scholarly journals Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders

2021 ◽  
Vol 22 (11) ◽  
pp. 5509
Author(s):  
Stefan W. Ryter
Keyword(s):  
Heme Oxygenase ◽  
Storage Proteins ◽  
Metabolic Enzyme ◽  
Heme Oxygenase 1 ◽  
Bile Pigments ◽  
Prosthetic Group ◽  
Biliverdin Reductase ◽  
Inflammatory Conditions ◽  
Heme Degradation ◽  
Activity Dependent

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.

Products of heme oxygenase and their potential therapeutic applications

2006 ◽  
Vol 290 (3) ◽  
pp. F563-F571 ◽  
Author(s):  
Kristin A. Kirkby ◽  
Christopher A. Adin
Keyword(s):  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Inexpensive Method ◽  
Waste Products ◽  
Biliverdin Reductase ◽  
Therapeutic Applications ◽  
Beneficial Effects ◽  
Tissue Protection ◽  
Organ Systems ◽  
Dose Dependent

Heme oxygenase 1 (HO-1) is induced in response to cellular stress and is responsible for converting the prooxidant heme molecule into equimolar quantities of biliverdin (BV), carbon monoxide (CO), and iron. BV is then converted to bilirubin (BR) by the enzyme biliverdin reductase. Experimental evidence suggests that induction of the HO system is an important endogenous mechanism for cytoprotection and that the downstream products of heme degradation, CO, BR, and BV, may mediate these powerful beneficial effects. These molecules, which were once considered to be toxic metabolic waste products, have recently been shown to have dose-dependent vasodilatory, antioxidant, and anti-inflammatory properties that are particularly desirable for tissue protection during organ transplantation. In fact, recent work has demonstrated that administration of exogenous CO, BR, or BV may offer a simple, inexpensive method to substitute for the cytoprotective effects of HO-1 in a variety of clinically applicable models. This review will attempt to summarize the relevant biochemical and cytoprotective properties of CO, BR, and BV, and will discuss emerging studies involving the therapeutic applications of these molecules in the kidney and other organ systems.

Functional Expression of Human Heme Oxygenase-1 Gene in Renal Structure of Spontaneously Hypertensive Rats

2003 ◽  
Vol 228 (5) ◽  
pp. 454-458 ◽  
Author(s):  
Alvin I. Goodman ◽  
Shou Quan ◽  
Liming Yang ◽  
Arika Synghal ◽  
Nader G. Abraham
Keyword(s):  
Blood Pressure ◽  
Heme Oxygenase ◽  
Spontaneously Hypertensive Rats ◽  
Rat Kidney ◽  
Functional Expression ◽  
Heme Oxygenase 1 ◽  
Thick Ascending Limb ◽  
Bile Pigments ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Heme oxygenase (HO), by catabolizing heme to bile pigments, regulates the levels and activity of cellular hemoprotein and HO activity. We examined the effect of delivery of the human HO-1 gene on cellular heme in renal tissue using a retroviral vector. We used a single intracardiac injection of the concentrated infectious viral particles in 5-day-old spontaneously hypertensive rats; 25 were transduced with empty vector and 25 were transduced with the human HO-1 gene. Functional expression of human and rat HO-1 was measured after 2 and 4 weeks. Reverse transcription polymerase chain reaction showed that human HO-1 mRNA was expressed as early as 2 weeks, with the highest levels in the kidney. Western blot analysis showed distribution of human HO-1 protein in rat kidney structures, predominantly in the thick ascending limb of the loop of Henle as well as in proximal tubules and preglomerular arterioles. These areas also demonstrated higher HO activity as measured by increased conversion of heme to bilirubin and carbon monoxide. Functional expression of the human HO-1 gene was associated with a decrease in blood pressure in 4- and 8-week-old spontaneously hypertensive rats. Compared with nontransduced rats, human HO-1 gene overexpression in transduced rats was associated with a 35% decrease in urinary 20-hydroxyeicosatetraenoic acid, a potent vasoconstrictor and an inhibitor of tubular Na+ transport, which may be related to the decrease in blood pressure.

scholarly journals Induction of Heme Oxygenase-1, Biliverdin Reductase and H-Ferritin in Lung Macrophage in Smokers with Primary Spontaneous Pneumothorax: Role of HIF-1α

PLoS ONE ◽  
2010 ◽  
Vol 5 (5) ◽  
pp. e10886 ◽  
Author(s):  
Delphine Goven ◽  
Anne Boutten ◽  
Véronique Leçon-Malas ◽  
Joëlle Marchal-Sommé ◽  
Paul Soler ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Spontaneous Pneumothorax ◽  
Primary Spontaneous Pneumothorax ◽  
Heme Oxygenase 1 ◽  
Biliverdin Reductase ◽  
Lung Macrophage

scholarly journals Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

2020 ◽  
Author(s):  
Alice S Chau ◽  
Bonnie L Cole ◽  
Jason S Debley ◽  
Kabita Nanda ◽  
Aaron BI Rosen ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Heme Oxygenase ◽  
Macrophage Activation ◽  
Autosomal Recessive Disorder ◽  
Clinical Findings ◽  
Heme Oxygenase 1 ◽  
Compound Heterozygous ◽  
Biliverdin Reductase ◽  
Frame Shift

Abstract Background: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.Case presentation: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow that can mimic systemic-onset juvenile arthritis.

scholarly journals Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

2020 ◽  
Author(s):  
Alice S. Chau ◽  
Bonnie L. Cole ◽  
Jason S. Debley ◽  
Kabita Nanda ◽  
Aaron B.I. Rosen ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Heme Oxygenase ◽  
Autosomal Recessive Disorder ◽  
Clinical Findings ◽  
Heme Oxygenase 1 ◽  
Compound Heterozygous ◽  
Biliverdin Reductase ◽  
Frame Shift ◽  
Whole Exome

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1 -deficiency is an exceedingly rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features indicating hemophagocytosis lymphohistiocytosis. Clinical findings have included asplenia, nephritis, hepatitis, and evidence of vasculitis. Pulmonary features and evaluation of the immune response have been limited. Results Here, we present the fifth reported case in literature of a young boy who remarkably also presented with chronic respiratory failure due to nonspecific interstitial pneumonia in addition to infection-triggered recurrent hyperinflammatory flares notable for hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

scholarly journals Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

2007 ◽  
Vol 43 (5) ◽  
pp. 580-592 ◽  
Author(s):  
Alok S. Pachori ◽  
Anthony Smith ◽  
Patricia McDonald ◽  
Lunan Zhang ◽  
Victor J. Dzau ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Akt Pathway ◽  
Heme Oxygenase 1 ◽  
Biliverdin Reductase ◽  
Hypoxia Reoxygenation

scholarly journals Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 829 ◽  
Author(s):  
William Durante
Keyword(s):  
Heme Oxygenase ◽  
Critical Role ◽  
Vascular Diseases ◽  
Phenotypic Switching ◽  
Heme Oxygenase 1 ◽  
Bile Pigments ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
Or Gene ◽  
Transplant Arteriosclerosis

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.

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