INVITED REVIEW
Heme oxygenase: colors of defense against cellular stress

Leo E. Otterbein1 and Augustine M. K. Choi1,2

1 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and 2 Division of Pulmonary and Care Medicine, Yale University, New Haven, Connecticut 06520


    ABSTRACT
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
HO-1 EXPRESSION IN THE...
CONCLUSIONS
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The discovery of the gaseous molecule nitric oxide in 1987 unraveled investigations on its functional role in the pathogenesis of a wide spectrum of biological and pathological processes. At that time, the novel concept that an endogenous production of a gaseous substance such as nitric oxide can impart such diverse and potent cellular effects proved to be very fruitful in enhancing our understanding of many disease processes including lung disorders. Interestingly, we have known for a longer period of time that there exists another gaseous molecule that is also generated endogenously; the heme oxygenase (HO) enzyme system generates the majority if not all of the endogenously produced carbon monoxide. This enzyme system also liberates two other by-products, bilirubin and ferritin, each possessing important biological functions and helping to define the uniqueness of the HO enzyme system. In recent years, interest in HO has emerged in numerous disciplines including the central nervous system, cardiovascular physiology, renal and hepatic systems, and transplantation. We review the functional role of HO in lung biology and its real potential application to lung diseases.

carbon monoxide; oxidative stress; acute lung injury; stress response genes


    INTRODUCTION
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
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CONCLUSIONS
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OVER ONE HUNDRED AND FIFTY YEARS AGO, a scientist by the name of Virchow (106) recognized that there was an association between hemoglobin breakdown and biliverdin. It was not until 1926, however, that this association was more formally established by Mann et al. (56). But certainly the manifestations of this metabolic process were recognized hundreds if not thousands of years earlier because the catabolism of heme is the only biological process in humans that is colorimetric. After receiving a blow to the skin, primitive man would have observed shortly thereafter a bruise that was black or purple. These are colors of heme, released into the dermis from pulverized erythrocytes. The black hue (heme) gradually transformed to green, the color of biliverdin, and finally to yellow, the color of bilirubin, the concluding product of this elegant enzymatic reaction. To this day, investigators have been intrigued by the role of this end product as well as that of ferritin, the iron storage protein in the cell induced by the release of free iron and carbon monoxide (CO) and released in equimolar concentrations as heme anabolism transpires (see Fig. 1).


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Fig. 1.   Enzymatic reaction of heme oxygenase. CO, carbon monoxide.


    HEME OXYGENASE
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
HO-1 EXPRESSION IN THE...
CONCLUSIONS
REFERENCES

Heme oxygenase (HO) was originally identified in 1968 and 1969 by Tenhunen et al. (100, 101) in seminal papers where they characterized the enzyme HO as well as its cellular localization. HO catalyzes the first and rate-limiting step in the degradation of heme. Via oxidation, HO cleaves the alpha -meso carbon bridge of b-type heme molecules to yield equimolar quantities of biliverdin IXa, CO, and free iron. Biliverdin is subsequently converted to bilirubin via the action of biliverdin reductase, and free iron is promptly sequestered into ferritin. To date, three isoforms (HO-1, HO-2, and HO-3) that catalyze this reaction have been identified (1, 54, 60, 61). HO-1 is a 32-kDa protein that is inducible by numerous stimuli (Table 1) and is the principal focus of this review. HO-2 is, for the most part, a constitutively synthesized 36-kDa protein existing primarily in the brain and testes. HO-3, a recently cloned gene product 33 kDa in size, also catalyzes heme degradation but much less than HO-2. Under physiological conditions, HO activity is highest in the spleen where senescent erythrocytes are sequestered and destroyed, but its activity has also been observed in all systemic organs.

                              
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Table 1.   Conditions that induce heme oxygenase-1

Although heme is the typical HO-1 inducer, studies by Keyse and Tyrrell (41), Maeshima et al. (53), and Vile and Tyrrell (105) demonstrated that HO enzyme activity could also be stimulated by a variety of nonheme products including ultraviolet irradiation, endotoxin, heavy metals, and oxidants such as hydrogen peroxide. One common feature of these inducers is their capacity to generate reactive oxygen species. Thus these studies not only demonstrated that HO-1 can be induced by agents causing oxidative stress but also supported the speculation that HO-1 can function as a cytoprotective molecule against oxidative stress. Indeed, ample evidence currently supports the notion that HO-1 serves to provide potent cytoprotective effects in many in vitro and in vivo models of oxidant-induced cellular and tissue injury.


    INDUCTION OF HO-1 EXPRESSION
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
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CONCLUSIONS
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Table 1 illustrates a list of the agents that when administered to cells or animals result in an increase in HO-1 expression. The list represents a wide variety of nonheme inducers of this enzyme, the scope of such indexes giving rise to a fundamental question as to the functional role(s) of the increased levels of this ubiquitous enzyme.

Although the function of this enzyme is still incompletely understood, accumulating evidence to date strongly suggests that the endogenous induction of HO-1 provides potent cytoprotective effects in various in vitro and in vivo models of cellular and tissue injury (34, 75, 93). This evolving paradigm is further supported by observations made in the HO-1-deficient [HO-1(-/-)] mouse and human. Poss and Tonegawa (80, 81) in 1997 generated HO-1(-/-) mice by targeted deletion of the mouse HO-1 gene. The majority of these HO-1(-/-) mice do not survive to term, and the mice that do survive to adulthood are abnormal and die within one year of birth (80, 81). These adult mice exhibit growth retardation and normochromic, microcytic anemia. Kidneys and livers from these mice show evidence of iron deposition, and as these HO-1(-/-) mice age, they also demonstrate an increased presence of chronic inflammation characterized by hepatosplenomegaly, leukocytosis, glomerulonephritis, and hepatic periportal inflammation. These authors also reported that cells obtained from these mice are more susceptible to oxidative stress induced by endotoxin. A recent report (111) demonstrating the first identified case of a HO-1-deficient human patient lends additional support to the evolving paradigm that HO-1 serves to provide cytoprotection against oxidative stress. This patient exhibited similar phenotypic alterations as those observed in the HO-1(-/-) mice, including growth retardation, anemia, leukocytosis, and increased sensitivity to oxidant stress.

The critical importance of HO is also demonstrated by recent reports (47, 65) that HO expression is conserved evolutionarily. It has been detected in prokaryotic bacteria as well as in plants and fungi. This conservation suggests that HO may play a role in diverse species as a modulator of cellular homeostasis, serving not only to degrade heme but also, via one or more of its catabolic by-products, to regulate a variety of critical cellular processes. For example, in plants, it is believed that HO possesses dual functions, one that generates tetrapyrroles and another that recycles heme and chlorophylls, both being important after damage to the photoreactive centers (65). In most bacteria, iron is required for survival and is particularly essential for pathogens to cause disease. To circumvent the low concentration of free extracellular iron, pathogenic bacteria have developed sophisticated mechanisms by which to acquire iron from iron-containing proteins found in their hosts. One such mechanism exploits a bacterial heme degradation enzyme similar to HO (47). In contrast to the mammalian HO, the primary purpose of which is to maintain iron homeostasis, the purpose of the bacterial HO is to release iron from heme so that the iron may be immediately utilized. Such conservation among species that express and regulate this enzyme gives credence to the belief that HO is critically important in maintaining cellular homeostasis.

Table 2 illustrates a list of disease states that have been associated with the increased expression of HO-1. Most recently, Schipper et al. (87) have described the use of HO-1 expression as an indicator of cellular stress and injury. Plasma and cerebrospinal fluid samples collected from Alzheimer's patients were analyzed by ELISA for HO-1 induction and found to be elevated in the blood of pathologically confirmed Alzheimer's patients (87). Although oxidative stress has been well described as a potent inducer of HO-1, this study presented the first reported evidence that suggested that HO-1 expression can be used as a diagnostic tool to evaluate patients with this disease. Indeed, these authors proposed that HO-1 levels can be used as a biological marker to diagnose and monitor those with this disease. Investigators (37, 77) have reported using the detection of CO as a measurable marker in the exhaled breath of patients as an index of oxidative stress and inflammation. Bilirubin has also been used as a marker of liver injury and neonatal jaundice for years and continues to provide valuable information as a biological marker.

                              
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Table 2.   Pathological conditions associated with heme oxygenase-1


    MECHANISM(S) OF CYTOPROTECTION BY HO-1
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
HO-1 EXPRESSION IN THE...
CONCLUSIONS
REFERENCES

The increased expression of HO-1 levels in a variety of pathological states begs the question as to the functional role for this heme catalyzing enzyme. Keyse and Tyrrell (40, 41), followed shortly thereafter by Nath et al. (66), demonstrated in critical studies that HO-1 provided cytoprotection against oxidative stress, particularly if HO-1 was induced before the stress. These two studies prompted increased investigations of this enzyme in disorders that do not relate to heme catabolism. Ample evidence now strongly suggests that HO-1 can function as a critical cytoprotective molecule. The mechanism(s) by which HO-1 can mediate these cytoprotective functions is not clear. However, the three major catalytic by-products, CO, ferritin, and bilirubin may represent potential targets.

CO. CO is one of the most commonly encountered toxic agents because it interferes with O2 delivery to cells and tissues. It is, after carbon dioxide (CO2), the most abundant atmospheric pollutant, emanating slowly from natural sources such as volcanoes and forest fires but more rapidly and abundantly as a by-product of industrial and technological activity (e.g., the combustion engine). In 1857, Claude Bernard described the affinity of CO for hemoglobin, thus initiating research that eventuated in an essentially universal scientific tenet assigning CO to the category of poisons and toxins that later came to include arsenic, nicotine, and opium. Before this time, it was common practice in Europe to pacify infants by holding them over a fire where CO-induced cerebral anoxia could exert its sedating and soothing effects. Since Bernard's discovery of the CO-hemoglobin affinity, the particulars of that association as well as its lethal consequences have been well delineated. In 1927, Nicloux discovered a baseline carboxyhemoglobin level in dogs and concluded that CO originated in the body itself. A year earlier, in 1926, Campbell was already calling the gas a "poison," a label that over the years has become as essential and self-evident a feature of its conceptualization as its atomic structure. In 1972, Weinstock and Niki observed, with a palpable trace of ironic understatement: "Carbon monoxide may be the basis of energy metabolism in some extraterrestrial civilization. Certainly endogenous CO metabolism is of less importance to life on earth."

The dangers of CO have been well defined. By binding avidly to hemoglobin, it replaces O2, induces general hypoxia, increases the stability of oxyhemoglobin by shifting the dissociation curve to the left, and impedes O2 delivery to the tissues. Furthermore, dissociation of CO2 is impaired, thus producing an increase in blood CO2 levels and removing the reflex stimulus to the respiratory centers in the brain. In addition, because no change occurs in the dissolved O2 levels in the blood, the carotid sinus detects no disparity because it responds only to partial pressure; so it likewise sends no signals to the respiratory centers of the brain that would otherwise force the individual to breathe more often to increase the blood O2 levels.

Because of its strong affinity for hemoglobin, the primary toxic effect of CO is hypoxia or anoxia. Increases in combustion through the use of fossil fuels over the past century and consequent increases in CO levels in the atmosphere have heightened public awareness of exposure to this gas and its noxious potential. The Environmental Protection Agency via various media instills in the public mind a need to avoid this gas, recommending elaborate protective alarms and detectors and publishing allowable exposure limits. The number of studies investigating these issues, particularly those relating to the toxic effects of CO, is immense. In 1970, the New York Academy of Sciences held a symposium on the physiological effects of exposure to this gas to address these issues. Toxicologists have outlined quite precisely the pathophysiological effects resulting from exposure to CO as shown in Table 3.

                              
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Table 3.   Carbon monoxide toxicity

Among all the negative connotations associated with this gaseous molecule, evidence accumulating in the past five years is beginning to shed new light on this historically categorized poison. At high concentrations, CO is unquestionably lethal. But recent studies (55, 64, 104) consistently support the emerging idea that CO at low concentrations exerts distinctly different effects on physiological and cellular functions, this revelation motivating the need to reevaluate its role.

Certainly, contemporary neurobiologists and vascular biologists believe it is important in their systems. The pioneering work of Snyder et al. (92) and Morita and Kourembanas (62) have clearly shown that CO generated from HO, the primary if not exclusive source of CO generation in the body, can regulate vasomotor tone as well as neurotransmission. These findings provided the first evidence that this simple gaseous molecule could impart critical biological functions akin to NO. Just as NO functions as a signaling molecule, so does CO play an important role in regulating vasomotor tone by promoting vasorelaxation (84). Furthermore, Yet et al. (114) have also observed that HO-1(-/-) mice exhibited a maladaptive response to chronic hypoxia, with the development of right ventricular infarcts and organized mural thrombi resulting in pulmonary hypertension (114). This regulatory function may indeed account for the anti-inflammatory effects of HO-1 expression in endothelial and smooth muscle cells because vasorelaxation may allow maintenance of blood flow at sites of inflammation, such relaxation countering those effects of coagulation and thrombosis that can lead to anoxia and tissue necrosis.

These effects of CO are mediated through the activation of guanylyl cyclase on the binding of CO to the heme moiety of this enzyme and subsequent cGMP generation (12). But the vasodilator function of CO is thought to be 50-100 times less potent than that of NO based on the capacity of both molecules to activate guanylyl cyclase, the common mediator of these molecules in modulating smooth muscle cell relaxation and vasodilatation (113). However, the relative inefficiency of CO in binding guanylyl cyclase may be largely neutralized because although NO is extremely reactive and labile, CO is chemically very stable. Unlike NO, CO reacts exclusively with heme and thus can accumulate in the cell to levels that are presumably much higher then those of NO. CO may also possess anti-inflammatory effects such as the capacity to inhibit platelet activation or aggregation through activation of guanylyl cyclase and subsequent generation of cGMP. Furthermore, CO when administered exogenously to rats or mice at very low concentrations can provide protection in models of lung injury (72, 73).

Recent studies also suggest that changes in CO measurements in exhaled breath are indicative of increased HO-1 activity and cellular stress and therefore can be correlated with the severity of some disease processes. For example, Paredi et al. (77) and Yamara et al. (113) have shown increased CO in the breath of patients with disease processes as diverse as asthma and diabetes (77, 113).

Biliverdin and bilirubin. Bilirubin is the most abundant endogenous antioxidant in mammalian tissues, accounting for the majority of the antioxidant activity of human serum (32). Bilirubin has been shown to be a potent antioxidant in the brain, acting to scavenge peroxyl radicals as efficiently as alpha -tocopherol or vitamin E (94). Bilirubin is best known, however, as a potentially toxic agent that accumulates in the serum of neonates, causing jaundice. In high concentrations, it deposits in selected brain regions to elicit neurotoxicity associated with kinicterus (33). On the other hand, neonatal jaundice could also have a protective effect for the infant arriving for the first time into an unsterile environment. In a recent report, Vachharajani et al. (103) observed that administration of biliverdin to rats modulates lipopolysaccharide-induced P- and E-selectin expression in the vascular system, providing evidence that bilirubin is able to modulate this inflammatory response regardless of the influences of HO-1, CO, and/or ferritin (103).

Biliverdin administration to rodents has also recently been shown to provide protection in a rat model of ischemic heart injury (103). Another report by Dore et al. (25) further demonstrated that bilirubin manifests cytoprotective properties in a model of hydrogen peroxide-induced oxidative injury to neurons as does a report by Clark et al. (18) who showed that bilirubin administration in a model of ischemic heart injury is protective, suggesting that this end product of heme catabolism is more than a waste product that simply requires elimination.

Ferritin. The release of free iron (its two free electrons capable of generating the vicious hydroxyl radical) through Fenton chemistry with the superoxide radical is rapidly sequestered into the iron storage protein ferritin (Fig. 1). Such sequestration can itself lower the prooxidant state of the cell by removing the free iron (8). Vile and Tyrrell (105) showed that ferritin levels increase in the presence of oxidative stress such as ultraviolet irradiation. This HO-1-dependent release of iron also results in the upregulation of ferritin, which might provide protection after irradiation. Eisenstein et al. (27) clearly showed that ferritin is increased in tandem with HO-1 and decreased with inhibition in HO-1 activity. Balla et al. (9) also showed that induction of ferritin was cytoprotective in a model of oxidant stress, demonstrating that cytotoxicity was greatly reduced and occurred independently of HO-1 activity. Finally, Otterbein et al. (71), in a model of endotoxic shock, demonstrated that when iron is chelated by the exogenous iron chelator desferoxamine, no ferritin is induced and protection is ablated.

Another recent report (10) demonstrated that overexpression of HO-1 also upregulates and interacts with an iron ATPase present in the endoplasmic reticulum. This iron pump is thought to limit intracellular iron content once HO-1 activity is upregulated. This limiting effect may be particularly important when cells are exposed to high levels of heme that increase HO-1 activity, thus generating high levels of intracellular free iron. The ability of cells expressing HO-1 to decrease iron content has recently been suggested to account in large measure for the antiapoptotic effects of HO-1 (15, 78, 89). Other molecules that chelate intracellular free iron are also thought to prevent apoptosis, suggesting that upregulation of ferritin by HO-1 may have a similar effect in preventing apoptosis.


    HO-1 EXPRESSION IN THE LUNG
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INTRODUCTION
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INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
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Like many of the organ systems affected by the pathologies listed in Table 2, the lung is no exception with regard to the induction of HO-1. The induction of HO-1 has been demonstrated in many models of lung injury including hyperoxia, endotoxemia, bleomycin, asthma, acute complement-dependent lung inflammation, and heavy metals. The physiological function of this robust HO-1 induction primarily points to the cytoprotective effects of HO-1. In an in vitro model of oxidative stress with stably transfected HO-1-overexpressing pulmonary epithelial cells, Lee et al. (48) demonstrated that these cells exhibited increased resistance to hyperoxic cell injury. Similar protective effects of HO-1 were also observed by Suttner et al. (98) in rat fetal lung cells exposed to hyperoxia. In studies by Petrache et al. (78) and Soares et al. (93), HO-1 also prevented tumor necrosis factor (TNF)-alpha -mediated apoptosis in fibroblasts and endothelial cells, respectively. Such findings further substantiated the involvement of HO-1 in cytoprotection. These findings, however, are not without controversy. Dennery et al. (21) demonstrated that HO-2-null mice were sensitized to hyperoxia-induced oxidative injury and mortality despite increased HO-1 expression. Furthermore, Suttner and Dennery (97) have also observed that moderate overexpression of HO-1 in fibroblasts is protective against oxidative injury, whereas high levels of HO-1 expression can be associated with significant O2 cytotoxicity. These authors speculate that the accumulation of reactive iron released from the catalysis of heme may impart cellular cytotoxicity.

Rodent models of septic shock and hyperoxic lung injury represent two clinically relevant research models in the study of lung injury. Each provides pertinent information that can lead to a better understanding of clinical disease because although they diverge in terms of their relative cytotoxic etiologies and tissue injury dynamics, they are closely intertwined at the intracellular level. Both generate enormous amounts of reactive oxygen species that represent the fundamental underlying mechanisms responsible for tissue injury. Otterbein and colleagues (71, 72, 74) have demonstrated that HO-1 induction correlated with cytoprotection against oxidative stress in vivo. Using hyperoxia as a model of acute respiratory distress syndrome in rats, they hypothesized that the exogenous administration of HO-1 by gene transfer would confer protection against oxidant-induced tissue injury. Adenoviral gene transfer of HO-1 (Ad5-HO-1) into the lungs of rats resulted in increased expression of HO-1 and, more importantly, a marked resistance to hyperoxic lung injury (74). Rats treated with Ad5-HO-1 showed reduced levels of hyperoxia-induced pleural effusion, neutrophil alveolitis, and bronchoalveolar lavage protein leakage. Furthermore, rats treated with Ad5-HO-1 showed increased survivability against hyperoxic stress versus those treated with the vector control virus AdV-beta Gal. These data are supported by Taylor et al. (99), who demonstrated that intratracheal administration of hemoglobin, a major inducer of HO-1, also provided protection from hyperoxic lung injury. They concluded, however, that the protection was perhaps conferred via ferritin and not directly by HO-1.

In view of the observations that exogenous administration of HO-1 via transgene delivery provided cytoprotection against hyperoxia in rats, Otterbein et al. (75) then examined whether exogenous CO could impart similar cytoprotective effects. Indeed, CO at low concentrations [10-500 parts/million (ppm)], well tolerated both by rodents and cells, provided protective effects against hyperoxia similar to those observed in the transgene studies (104). Previous work by Stupfel and Bouley (96) had clearly shown that rodents can be exposed to 500 ppm CO continuously for up to 2 yr without deleterious effects on multiple physiological and biochemical parameters. Based on these studies and many others, concentrations chosen for exposures ranged from 50 to 500 ppm. Rats exposed to hyperoxia in the presence of a low concentration of CO (250 ppm) were similarly protected from hyperoxic stress, with reduced markers of injury and increased survivability. These studies strongly suggested that CO exerted its protective effects via anti-inflammatory and/or antiapoptotic effects.

These results provided the direction for the next series of studies in which an attempt was made to delineate the potential mechanism(s) by which CO provided cytoprotection against oxidative stress. Otterbein et al. (73) hypothesized that CO mediated the anti-inflammatory effects, thus providing the potent cytoprotection. This hypothesis was tested in vivo in mice and in vitro in RAW 264.7 macrophage cells. CO inhibited the lipopolysaccharide-induced proinflammatory cytokines TNF-alpha , interleukin (IL)-1beta , and macrophage inflammatory protein (MIP)-1alpha but augmented the anti-inflammatory cytokine IL-10 expression in vitro. Likewise, inhibition of the proinflammatory cytokine TNF-alpha and augmentation of the cytokine IL-10 were also observed in vivo. Because of the evidence that cGMP serves as an important mediator involved in CO and NO signaling in other model systems, in particular the central nervous system and vascular cells, Otterbein et al. (73) examined whether CO mediated the anti-inflammatory effects via the guanylyl cyclase/cGMP pathway. Interestingly, cGMP was not involved, but rather the observed anti-inflammatory effects of CO were dependent on the mitogen-activated protein kinase kinase (MKK-3)/p38 mitogen-activated protein kinase pathway. Further studies (73) to corroborate the involvement of p38 in the mechanism producing the CO effects were performed in mice deficient in MKK-3, the major upstream kinase activator of p38. Endotoxin administration to MKK-3-deficient mice exposed to air resulted in the inhibition in TNF-alpha as expected but with no additional inhibition when exposed to CO. Further examination revealed that IL-10 levels were not augmented in the presence of CO in these mice as observed in the wild-type littermates. These findings confirmed the involvement of the MKK-3/p38 pathway in the effects observed with CO.


    CONCLUSIONS
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ABSTRACT
INTRODUCTION
HEME OXYGENASE
INDUCTION OF HO-1 EXPRESSION
MECHANISM(S) OF CYTOPROTECTION...
HO-1 EXPRESSION IN THE...
CONCLUSIONS
REFERENCES

Although the mechanism(s) mediating HO-1-induced cytoprotection remains elusive, recent data point to one of the by-products of heme catabolism [CO, Fe2+ (ferritin), or bilirubin] as potential mediators of HO-1 cytoprotection. Even though each product has been shown to be protective, it could indeed be a combination of the three by-products that act adaptively to protect the cell and tissue from further insult. Although progress has been made in our understanding of the function of HO-1 after oxidative stress, there is much work to be done to delineate more clearly the role of HO-1 induction in lung biology and pathology. The players (CO, ferritin, and bilirubin) have been identified, but the destinies and interactions among these characters remain elusive; gas molecules, metal ions, and organic antioxidants, all intermingling within the cellular milieu affecting biological processes, all categorically toxic, all possess some manner of physiological function in the vastly complex cellular and molecular environment. At some point, investigators may fully understand the interplay of these characters and, most importantly, the mechanism by which this remarkable enzyme invokes the colors of defense against a plethora of insults. And hopefully, in the near future, this knowledge will help in the discovery of novel therapeutic modalities with which to treat acute lung injury as well as a multitude of other disease states.


    ACKNOWLEDGEMENTS

The work by A. M. K. Choi was supported by National Heart, Lung, and Blood Institute Grants HL-55330 and HL-60234; National Institute of Allergy and Infectious Diseases Grant AI-42365; and an American Heart Association Established Investigator Award.


    FOOTNOTES

Address for reprint requests and other correspondence: A. M. K. Choi, Division of Pulmonary, Allergy, and Critical Care Medicine, Univ. of Pittsburgh School of Medicine, MUH, NW 628, 3459 Fifth Ave., Pittsburgh, PA 15213 (E-mail: choiam{at}msx.upmc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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1.   Abraham, NG, Lin JH, Dunn MW, and Schwartzman ML. Presence of human heme oxygenase and NADPH cytochrome P-450 (c) reductase in human corneal epithelium. Invest Opthalmol Vis Sci 28: 1464-1472, 1987[Abstract].

2.   Acevedo, CH, and Ahmed A. Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy. J Clin Invest 101: 949-955, 1998[Abstract/Free Full Text].

3.   Agarwal, A, Balla J, Alam J, Croatt AJ, and Nath KA. Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. Kidney Int 48: 1298-1307, 1995[ISI][Medline].

4.   Agarwal, A, Kim Y, Matas AJ, Alam J, and Nath KA. Gas-generating systems in acute renal allograft rejection in the rat: co-induction of heme oxygenase and nitric oxide synthase. Transplantation 61: 93-98, 1996[ISI][Medline].

5.   Alam, J, and Den Z. Distal AP-1 binding sites mediate basal level enhancement and TPA induction of the mouse heme oxygenase-1 gene. J Biol Chem 267: 21894-21900, 1992[Abstract/Free Full Text].

6.   Amersi, F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busittil RW, and Kupiec-Weglinski JW. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 104: 1631-1639, 1999[Abstract/Free Full Text].

7.   Bakken, AF, Thaler MM, and Schmid R. Metabolic regulation of heme catabolism and bilirubin production. I. Hormonal control of hepatic heme oxygenase activity. J Clin Invest 51: 530-536, 1972[ISI][Medline].

8.   Balla, G, Jacob HS, and Balla J. Induction of endothelial ferritin: a cytoprotective antioxidant stratagem of the vessel wall. J Biol Chem 267: 18148-18153, 1992[Abstract/Free Full Text].

9.   Balla, G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, and Vercellotti GM. Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 267: 18148-18153, 1992[Abstract/Free Full Text].

10.   Baranano, DE, Wolosker H, Bae BI, Barrow RK, Snyder SH, and Ferris CD. A mammalian iron ATPase induced by iron. J Biol Chem 275: 15166-15173, 2000[Abstract/Free Full Text].

11.   Camhi, SL, Alam J, Otterbein L, Sylvester SL, and Choi AM. Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. Am J Respir Cell Mol Biol 130: 387-398, 1995.

12.   Cardell, LO, Lou YP, Takeyama K, Ueki IF, Lausier J, and Nadel JA. Carbon monoxide, a cyclic GMP-related messenger, involved in hypoxic bronchodilation in vivo. Pulm Pharmacol Ther 11: 309-315, 1998[ISI][Medline].

13.   Carraway, MS, Ghio AJ, Carter JD, and Piantadosi CA. Expression of heme oxygenase-1 in the lung in chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 278: L806-L812, 2000[Abstract/Free Full Text].

14.   Carraway, MS, Ghio AJ, Taylor JL, and Piantadosi CA. Induction of ferritin and heme oxygenase-1 by endotoxin in the lung. Am J Physiol Lung Cell Mol Physiol 275: L583-L592, 1998[Abstract/Free Full Text].

15.   Chen, K, Gunter K, and Maines MD. Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem 75: 304-313, 2000[ISI][Medline].

16.   Chen, W, Hunt DM, Lu H, and Hunt RC. Expression of antioxidant protective proteins in the rat retina during prenatal and postnatal development. Invest Opthalmol Vis Sci 40: 744-751, 1999[Abstract].

17.   Choi, AM, Sylvester S, Otterbein L, and Holbrook NJ. Molecular responses to hyperoxia in vivo: relationship to increased tolerance in aged rats. Am J Respir Cell Mol Biol 13: 74-82, 1995[Abstract].

18.   Clark, JE, Foresti R, Sarathchandra P, Kaur H, Green CJ, and Motterlini R. Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol 278: H643-H651, 2000[Abstract/Free Full Text].

19.   Csonka, C, Varga E, Kovacs P, Ferdinandy P, Blasig IE, Szilvassy Z, and Tosaki A. Heme oxygenase and cardiac function in ischemic/reperfused rat hearts. Free Radic Biol Med 27: 119-126, 1999[ISI][Medline].

20.   Datta, PK, and Lianos EA. Nitric oxide induces heme oxygenase-1 gene expression in mesangial cells. Kidney Int 55: 1734-1739, 1999[ISI][Medline].

21.   Dennery, PA, Spitz DR, Yang G, Tatarov A, Lee CS, Shegog ML, and Poss KD. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest 101: 1001-1011, 1998[Abstract/Free Full Text].

22.   Deramaudt, BM, Braunstein S, Remy P, and Abraham NG. Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem 68: 121-127, 1998[ISI][Medline].

23.   Doi, K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, Shibahara S, Ogawa M, and Maeda H. Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer 80: 1945-1954, 1999[ISI][Medline].

24.   Donat, ME, Wong K, Staines WA, and Krantis A. Heme oxygenase immunoreactive neurons in the rat intestine and their relationship to nitrergic neurons. J Auton Nerv Syst 77: 4-12, 1999[ISI][Medline].

25.   Dore, S, Takahashi M, Ferris CD, Hester LD, Guastella D, and Snyder SH. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci USA 6: 2445-2450, 1999.

26.   Downard, PJ, Wilson MA, Spain DA, Matheson PJ, Siow Y, and Garrison RN. Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. J Surg Res 71: 7-12, 1997[ISI][Medline].

27.   Eisenstein, RS, Garcia-Mayol D, Pettingell W, and Munroe HN. Regulation of ferritin and heme oxygenase in rat fibroblasts by different forms of iron. Proc Natl Acad Sci USA 88: 688-692, 1991[Abstract].

28.   Elbirt, KK, Whitmarsh AJ, Davis RJ, and Bonkovsky HL. Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. J Biol Chem 273: 8922-8931, 1998[Abstract/Free Full Text].

29.   Ewing, JF, and Maines MD. Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: heme oxygenase 2 is not a heat shock protein. Proc Natl Acad Sci USA 88: 5364-5368, 1991[Abstract].

30.   Ewing, JF, and Maines MD. Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain. J Neurochem 60: 1512-1519, 1993[ISI][Medline].

31.   Eyssen-Hernandez, R, Ladoux A, and Frelin C. Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Lett 382: 229-233, 1996[ISI][Medline].

32.   Gopinathan, V, Miller NJ, Milner AD, and Rice-Evans CA. Bilirubin and ascorbate antioxidant activity in neonatal plasma. FEBS Lett 349: 197-200, 1994[ISI][Medline].

33.   Gourley, GR. Bilirubin metabolism and kernicterus. Adv Pediatr 44: 173-229, 1997[Medline].

34.   Hancock, WW, Buelow R, Sayegh MH, and Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med 4: 1392-1396, 1998[ISI][Medline].

35.   Hara, E, Takahashi K, Takeda K, Nakayama M, Yoshizawa M, Fujita H, Shirato K, and Shibahara S. Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors. Biochem Pharmacol 58: 227-236, 1999[ISI][Medline].

36.   Henningsson, R, Alm P, and Lundquist I. Occurrence and putative hormone regulatory function of a constitutive heme oxygenase in rat pancreatic islets. Am J Physiol Cell Physiol 273: C703-C709, 1997[Abstract/Free Full Text].

37.   Horvath, I, Donnelly LE, Kiss A, Paredi P, Kharitonov SA, and Barnes PJ. Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress. Thorax 53: 668-672, 1998[Abstract/Free Full Text].

38.   Ishikawa, K, Navab M, Leitinger N, Fogelman AM, and Lusis AJ. Induction of heme oxygenase-1 inhibits monocyte transmigration induced by mildly oxidized LDL. J Clin Invest 100: 1209-1216, 1997[Abstract/Free Full Text].

39.   Ishizaka, N, de Leon H, Laursen JB, Fukui T, Wilcox JN, Keulenaer GD, Griendling KK, and Alexander RW. Angiotensin II-induced hypertension increases heme oxygenase-1 expression in rat aorta. Circulation 96: 1923-1929, 1997[Abstract/Free Full Text].

40.   Keyse, SM, and Tyrrell RM. Both near ultraviolet radiation and the oxidizing agent hydrogen peroxide induce a 32-kDa stress protein in normal human skin fibroblasts. J Biol Chem 262: 14821-14825, 1987[Abstract/Free Full Text].

41.   Keyse, SM, and Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 86: 99-103, 1989[Abstract].

42.   Koizumi, T, Negishi M, and Ichikawa A. Induction of heme oxygenase by delta 12-prostaglandin J2 in porcine aortic endothelial cells. Prostaglandins 43: 121-131, 1992[Medline].

43.   Kurata, S, and Nakajima H. Transcriptional activation of the heme oxygenase gene by TPA in mouse M1 cells during their differentiation to macrophage. Exp Cell Res 191: 89-94, 1990[ISI][Medline].

44.   Laniado-Schwartzman, M, Abraham NG, Conners M, Dunn MW, Levere RD, and Kappas A. Heme oxygenase induction with attenuation of experimentally induced corneal inflammation. Biochem Pharmacol 53: 1069-1075, 1997[ISI][Medline].

46.   Lautier, D, Luscher P, and Tyrrell RM. Endogenous glutathione levels modulate both constitutive and UVA radiation/hydrogen peroxide inducible expression of the human heme oxygenase gene. Carcinogenesis 13: 227-232, 1992[Abstract].

47.   Lee, BC. Quelling the red menace: haem capture by bacteria. Mol Microbiol 18: 383-390, 1995[ISI][Medline].

48.   Lee, PJ, Alam J, Sylvester SL, Inamdar N, Otterbein L, and Choi AM. Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury. Am J Respir Cell Mol Biol 14: 556-568, 1996[Abstract].

49.   Lee, PJ, Alam J, Wiegand GW, and Choi AMK Overexpression of heme oxygenase-1 expression in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proc Natl Acad Sci USA 93: 10393-10398, 1996[Abstract/Free Full Text].

50.   Lee, PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, and Choi AM. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 272: 5375-5381, 1997[Abstract/Free Full Text].

51.   Levere, RD, Staudinger R, Loewy G, Kappas A, Shibahara S, and Abraham NG. Elevated levels of heme oxygenase activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients. Am J Hematol 43: 19-23, 1993[ISI][Medline].

52.   Lyall, F, Barber A, Myatt L, Bulmer JN, and Robson SC. Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function. FASEB J 14: 208-219, 2000[Abstract/Free Full Text].

53.   Maeshima, H, Sato M, Ishikawa K, Katagata Y, and Yoshida T. Participation of altered upstream stimulatory factor in the induction of rat heme oxygenase-1 by cadmium. Nucleic Acids Res 24: 2959-2965, 1996[Abstract/Free Full Text].

54.   Maines, MD. Heme oxygenase: function, multiplicity, regulatory mechanisms and clinical implications. FASEB J 2: 2557-2568, 1988[Abstract/Free Full Text].

55.   Mancuso, C, Preziosi P, Grossman AB, and Navarra P. The role of carbon monoxide in the regulation of neuroendocrine function. Neuroimmunomodulation 4: 225-229, 1997[ISI][Medline].

56.   Mann, FC, Sheard C, and Bollman JL. The formation of bile pigment from hemoglobin. Am J Physiol 76: 306-315, 1926.

57.   Matz, PG, Weinstein PR, and Sharp FR. Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage. Neurosurgery 40: 152-160, 1997[ISI][Medline].

58.   Maulik, N, Sharma HS, and Das DK. Induction of the haem oxygenase gene expression during the reperfusion of ischemic rat myocardium. J Mol Cell Cardiol 28: 1261-1270, 1996[ISI][Medline].

59.   Mautes, AE, Kim DH, Sharp FR, Panter S, Sata M, Maida N, Bergeron M, Guenther K, and Noble LJ. Induction of heme oxygenase-1 (HO-1) in the contused spinal cord of the rat. Brain Res 795: 17-24, 1998[ISI][Medline].

60.   McCoubrey, WK, Ewing JF, and Maines MD. Human heme oxygenase-2: characterization and expression of a full-length cDNA and evidence suggesting that the two HO-2 transcripts may differ by choice of polyadenylation signal. Arch Biochem Biophys 295: 13-20, 1992[ISI][Medline].

61.   McCoubrey, WK, Huang TJ, and Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247: 725-732, 1997[Abstract].

62.   Morita, T, and Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest 96: 2676-2682, 1995[ISI][Medline].

63.   Motterlini, R, Foresti R, Bassi R, Calabrese V, Clark JE, and Green CJ. Endothelial heme oxygenase-1 induction by hypoxia. Modulation by inducible nitric-oxide synthase and s-nitrosothiols. J Biol Chem 275: 13613-13620, 2000[Abstract/Free Full Text].

64.   Motterlini, R, Gonzales A, Foresti R, Clark JE, Green CJ, and Winslow RM. Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive response in vivo. Circ Res 83: 568-577, 1998[Abstract/Free Full Text].

65.   Muramoto, T, Kohchi T, Yokota A, Hwang I, and Goodman HM. The Arabidopsis photomorphogenic mutant hy1 is deficient in phytochrome chromophore biosynthesis as a result of a mutation in a plastid heme oxygenase. Plant Cell 11: 335-348, 1999[Abstract/Free Full Text].

66.   Nath, KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, and Rosenberg ME. Induction of heme oxygenase is a rapid protective response in rhabdomyolysis in the rat. J Clin Invest 90: 267-270, 1992[ISI][Medline].

67.   Nishie, A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, and Kuwano M. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5: 1107-1113, 1999[Abstract/Free Full Text].

68.   Oguro, T, Hayashi M, Numazawa S, Asakawa K, and Yoshida T. Heme oxygenase-1 gene expression by a glutathione depletor, phorone, mediated through AP-1 activation in rats. Biochem Biophys Res Commun 221: 259-265, 1996[ISI][Medline].

69.   Oshiro, S, Takeuchi H, Matsumoto M, and Kurata S. Transcriptional activation of heme oxygenase-1 gene in mouse spleen, liver and kidney cells after treatment with lipopolysaccharide or hemoglobin. Cell Biol Int 23: 465-474, 1999[ISI][Medline].

70.   Ossola, JO, and Tomaro ML. Heme oxygenase induction by UVA radiation. A response to oxidative stress in rat liver. Int J Biochem Cell Biol 30: 285-292, 1998[ISI][Medline].

71.   Otterbein, L, Chin BY, Otterbein SL, Lowe VC, Fessler HE, and Choi AMK Mechanism of hemoglobin-induced protection against endotoxemia in rats: a ferritin-independent pathway. Am J Physiol Lung Cell Mol Physiol 272: L268-L275, 1997[Abstract/Free Full Text].

72.   Otterbein, L, Sylvester SL, and Choi AM. Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. Am J Respir Cell Mol Biol 13: 595-601, 1995[Abstract].

73.   Otterbein, LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, and Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6: 422-428, 2000[ISI][Medline].

74.   Otterbein, LE, Kolls JK, Mantell LL, Cook JL, Alam J, and Choi AM. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest 103: 1047-1054, 1999[Abstract/Free Full Text].

75.   Otterbein, LE, Mantell LL, and Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol 276: L688-L694, 1999[Abstract/Free Full Text].

76.   Panchenko, MV, Farber HW, and Korn JH. Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol 278: C92-C101, 2000[Abstract/Free Full Text].

77.   Paredi, P, Biernacki W, Invernizzi G, Kharitonov SA, and Barnes PJ. Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood: a new test for monitoring the disease? Chest 116: 1007-1111, 1999[Abstract/Free Full Text].

78.   Petrache, I, Otterbein LE, Alam J, Wiegand GW, and Choi AM. Heme oxygenase-1 inhibits TNF-alpha -induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol 278: L312-L319, 2000[Abstract/Free Full Text].

79.   Polte, T, Abate A, Dennery PA, and Schroder H. Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler Thromb Vasc Biol 20: 1209-1215, 2000[Abstract/Free Full Text].

80.   Poss, KD, and Tonegawa S. Heme oxygenase-1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94: 10919-10924, 1997[Abstract/Free Full Text].

81.   Poss, KD, and Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94: 10925-10930, 1997[Abstract/Free Full Text].

82.   Rizzardini, M, Zappone M, Villa P, Gnocchi P, Sironi M, Diomede L, Meazza C, Monshouwer M, and Cantoni L. Kupffer cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemic inflammation in mice: role of interleukin 1beta. Hepatology 27: 703-710, 1998[ISI][Medline].

83.   Rossi, A, and Santoro MG. Induction by prostaglandin A1 of haem oxygenase in myoblastic cells: an effect independent of expression of the 70 kDa heat shock protein. Biochem J 308: 455-463, 1995[ISI][Medline].

84.   Sammut, IA, Foresti R, Clark JE, Exon DJ, Vesely MJ, Sarathchandra P, Green CJ, and Motterlini R. Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of heme oxygenase-1. Br J Pharmacol 125: 1437-1444, 1998[Abstract].

85.   Sardana, MK, Drummond GS, Sassa S, and Kappas A. The potent heme oxygenase inducing action of arsenic and parasiticidal arsenicals. Pharmacology 23: 247-253, 1981[ISI][Medline].

86.   Sato, H, Siow RC, Bartlett S, Taketani S, Ishi T, Bannai S, and Mann GE. Expression of stress proteins heme oxygenase-1 and -2 in acute pancreatitis and pancreatic islet betaTC3 and acinar AR42J cells. FEBS Lett 405: 219-223, 1997[ISI][Medline].

87.   Schipper, HM, Chertkow H, Mehindate K, Frankel D, Melmed C, and Bergman H. Evaluation of heme oxygenase-1 as a systemic biological marker of sporadic AD. Neurology 54: 1297-1304, 2000[Abstract/Free Full Text].

88.   Shibahara, S, Muller RM, and Taguchi H. Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem 262: 12889-12892, 1987[Abstract/Free Full Text].

89.   Shiraishi, F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, and Agarwal A. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol 278: F726-F736, 2000[Abstract/Free Full Text].

90.   Siow, RCM, Sata H, and Mann GE. Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? Cardiovasc Res 41: 385-394, 1999[ISI][Medline].

91.   Smith, MA, Kutty RK, Richey PL, Yan SD, Stern D, Hader GJ, Wiggert B, Petersen RB, and Perry G. Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am J Pathol 145: 42-47, 1994[Abstract].

92.   Snyder, SH, Jaffrey SR, and Zakhary R. Nitric oxide and carbon monoxide: parallel roles as neural messengers. Brain Res Brain Res Rev 2-3: 167-175, 1998.

93.   Soares, MP, Lin Y, Anrather J, Csizmadia E, Takigami K, Sata K, Grey ST, Colvin RB, Choi AM, Poss KD, and Bach FH. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med 4: 1073-1077, 1998[ISI][Medline].

94.   Stocker, R, Yamamoto Y, McDonagh AF, Glazer AN, and Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 235: 1043-1045, 1987[ISI][Medline].

95.   Stuhlmeier, KM. Activation and regulation of Hsp32 and Hsp70. Eur J Biochem 267: 1161-1167, 2000[Abstract/Free Full Text].

96.   Stupfel, M, and Bouley G. Physiological and biochemical effects on rats and mice exposed to small concentrations of carbon monoxide for long periods. Ann NY Acad Sci 174: 342-368, 1970[ISI][Medline].

97.   Suttner, DM, and Dennery PA. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 13: 1800-1809, 1999[Abstract/Free Full Text].

98.   Suttner, DM, Sridhar K, Lee CS, Tomura T, Hansen TN, and Dennery PA. Protective effects of transient HO-1 overexpression on susceptibility to oxygen toxicity in lung cells. Am J Physiol Lung Cell Mol Physiol 276: L443-L451, 1999[Abstract/Free Full Text].

99.   Taylor, JL, Carraway MS, and Piantadosi CA. Lung-specific induction of heme oxygenase-1 and hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol 274: L582-L590, 1998[Abstract/Free Full Text].

100.   Tenhunen, R, Marver HS, and Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61: 748-755, 1968[ISI][Medline].

101.   Tenhunen, R, Marver HS, and Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem 244: 6388-6394, 1969[Abstract/Free Full Text].

102.   Terry, CM, Clikeman JA, Hoidal JR, and Callahan KS. Effect of tumor necrosis factor-alpha and interleukin-1alpha on heme oxygenase-1 expression in human endothelial cells. Am J Physiol Heart Circ Physiol 274: H883-H891, 1998[Abstract/Free Full Text].

103.   Vachharajani, TJ, Work J, Sekutz AC, and Granger DN. Heme oxygenase modulates selectin expression in different regional vascular beds. Am J Physiol Heart Circ Physiol 278: H1613-H1617, 2000[Abstract/Free Full Text].

104.   Verma, A, Hirsch DJ, Glatt CE, Ronnett GV, and Snyder SH. Carbon monoxide: a putative neural messenger. Science 259: 381-384, 1993[ISI][Medline].

105.   Vile, GF, and Tyrrell RM. Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin. J Biol Chem 268: 14678-14681, 1993[Abstract/Free Full Text].

106.   Virchow, R. Die pathologischen pigments. Arch Pathol Anat 1: 379-486, 1847.

107.   Vogt, BA, Shanley TP, Croatt A, Alam J, Johnson KJ, and Nath KA. Glomerular inflammation induces resistance to tubular injury in the rat: a novel form of acquired, heme oxygenase-dependent resistance to renal injury. J Clin Invest 98: 2139-2145, 1996[Abstract/Free Full Text].

108.   Wagner, CT, Durante W, Christodoulides N, Hellums JD, and Schafer AI. Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. J Clin Invest 100: 589-596, 1997[Abstract/Free Full Text].

109.   Wang, LJ, Lee TS, Lee FY, Pai RC, and Chau LY. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol 152: 711-720, 1998[Abstract].

110.   Willis, D, Moore AR, Frederick R, and Willoughby DA. Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2: 87-90, 1996[ISI][Medline].

111.   Yachie, A, Niida Y, Wada T, Igarashi N, and Kaneda H. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103: 129-135, 1999[Abstract/Free Full Text].

112.   Yamada, N, Yamaya M, Okinaga S, Nakayama K, Sekizawa K, Shibahara S, and Sasaki H. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet 66: 187-195, 2000[ISI][Medline].

113.   Yamara, M, Sekizawa K, Ishizuka S, Monma M, and Sasaki H. Exhaled carbon monoxide levels during treatment of acute asthma. Eur Respir J 12: 757-760, 1999.

114.   Yet, SF, Perrella MA, Layne MD, Hsieh CM, Maemura K, Kobzik L, Wiesel P, Christou H, Kourembanas S, and Lee ME. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 103: R23-R29, 1999[Abstract/Free Full Text].

115.   Yet, SF, Pellacani A, Patterson C, Tan L, Folta SC, Foster L, Lee WS, Hsieh CM, and Perrella MA. Induction of heme oxygenase-1 expression in vascular smooth muscle cells: a link to endotoxic shock. J Biol Chem 272: 4295-4301, 1997[Abstract/Free Full Text].


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