scholarly journals Therapeutic Potential of Heme Oxygenase-1/Carbon Monoxide in Lung Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Myrna Constantin ◽  
Alexander J. S. Choi ◽  
Suzanne M. Cloonan ◽  
Stefan W. Ryter
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Heme Oxygenase 1 ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Oxidative Breakdown ◽  
Biliverdin Ix

Heme oxygenase (HO), a catabolic enzyme, provides the rate-limiting step in the oxidative breakdown of heme, to generate carbon monoxide (CO), iron, and biliverdin-IXα. Induction of the inducible form, HO-1, in tissues is generally regarded as a protective mechanism. Over the last decade, considerable progress has been made in defining the therapeutic potential of HO-1 in a number of preclinical models of lung tissue injury and disease. Likewise, tissue-protective effects of CO, when applied at low concentration, have been observed in many of these models. Recent studies have expanded this concept to include chemical CO-releasing molecules (CORMs). Collectively, salutary effects of the HO-1/CO system have been demonstrated in lung inflammation/acute lung injury, lung and vascular transplantation, sepsis, and pulmonary hypertension models. The beneficial effects of HO-1/CO are conveyed in part through the inhibition or modulation of inflammatory, apoptotic, and proliferative processes. Recent advances, however, suggest that the regulation of autophagy and the preservation of mitochondrial homeostasis may serve as additional candidate mechanisms. Further preclinical and clinical trials are needed to ascertain the therapeutic potential of HO-1/CO in human clinical disease.

scholarly journals Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1150
Author(s):  
Wei-Cheng Jiang ◽  
Chen-Mei Chen ◽  
Candra D. Hamdin ◽  
Alexander N. Orekhov ◽  
Igor A. Sobenin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Vascular Diseases ◽  
High Rate ◽  
Heme Oxygenase 1 ◽  
High Morbidity ◽  
Attractive Option

Abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA) are serious arterial diseases in the aorta and brain, respectively. AAA and IA are associated with old age in males and females, respectively, and if rupture occurs, they carry high morbidity and mortality. Aneurysmal subarachnoid hemorrhage (SAH) due to IA rupture has a high rate of complication and fatality. Despite these severe clinical outcomes, preventing or treating these devastating diseases remains an unmet medical need. Inflammation and oxidative stress are shared pathologies of these vascular diseases. Therefore, therapeutic strategies have focused on reducing inflammation and reactive oxygen species levels. Interestingly, in response to cellular stress, the inducible heme oxygenase-1 (HO-1) is highly upregulated and protects against tissue injury. HO-1 degrades the prooxidant heme and generates molecules with antioxidative and anti-inflammatory properties, resulting in decreased oxidative stress and inflammation. Therefore, increasing HO-1 activity is an attractive option for therapy. Several HO-1 inducers have been identified and tested in animal models for preventing or alleviating AAA, IA, and SAH. However, clinical trials have shown conflicting results. Further research and the development of highly selective HO-1 regulators may be needed to prevent the initiation and progression of AAA, IA, or SAH.

scholarly journals Carbon Monoxide Protects against Liver Failure through Nitric Oxide–induced Heme Oxygenase 1

2003 ◽  
Vol 198 (11) ◽  
pp. 1707-1716 ◽  
Author(s):  
Brian S. Zuckerbraun ◽  
Timothy R. Billiar ◽  
Sherrie L. Otterbein ◽  
Peter K.M. Kim ◽  
Fang Liu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Cell Death ◽  
Protective Effect ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Protective Effects ◽  
In Vivo Models

Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor α–induced hepatocyte cell death in mice, we find that activation of nuclear factor κB and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection.

Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?

2018 ◽  
Vol 24 (20) ◽  
pp. 2264-2282 ◽  
Author(s):  
Christopher P. Hopper ◽  
Lorenz Meinel ◽  
Christoph Steiger ◽  
Leo E. Otterbein
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Capital Investment ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Commercial Development ◽  
Protective Enzyme ◽  
Rate Limiting Step ◽  
Rate Limiting ◽  
Development Perspective

Heme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physician’s toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?

Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock

2009 ◽  
Vol 36 (1) ◽  
pp. 42-48 ◽  
Author(s):  
Shoji Takaki ◽  
Naoshi Takeyama ◽  
Yuka Kajita ◽  
Teru Yabuki ◽  
Hiroki Noguchi ◽  
...  
Keyword(s):  
Septic Shock ◽  
Carbon Monoxide ◽  
Severe Sepsis ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Beneficial Effects

scholarly journals Therapeutic Potential of Carbon Monoxide (CO) and Hydrogen Sulfide (H2S) in Hemolytic and Hemorrhagic Vascular Disorders—Interaction between the Heme Oxygenase and H2S-Producing Systems

2020 ◽  
Vol 22 (1) ◽  
pp. 47
Author(s):  
Tamás Gáll ◽  
Dávid Pethő ◽  
Annamária Nagy ◽  
György Balla ◽  
József Balla
Keyword(s):  
Carbon Monoxide ◽  
Hydrogen Sulfide ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Cellular Metabolism ◽  
Heme Oxygenase 1 ◽  
New Therapeutic Approaches ◽  
Hemoglobin Oxidation ◽  
Biological Responses ◽  
Human Disorders

Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit.

scholarly journals Heme Oxygenase-1 and Carbon Monoxide in the Heart

2016 ◽  
Vol 118 (12) ◽  
pp. 1940-1959 ◽  
Author(s):  
Leo E. Otterbein ◽  
Roberta Foresti ◽  
Roberto Motterlini
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Cardiovascular Health ◽  
Tissue Injury ◽  
Cellular Reprogramming ◽  
Heme Oxygenase 1 ◽  
Heart Repair ◽  
Inflammatory Processes ◽  
Cardiac Cell Therapy ◽  
Shock Proteins

Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.

scholarly journals Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury

2016 ◽  
Vol 310 (5) ◽  
pp. F385-F394 ◽  
Author(s):  
Subhashini Bolisetty ◽  
Amie Traylor ◽  
Reny Joseph ◽  
Abolfazl Zarjou ◽  
Anupam Agarwal
Keyword(s):  
Transgenic Mice ◽  
Proximal Tubule ◽  
Heme Oxygenase ◽  
Kidney Injury ◽  
Cellular Level ◽  
Proximal Tubules ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Beneficial Effects ◽  
By Products

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. The beneficial effects of HO-1 expression are not merely due to degradation of the pro-oxidant heme but are also credited to the by-products that have potent, protective effects, including antioxidant, anti-inflammatory, and prosurvival properties. This is well reflected in the preclinical animal models of injury in both renal and nonrenal settings. However, excessive accumulation of the by-products can be deleterious and lead to mitochondrial toxicity and oxidative stress. Therefore, use of the HO system in alleviating injury merits a targeted approach. Based on the higher susceptibility of the proximal tubule segment of the nephron to injury, we generated transgenic mice using cre-lox technology to enable manipulation of HO-1 (deletion or overexpression) in a cell-specific manner. We demonstrate the validity and feasibility of these mice by breeding them with proximal tubule-specific Cre transgenic mice. Similar to previous reports using chemical modulators and global transgenic mice, we demonstrate that whereas deletion of HO-1, specifically in the proximal tubules, aggravates structural and functional damage during cisplatin nephrotoxicity, selective overexpression of HO-1 in proximal tubules is protective. At the cellular level, cleaved caspase-3 expression, a marker of apoptosis, and p38 signaling were modulated by HO-1. Use of these transgenic mice will aid in the evaluation of the effects of cell-specific HO-1 expression in response to injury and assist in the generation of targeted approaches that will enhance recovery with reduced, unwarranted adverse effects.

scholarly journals Beneficial effects of the heme oxygenase-1/carbon monoxide system

Critical Care ◽  
2009 ◽  
Vol 13 (Suppl 1) ◽  
pp. P367
Author(s):  
N Takeyama ◽  
S Takaki ◽  
Y Kajita ◽  
T Yabuki ◽  
H Noguchi ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Beneficial Effects
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