Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease

doi:10.1016/j.freeradbiomed.2009.04.007

Free Radical Biology and Medicine

Volume 47, Issue 1, 1 July 2009, Pages 1-12

https://doi.org/10.1016/j.freeradbiomed.2009.04.007 Get rights and content

Abstract

Increases in cell death by programmed (i.e., apoptosis, autophagy) or nonprogrammed mechanisms (i.e., necrosis) occur during tissue injury and may contribute to the etiology of several pulmonary or vascular disease states. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXα, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen-activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-κB, phosphatidylinositol 3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.

Introduction

Heme oxygenase-1 (HO-1) provides an inducible defense mechanism that can be activated ubiquitously in cells and tissues in response to noxious stimuli, conferring cellular protection against injury inflicted by such stimuli [1], [2], [3]. HO-1 serves a vital metabolic function as the rate-limiting step in the oxidative catabolism of heme-b, to generate equimolar carbon monoxide (CO), biliverdin-IXα (BV), and ferrous iron; the BV generated is subsequently converted to bilirubin-IXα (BR) by NADPH biliverdin reductase (BVR) [4]. The essential role of HO-1 in stress adaptation has been demonstrated by the phenotype of ho-1^−/− (null) mice and in a unique case of human HO-1 deficiency. The ho-1^−/− mice exhibit altered tissue iron distribution, increased susceptibility to pulmonary ischemia/reperfusion (I/R) injury, but paradoxical resistance to hyperoxic lung injury [5], [6], [7], [8]. The HO-1-deficient child exhibits extensive endothelial cell damage, anemia, hyperbilirubinemia, aberrant tissue iron deposition, and increased inflammatory indices [9]. Furthermore, vascular endothelial cells derived from ho-1^−/− mice or the HO-1-deficient child exhibit enhanced susceptibility to oxidative stress in vitro [6], [9].

HO-1 expression can confer cytoprotection in many lung and vascular injury and disease models [1], [2], [3]. The cytoprotective effects of HO-1 are related to end-product formation (Fig. 1) [1], [10], [11], though noncatalytic functions of the protein have also been proposed [12]. The pharmacological application of CO and BV/BR can mimic the HO-1-dependent cytoprotection in many injury models [1], [10], [11]. Tissue protection generally involves inhibition of apoptosis and related cell death pathways, although inhibition of inflammation and/or cell proliferation may also be involved, depending on the specific injury model [1]. In recent years, intensive investigation has focused on potential therapeutic tools to manipulate apoptosis to alter the outcome of pulmonary or vascular diseases. Such approaches have involved the use of agonists or inhibitors of specific signal transduction components (e.g., mitogen-activated protein kinases, or MAPK) or antioxidants, thus far with limited clinical efficacy [13], [14]. In this regard, the targeted manipulation of HO-1 or of its end-products remains a promising experimental and translational strategy. This review will focus on the role of HO-1/CO in modulating cell death mechanisms in tissue injury and pathology models. The specific roles of HO-1 in inflammation and carcinogenesis have been reviewed elsewhere [15], [16]. Recent work examining the therapeutic potential of HO-1/CO in models of oxidative stress, I/R injury, cigarette smoke exposure, and other forms of acute and chronic lung or vascular injuries will be described.

Section snippets

Mechanisms of cell death

Just like the multicellular organisms they constitute, cells must die. The method of cell death may be traumatic, resulting from acute, accidental, or nonphysiological injury (i.e., necrosis), or may arise as the consequence of genetic programs (i.e., apoptosis or Type I programmed cell death). Apoptosis provides essential homeostatic functions in regulating growth and development of organs and in tissue responses to injurious stimuli, such as exposure to xenobiotics or adverse environmental

Heme oxygenase-1: biochemical properties and subcellular localization

HO-1, the inducible HO isozyme, is the major inducible low-molecular-weight (32–34 kDa) stress protein of mammalian cells and tissues [46]. Heme oxygenase has a major constitutively expressed isozyme, heme oxygenase-2 (HO-2) [47]. HO-1 and HO-2 represent the products of two distinct genes [48]. Although HO-1 and HO-2 both catalyze heme-b to biliverdin, the two enzymes differ in primary structure and biochemical/biophysical properties [48], [49]. A highly conserved sequence of 24 amino acid

Regulation of HO-1 transcription

The transcriptional upregulation of the ho-1 gene, and subsequent de novo synthesis of the corresponding protein, occurs in response to elevated levels of its natural substrate heme and to a multiplicity of endogenous factors including NO, cytokines, heavy metals, hormones, and growth factors (reviewed in [1]). Many agents that induce HO-1 are associated with oxidative stress in that they (i) directly or indirectly promote the intracellular generation of reactive oxygen species (ROS), (ii) fall

Cytokine-mediated apoptosis

The antiapoptotic effects of CO were originally described in vitro, and several potential mechanisms were implicated. Exogenous CO was shown to inhibit tumor necrosis factor-α (TNFα)-initiated apoptosis in mouse fibroblasts [118] and endothelial cells [119]. In fibroblasts, an antiapoptotic effect was also observed with HO-1 overexpression [118]. In endothelial cells, the inhibitory effect of CO on TNFα-induced apoptosis could be abolished with the selective p38α/β MAPK inhibitor SB203580 or a

HO-1 in cytoprotection against cigarette smoke-induced cell death

Cigarette smoke contains over 4500 distinct chemical species. Because CS contains ROS, NO, and other free radicals; electrophilic substances; and heavy metals, and furthermore can trigger the intracellular production of ROS and deplete natural antioxidants, it is generally regarded as an oxidative cellular stress [135]. Whereas animals in inhalation studies are typically exposed to mainstream or side-stream CS, cell culture studies typically utilize aqueous cigarette smoke extract (CSE) [136].

Endoplasmic reticulum stress

The ER is a vital organelle involved in the protein secretory pathway and lipid biosynthesis. Various stress conditions, including alterations in intracellular calcium homeostasis, inhibition of protein glycosylation, and/or accumulation of misfolded proteins, can induce an ER stress response, characterized by increased synthesis of ER stress proteins. Excessive ER stress and ER dysfunction can promote apoptotic cell death through the activation of caspases (i.e., caspase-12, -9, -8) [145],

Role of biliverdin/bilirubin in cytoprotection

The bile pigments BV and BR, generated from the action of HO and BVR, respectively, have also been implicated in both toxicity and cytoprotection, depending on the dose and model system. The overproduction of BR in neonates is neurotoxic; thus strategies to remove BR (phototherapy) or inhibit its formation (competitive inhibitors of HO activity) are implemented clinically. BV and BR have been demonstrated to have antioxidant properties in in vitro model systems, which include the inhibition of

Role of iron in cytotoxicity and protection

Despite the essential requirement for iron in various cellular processes, such as heme synthesis, DNA replication, mitochondrial function, and oxygen sensing, iron potentially poses a toxic insult to cells by catalyzing free radical-generating reactions. Iron loading sensitizes endothelial cells to oxidant-mediated cell killing [158]. On the other hand, complete deprivation of iron leads to apoptosis, as shown by proapoptotic effects of metal chelator treatments, suggesting that at least a

Pulmonary I/R

Pulmonary I/R caused by temporal clamping of the pulmonary artery induced the biochemical features of apoptosis in rodent lungs, including increased expression of Fas and FasL, activation of caspases (-3, -8, -9), modulation of Bcl2-related proteins, PARP cleavage, and Cyt-c release [132]. The protective effect of CO pretreatment on mice subjected to lung I/R injury in vivo was associated with the inhibition of apoptosis markers, including caspase-3 activation, and depended on activation of

Conclusions

There now exists ample evidence that the HO-1 system, as well as the pharmacological application of HO pathway end-products, provides robust protection against cellular stress. Although considerable progress has been made in defining the therapeutic potential of HO-1 in vitro and in preclinical models of organ injury and disease, the clinical benefit of therapies involving HO-1 has yet to be demonstrated in humans. Of the preclinical disease models exploring medical applications for HO-1,

Acknowledgments

This work was supported in part by NIH Grant P01-HL70807 (A.M.K. Choi and S. Ryter) and by R01-HL60234, R01-HL55330, and R01-HL079904, awarded to A.M.K. Choi.

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Review ArticleHeme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease

Abstract

Introduction

Section snippets

Mechanisms of cell death

Heme oxygenase-1: biochemical properties and subcellular localization

Regulation of HO-1 transcription

Cytokine-mediated apoptosis

HO-1 in cytoprotection against cigarette smoke-induced cell death

Endoplasmic reticulum stress

Role of biliverdin/bilirubin in cytoprotection

Role of iron in cytotoxicity and protection

Pulmonary I/R

Conclusions

Acknowledgments

J. Biol. Chem.

Free Radic. Biol. Med.

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Blood

Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications

Physiol. Rev.

Heme oxygenase-1: the "emerging molecule" has arrived

Am. J. Respir. Cell Mol. Biol.

Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance

Mol. Cell. Biochem.

Heme oxygenase-1 is required for mammalian iron reutilization

Proc. Natl. Acad. Sci. USA

Reduced stress defense in heme oxygenase-1 deficient cells

Proc. Natl. Acad. Sci. USA

Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis

Nat. Med.

Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency

J. Clin. Invest.

Protective functions of heme oxygenase-1 and carbon monoxide in the respiratory system

Antioxid. Redox Signal.

Carbon monoxide and bilirubin: potential therapies for pulmonary/vascular injury and disease

Am. J. Respir. Cell Mol. Biol.

Emerging role of MAP kinase pathways as therapeutic targets in COPD

Int. J. Chronic Obstruct. Pulm. Dis.

Heme oxygenase-1 in tumors: is it a false friend?

Antioxid. Redox Signal.

Cell death modalities: classification and pathophysiological implications

Cell Death Differ.

Autoimmunity and apoptosis-therapeutic implications

Curr. Med. Chem.

Functional significance of apoptosis in chronic obstructive pulmonary disease

COPD

Mechanisms of cell death in oxidative stress

Antioxid. Redox Signal.

Evolving concepts of apoptosis in idiopathic pulmonary fibrosis

Proc. Am. Thorac. Soc.

Heme oxygenase-1 in organ transplantation

Review Article
Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease