Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

Abstract

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Keywords: HO-1 deficiency; heme oxygenase; inflammation; oxidative stress.

Figure 1

Heme oxygenase (HO)-1 and the heme degradation pathway. Free hemoglobin (Hb) quickly binds with haptoglobin (Hp) to form a molecular complex (Hb-Hp). Hb-Hp is rapidly incorporated through the scavenger receptor, now known as CD163, expressed on the cell surface of tissue macrophages such as hepatic Kupffer cells. Heme derived from Hb is degraded by HO-1 into free iron (Fe⁺⁺), carbon monoxide (CO) and biliverdin. Biliverdin is further degraded into bilirubin by biliverdin reductase. All these heme degradation products are known to exert potent anti-inflammatory and anti-oxidative stress functions, which in turn play significant roles in preventing various chronic diseases.

Figure 2

Serum characteristics of HO-1 deficiency. Patient serum separated immediately after blood drawing is characterized by a turbid, dark-brown color (A). Fresh hemolysate of the patient’s erythrocytes shows only the peaks of oxyhemoglobin (OxyHb) (B). Absorption spectrum of the patient’s serum reveals inclusion of large amounts of both OxyHb and methemoglobin (MetHb) (C).

Figure 3

Proposed mechanism of MetHb accumulation in blood. Under normal conditions, small amounts of Hb derived from hemolysis are rapidly bound by circulating Hp, forming Hb-Hp complexes, which are rapidly taken up by the liver through CD163 (A). When massive hemolysis occurs, as in the case of hemolytic anemia, large amounts of free Hb are bound by serum Hp and transferred to the liver (B). This results in a significant reduction of serum Hp and increased indirect bilirubin (Bil) derived from the heme degradation pathway. In HO-1-deficient patients, both OxyHb and MetHb bound to Hp accumulate within the serum. Despite the apparent intravascular hemolysis, total Hp content is significantly increased, serum bilirubin level remains low, and overflow of Hb-Hp complex into the urine is seen (C).

Figure 4

HO-1 deficiency and splenic development. In human cases of HO-1 deficiency with mutations found in Japan and India, the patients were found to be asplenic, presumably reflecting intrauterine defects in splenic development. In mouse models of HO-1 deficiency and human cases with mutations found in Turkey and Iran, the spleens showed transient splenomegaly followed by progressive atrophy after birth.

Figure 5

HO-1 deficiency and oxidative stress. Pathogen-associated molecular patterns (PAMPs) bind toll-like receptors (TLRs) on vascular endothelial cells or monocytes. Lack of HO-1 results in unregulated activation of macrophages with excess release of inflammatory cytokines. Hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) may result. At the same time, HO-1 deficiency results in overproduction of tissue factors by endothelial cells, leading to abnormal activation of the coagulation/fibrinolysis system, and disseminated intravascular coagulation (DIC). Prolonged and sustained activation of monocytes, platelets and endothelial cells leads to exhaustion and dysfunction of these cells.