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Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders

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Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders antioxidants Review Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders Stefan W. Ryter Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, 525 East 68th Street, Room M-522, Box 130, New York, NY 10065, USA; [email protected] Received: 19 September 2020; Accepted: 2 November 2020; Published: 19 November 2020 Abstract: Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the oxidative conversion of heme to carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is converted to bilirubin (BR) by biliverdin reductase. HO-1 has been implicated as a cytoprotectant in various models of acute organ injury and disease (i.e., lung, kidney, heart, liver). Thus, HO-1 may serve as a general therapeutic target in inflammatory diseases. HO-1 may function as a pleiotropic modulator of inflammatory signaling, via the removal of heme, and generation of its enzymatic degradation-products. Iron release from HO activity may exert pro-inflammatory effects unless sequestered, whereas BV/BR have well-established antioxidant properties. CO, derived from HO activity, has been identified as an endogenous mediator that can influence mitochondrial function and/or cellular signal transduction programs which culminate in the regulation of apoptosis, cellular proliferation, and inflammation. Much research has focused on the application of low concentration CO, whether administered in gaseous form by inhalation, or via the use of CO-releasing molecules (CORMs), for therapeutic benefit in disease. The development of novel CORMs for their translational potential remains an active area of investigation. Evidence has accumulated for therapeutic effects of both CO and CORMs in diseases associated with critical care, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS), mechanical ventilation-induced lung injury, pneumonias, and sepsis. The therapeutic benefits of CO may extend to other diseases involving aberrant inflammatory processes such as transplant-associated ischemia/reperfusion injury and chronic graft rejection, and metabolic diseases. Current and planned clinical trials explore the therapeutic benefit of CO in ARDS and other lung diseases. Keywords: acute lung injury; acute respiratory distress syndrome; carbon monoxide; heme oxygenase; ischemia/reperfusion injury 1. Introduction Heme oxygenase-1, a vital heme degradative enzyme and inducible stress protein. Heme oxygenase (HO; E.C. 1:14:99:3) is a metabolic enzyme system first described in the late 1960s which provides the rate-limiting step in the oxidative degradation of heme [1,2]. Heme catalysis by HO requires molecular oxygen (O2) and NADPH: cytochrome p-450 reductase as the electron source [1,2] (Figure1). The HO reaction generates several products, each with biological sequelae, including carbon monoxide (CO) (which evolves from the α-methene bridge carbon of heme), the bile pigment biliverdin-IXα (BV), and free ferrous iron, Fe(II). BV is subsequently converted to its lipid soluble metabolite bilirubin-IXα (BR) by cytosolic NADPH: biliverdin reductase (BVR) [3]. Heme degradative activity is catalyzed by two major isoforms of HO, a constitutive form (heme oxygenase 2, HO-2) and an inducible form (heme oxygenase 1, HO-1), which are products of distinct Antioxidants 2020, 9, 1153; doi:10.3390/antiox9111153 www.mdpi.com/journal/antioxidants AntioxidantsAntioxidants2020 2020, 9,, 9 1153, x FOR PEER REVIEW 2 of 223 of 23 genes [4,5]. The enzymatic HO substrate, heme, provides prosthetic groups for hemoglobin, the genes [4,5]. The enzymatic HO substrate, heme, provides prosthetic groups for hemoglobin, the principal O2 carrier in the blood, and serves as a cofactor for mitochondrial cytochromes and other principalmetabolic O2 enzymescarrier in[6,7]. the Heme, blood, in and free serves form, may as a also cofactor represent for mitochondrial a hazardous pro-oxidant cytochromes compound and other metabolicdue to the enzymes presence [6 of,7 the]. Heme, central in iron, free a form,potential may catalyst also represent of harmful a hazardous free radical pro-oxidant generating processes compound due[8]. to theIndeed, presence heme of theaccumulation central iron, has a potential been implicated catalyst of harmfulas a pathological free radical generatingmediator in processes various [8]. Indeed,inflammatory heme accumulation conditions hassuch been as implicatedsepsis [9–11], as a pathologicalmalaria [12], mediatorsickle cell in variousdisease inflammatory[13], and conditionsatherosclerosis such as[14]; sepsis with [ 9its–11 clearance], malaria by [ HO-112], sickle implicated cell disease as a protective [13], and and atherosclerosis anti-oxidative [14 strategy]; with its clearancein these byand HO-1 other implicated diseases. as a protective and anti-oxidative strategy in these and other diseases. HO-1HO-1 is is not not only only recognized recognized as as an an essential essential metabolic metabolic enzyme, enzyme, but but also also as as a a key key intermediate intermediate in in the stressthe responsestress response and in and cellular in cellular adaptation adaptation to injury to [ 15injury]. The [15]. upregulation The upregulation of HO activity, of HO specificallyactivity, viaspecifically the transcriptional via the regulationtranscriptional of HO-1, regulation has been of widelyHO-1, associatedhas been withwidely cytoprotection associated andwith the protectivecytoprotection dampening and the of inflammationprotective dampening in many cellularof inflammation and preclinical in many models cellular of injuryand preclinical [16–18]. modelsUnder of conditionsinjury [16–18]. where HO-1 is found to be associated with cytoprotection, a plausible hypothesis is thatUnder the individual conditions HO where reaction HO-1 products is found contribute, to be associated individually with orcytoprotection, collectively, toa theplausible implicit hypothesis is that the individual HO reaction products contribute, individually or collectively, to the cytoprotective properties of HO-1 [19]. This hypothesis does not exclude activity-independent implicit cytoprotective properties of HO-1 [19]. This hypothesis does not exclude activity- functions of the protein, such as potential intramolecular interactions resulting in the regulation of independent functions of the protein, such as potential intramolecular interactions resulting in the other proteins [20]. The iron release from the HO reaction drives the synthesis of ferritin, an iron regulation of other proteins [20]. The iron release from the HO reaction drives the synthesis of ferritin, sequestering macromolecule that may contribute to cytoprotection in vascular endothelium and other an iron sequestering macromolecule that may contribute to cytoprotection in vascular endothelium celland types other [21 cell]. Both types BV, [21]. and Both its metaboliteBV, and its BR, metabo are knownlite BR, toare exert known natural to exert antioxidant natural antioxidant properties in serumproperties and bile in [serum22–24 ].and CO bile evolution [22–24]. may CO contributeevolution may to the contribute modulation to the of cellular modulation function of cellular resulting infunction cellular adaptation,resulting in andcellular this adaptation, notion has and provided this notion a rationale has provided for the a application rationale for of the pharmacological application orof gaseous pharmacological CO to harness or gaseous its therapeutic CO to potentialharness its [25 therapeutic,26]. In contrast, potential pro-pathogenic [25,26]. In contrast, and detrimental pro- rolespathogenic of excess and HO-1 detrimental activation roles have of excess also been HO-1 proposed activation [27 have,28]. al Forso been example, proposed the cytoprotective[27,28]. For propertiesexample, ofthe HO-1 cytoprotective may confer properties a survival of HO-1 advantage may confer to tumor a survival cells, advantage and thus to contribute tumor cells, to cancerand progressionthus contribute [29]. to In cancer neurodegenerative progression [29]. diseases, In neurodegenerative the excessive releasediseases, of the pro-oxidant excessive release iron by of HO activitypro-oxidant may contribute iron by HO to activity neural may injury contribute and disease to neural pathogenesis injury and [30 disease]. pathogenesis [30]. FigureFigure 1. Heme1. Heme oxygenase oxygenase activity activ andity and end-product end-product generation. generation.Heme Heme oxygenase oxygenase (HO) is(HO) a metabolic is a enzymemetabolic that enzyme catalyzes that the catalyzes rate-limiting the rate-limiting step in the step oxidative in the oxidative catabolism catabolism of heme of toheme generate to generate the bile pigment biliverdin-IXα (BV) [1,2]. The HO reaction requires molecular oxygen (O2) and reducing equivalents from NADPH cytochrome p-450 reductase. The HO reaction releases the α-methene bridge Antioxidants 2020, 9, 1153 3 of 23 carbon of heme as carbon monoxide (CO). The heme iron is released as ferrous iron (Fe II). BV is further metabolized to bilirubin-IXα (BR) by NAD(P)H biliverdin reductase [1–3]. Both BV and BR are potent antioxidants [22–24]. The metabolic fate of iron released by HO activity remains incompletely understood. Iron may act as a catalyst for the Haber-Weiss cycle, leading to the production of the highly reactive and deleterious hydroxyl radical, and may promote other free radical generating reactions such as the decomposition
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