Heme oxygenase-1: unleashing the protective properties of heme

Otterbein, Leo E.; Soares, Miguel P.; Yamashita, Kazuo; Bach, Fritz H.

doi:10.1016/s1471-4906(03)00181-9

Cited by 1,088 publications

(931 citation statements)

References 55 publications

Supporting

Mentioning

886

Contrasting

Unclassified

Order By: Relevance

“…The known cytoprotective, antioxidative and anti-inflammatory properties of the CD163/heme oxygenase-1 system 16,18 together with the data on its adipose tissue expression presented here, make low heme oxygenase-1 expression a putative powerful marker for detrimental adipose tissue quality. This notion is strongly confirmed by the negative correlation of relative visceral adipose HMOX1 expression with the HOMA-IR (Figure 4).…”

Section: Discussionmentioning

confidence: 71%

“…16 Moreover, CD163-mediated uptake of hemoglobin into the macrophage fuels an anti-inflammatory response driven by heme oxygenase-1 activity, leading to potent anti-inflammatory heme metabolites. 17,18 A soluble form of CD163 (sCD163) of unknown function is found in serum and its concentration is elevated in sepsis, myeloid leukemia, Gaucher disease 19 and atherosclerosis. 20 Moreover, sCD163 serum concentration has been shown to increase with obesity in patients with chronic kidney disease.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

et al. 2009

View full text Add to dashboard Cite

Objective: Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance. Methods: CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI) 440 kg m À2 ), who underwent laparoscopic surgery for gastric banding (n ¼ 20), matched for age and sex to controls (BMIo30 kg m À2 ; n ¼ 20) was analyzed. Results: CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P ¼ 0.024). Conclusions: Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

show abstract

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

et al. 2009

View full text Add to dashboard Cite

show abstract

“…SnPP, a selective inhibitor of HO-1 activity [61], was obtained from Frontier Scientific (Logan, UT). Recombinant murine CXCL1 and CXCL2 were purchased from PeproTech (London, UK).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

View full text Add to dashboard Cite

Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All antigranulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAPinduced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury. IntroductionAcetaminophen (APAP) is widely prescribed as an analgesic and antipyretic drug in clinics and is also sold as numerous over-counter preparations as a single compound or in combination with other medications [1, 2]. Although it is generally safe, an overdose of APAP can cause severe liver failure with a significant morbidity and mortality. Thus, its wide availability and severe toxicities has placed APAP overdose as the leading cause for calls to Poison Control Centers in the United States (>100 000/year). Moreover, APAP overdose accounts for more than 56 000 emergency room visits, 2600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year in the United States alone [3]. The toxic response is initiated by the metabolism of APAP to a toxic metabolite, N-acetyl-p-benzoquinone imine. Because N-acetyl-p-benzoquinone imine can react rapidly with sulfhydryl groups, it first depletes glutathione in hepatocytes and then reacts with a number of intracellular proteins, thereby causing their dysfuntions [4, 5]. APAP-induced liver injury is histopathologically characterized by centrilobular hepatic necrosis with a massive infiltration of leukocytes, particularly neutrophils. The recruitment of leukocytes in the damaged tissue is a hallmark of the inflammatory process, which may contribute to the development of APAP-induced liver injury [6,7]. In line with this assumption, accumulating evidence has implicated neutrophils as the leukocyte type essentially involved i...

show abstract

“…In addition, the previously diseased or injured lungs are more susceptible to subsequent mechanical ventilation, releasing more proinflammatory cytokines than healthy lungs, perhaps reflecting the cumulative effects of multiple injuries (8, 9). Lipopolysaccharide (LPS), acid aspiration, and cecal ligation/perforation-induced sepsis are commonly used models for approximating previous lung injury in .Accumulating data exist in the literature supporting the paradigm that the stress-inducible heme oxygenase-1 (HO-1), or its catalytic by-product, carbon monoxide (CO), can confer potent cytoprotective effects in various models of tissue and cellular injury (13)(14)(15)(16)(17)(18)(19). One mechanism by which HO-1 or CO mediate a cytoprotective effect is via its potent antiinflammatory properties (13,14).…”

mentioning

confidence: 99%

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Dolinay

Szilasi

Liu

et al. 2004

Am J Respir Crit Care Med

138

127

View full text Add to dashboard Cite

Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units. The stress-inducible gene product, heme oxygenase-1, and carbon monoxide (CO), a major byproduct of heme oxygenase catalysis of heme, have been shown to confer potent antiinflammatory effects in models of tissue and cellular injury. In this study, we observed increased expression of heme oxygenase-1 mRNA and protein in a rat model of VILI. To assess the physiologic function of heme oxygenase-1 induction in VILI, we determined whether low concentration of inhaled CO could serve to protect the lung against VILI. Low concentration of inhaled CO significantly reduced tumor necrosis factor-␣ levels and total cell count in lavage fluid, while simultaneously elevating levels of antiinflammatory interleukin-10 levels. To better characterize the mechanism of CO-mediated antiinflammatory effects, we examined key signaling pathways, which may mediate CO-induced antiinflammatory effects. We demonstrate that inhaled CO exerts antiinflammatory effects in VILI via the p38 mitogen-activated protein kinase pathway but independent of activator protein-1 and nuclear factor-B pathways. Our data lead to a tempting speculation that inhaled CO might be useful in minimizing VILI. Keywords: cytokines; heme oxygenase-1; p38 MAPKAccording to an international study, an average of 39% of intensive care unit patients requires mechanical ventilation worldwide (1). Many of these patients develop ventilator-induced lung injury (VILI) (2). Eventually VILI contributes to acute respiratory distress syndrome (ARDS), which has a 40 to 50% mortality rate (3). Although clinical trials showed that ARDS/VILI-related mortality could be attenuated with lower tidal volume ventilation, positive end-expiratory pressure (PEEP) ventilation, and more recently, with recruitment maneuver combined with protective ventilation strategy, the syndrome remains a major problem in intensive care units (3)(4)(5).It is established that mechanical ventilators that apply high volumes and pressures can lead to increased alveolar-capillary permeability (6). This loss of compartmentalization results in increased fluid influx to the alveoli from the capillaries, causing pulmonary edema. The injured or ruptured cells attract neutrophil leukocytes and activate alveolar macrophages, causing inflammation in the lung (6). Tremblay and colleagues have suggested that ventilation can provoke an inflammatory response in the distal airway and alveolar cells (7), manifested by increased production of proinflammatory cytokines. It is speculated that the released proinflammatory cytokines could enter the circulation causing inflammation in other systemic organs. In addition, the previously diseased or injured lungs are more susceptible to subsequent mechanical ventilation, releasing more proinflammatory cytokines than healthy lungs, perhaps reflecting the cumulative effects of multiple injuries (8, 9). Lipopolysaccharide (LPS), acid aspiration, and cecal ligation/perforation-induced sep...

show abstract

Heme oxygenase-1: unleashing the protective properties of heme

Cited by 1,088 publications

References 55 publications

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Contact Info

Product

Resources

About