pathological conditions (36), the actual mechanism behind the anti-inflammatory and cytoprotective actions of HO-1 is still not very clear.…”

The role of bile pigments in health and disease: effects on cell signaling, cytotoxicity and cytoprotection

“…The topic is discussed by leading experts in the field of bile pigments, and presented in 15 Reviews, 3 Original Research articles and 1 Opinion article. It covers important aspects related to the enzymes involved in the heme catabolic pathway: the role of heme oxygenase in inflammation and fibrosis (Lundvig et al, 2012) as well as in atherosclerosis (Araujo et al, 2012) and immune-mediated inflammatory diseases (Larsen et al, 2012), the regulation of cell signaling by biliverdin reductase and its peptide fragments (Gibbs et al, 2012), and the regulation of bilirubin clearance (Bock, 2011).…”