Heme oxygenase-1 inhibitor tin-protoporphyrin improves liver regeneration after partial hepatectomy

Background Heme oxygenase 1 (HO-1) has been shown to attenuate neuronal injury. Therefore, the authors examined whether HO-1 would reduce the brain damage caused by cardiac arrest. Methods Rats anesthetized with halothane were subjected to 8 min of cardiac arrest by asphyxia without any pretreatment (control group) or pretreated with an inducer of HO-1 (hemin group) or with an inhibitor of HO-1 (tin protoporphyrin group). Then, the animals were resuscitated with a standardized method. Brain water content (1 and 6 h after resuscitation), neurologic deficit score, viable neuronal counts, and caspase-3 immunostaining in the hippocampus (4 and 14 days) were evaluated. Results Water content in the hemin group was significantly reduced (mean +/- SD: 83.1 +/- 1.9% for 1 h after resuscitation; P = 0.03) and significantly greater in the tin protoporphyrin group (91.1 +/- 2.0% for 1 h after resuscitation; P = 0.035) when compared with the control group (88.2 +/- 2.4%). Water content of the cortex was nearly the same as that of the hippocampus. Neurologic deficit scores and neuronal survival were significantly better in the hemin group than in the control group on the 4th and 14th days. In rats that survived for 4 days, the amount of caspase 3-positive neurons was 27 +/- 7 in the control group, whereas the value was 14 +/- 6 in the hemin group (P < 0.05). Conclusions In rats resuscitated from cardiac arrest, induction of HO-1 by hemin reduced brain edema, improved neurologic outcome, and protected neurons against apoptosis.

Download Full-text

Lung-specific induction of heme oxygenase-1 and hyperoxic lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.4.l582 ◽

1998 ◽

Vol 274 (4) ◽

pp. L582-L590 ◽

Cited By ~ 12

Author(s):

Jennifer L. Taylor ◽

Martha Sue Carraway ◽

Claude A. Piantadosi

Keyword(s):

Oxidative Stress ◽

Enzyme Activity ◽

Lung Injury ◽

Heme Oxygenase ◽

Normal Saline ◽

Dry Weight ◽

Heme Oxygenase 1 ◽

Specific Induction ◽

Hyperoxic Lung Injury ◽

Tin Protoporphyrin

Heme oxygenase (HO)-1, which catalyzes heme breakdown, is induced by oxidative stress and may protect against oxidative injury. We hypothesized that induction of HO-1 by hemoglobin (Hb) in the lung would protect the rat from pulmonary O2 toxicity. Rats given intratracheal (IT) Hb showed lung-specific induction of HO-1 by 8 h by Western analysis. Rats were then pretreated for 8 h before 60 h of exposure to 100% O2 with either IT normal saline, Hb, or Hb plus the HO-1 inhibitor tin-protoporphyrin (SnPP). Both the Hb+O2 and Hb+O2+ SnPP animals had less lung injury than normal saline controls as indicated by lower pleural fluid volumes and wet-to-dry weight ratios ( P < 0.01). The improvement in injury in the two Hb-treated groups was the same despite a 61% decrease in HO enzyme activity in the Hb+SnPP group after 60 h of O2. In addition, inhibition of HO activity with SnPP alone before O2exposure did not augment the extent of hyperoxic lung injury. These results demonstrate that IT Hb induces lung HO-1 in the rat and protects against hyperoxia; however, the protection is not mediated by increased HO enzyme activity.

Download Full-text

Induction of ferritin and heme oxygenase-1 by endotoxin in the lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.275.3.l583 ◽

1998 ◽

Vol 275 (3) ◽

pp. L583-L592 ◽

Cited By ~ 19

Author(s):

M. S. Carraway ◽

A. J. Ghio ◽

J. L. Taylor ◽

C. A. Piantadosi

Keyword(s):

Oxidative Stress ◽

Enzyme Activity ◽

Heme Oxygenase ◽

Bronchial Epithelium ◽

Heme Oxygenase 1 ◽

Mrna Synthesis ◽

Alveolar Region ◽

Iron Sequestration ◽

Tin Protoporphyrin ◽

Expression And Activity

Heme oxygenase (HO)-1 expression is increased by forms of oxidative stress that also induce ferritin. Even though this could result from release of iron by heme degradation, we hypothesized that ferritin expression in the lung after endotoxin [lipopolysaccharide (LPS)] would occur independently of HO-1 because iron sequestration is an important response to infection. We tested this hypothesis by instilling saline or LPS (1 mg) into lungs of rats and measuring ferritin expression, HO-1 expression and activity, and HO-1 and ferritin mRNAs at different times. Lungs were also inflation fixed for immunohistochemistry for HO-1 and ferritin. Studies were performed with and without the HO inhibitor tin protoporphyrin. Ferritin and HO-1 labeling were minimal (macrophages only) in control lungs. By 4 h after LPS instillation, ferritin staining was present in bronchial epithelium and macrophages, became diffuse at 16 h, and was nearly gone by 48–72 h. HO-1 was detectable in macrophages 4 and 16 h after LPS instillation, increased in macrophages and bronchial epithelium at 24 h, and diffusely increased in bronchial epithelium and the alveolar region at 48–72 h. Lung ferritin content increased significantly by 4 h and peaked at 16 h before declining. HO-1 protein was present by Western blot in control lung, stable at 4 h, and increased by 24 h after LPS instillation, whereas HO enzyme activity had increased by 4 h after LPS instillation. After complete inhibition of HO enzyme activity with tin protoporphyrin, ferritin increased threefold at 4 h and sixfold at 24 h after LPS instillation. HO-1 mRNA increased by 4 h and was sustained at 24 h, whereas ferritin mRNA did not change after LPS instillation. These results indicate that intratracheal LPS rapidly induces ferritin protein in the lung independently of its mRNA synthesis or HO enzyme activity. LPS induces HO-1 mRNA, which is followed by increased expression of protein.

Download Full-text

Nitric oxide synthase inhibition and the induction of cytochrome P-450 affect heme oxygenase-1 messenger RNA expression after partial hepatectomy and acute inflammation in rats

Critical Care Medicine ◽

10.1097/00003246-199810000-00023 ◽

1998 ◽

Vol 26 (10) ◽

pp. 1683-1689 ◽

Cited By ~ 10

Author(s):

Said Lyoumi ◽

Herve Puy ◽

Fabienne Tamion ◽

Michel Scotte ◽

Maryvonne Daveau ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Partial Hepatectomy ◽

Heme Oxygenase ◽

Messenger Rna ◽

Acute Inflammation ◽

Heme Oxygenase 1 ◽

Rna Expression ◽

Oxide Synthase ◽

Cytochrome P 450

Download Full-text

Motexafin Gadolinium and Other Metallotexaphyrins Upregulate Heme Oxygenase-1.

Blood ◽

10.1182/blood.v106.11.4468.4468 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4468-4468

Author(s):

Mint Sirisawad ◽

Jun Chen ◽

Jason Ramos ◽

Richard A. Miller ◽

Louie Naumovski

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Chemical Structure ◽

Heme Oxygenase 1 ◽

Oxygen Species ◽

Redox Stress ◽

Motexafin Gadolinium ◽

Protein Thiols ◽

Tin Protoporphyrin ◽

First Time

Abstract Heme oxygenase-1 (HO-1) is an inducible enzyme that is upregulated by heme and acts to degrade heme into bilirubin, carbon monoxide and iron. HO-1 is known to be upregulated in response to oxidative stress and has anti-apoptotic properties. Motexafin gadolinium (MGd, Xcytrin®) is a tumor-selective redox mediator that produces oxidative stress in cancer cells by reacting with various reducing metabolites and protein thiols to generate reactive oxygen species. Also, MGd is an expanded porphyrin that has a chemical structure which resembles heme. Since redox stress and heme upregulate HO-1 expression, we hypothesized that MGd would produce similar effects. We treated 8 hematopoietic tumor-derived cell lines with MGd and found that 2 of them (Ramos and HF-1) upregulated HO-1 protein. In Ramos lymphoma cells, we found that MGd induced HO-1 up to 8 fold by 24 hrs and that longer incubations did not result in appreciably greater amounts of protein. HO-1 levels returned to baseline in Ramos cells 48 hrs after cells were cultured in fresh media in the absence of MGd. HO-1 levels were elevated at baseline in HF-1 cells (compared to Ramos) and increased about 2 fold with MGd treatment. Other metallotexaphyrins, europium texaphyrin and dysprosium texaphyrin, also induced HO-1 expression. To determine if HO-1 expression was important for cell survival, we co-treated cells with MGd and tin protoporphyrin (SnPP), an inhibitor of HO-1 enzymatic activity. We found that both HF-1 and Ramos cells were sensitized to MGd-induced cell death by SnPP. These results demonstrate for the first time that metallotexaphyrins can upregulate HO-1 expression. The induction of HO-1 could be related to oxidative stress and/or metallotexaphyrins acting as heme mimetics.

Download Full-text

Regulation of Heme Oxygenase 1 Expression by miR-27b With Stem Cell Therapy for Liver Regeneration in Rats

Transplantation Proceedings ◽

10.1016/j.transproceed.2013.12.013 ◽

2014 ◽

Vol 46 (4) ◽

pp. 1198-1200 ◽

Cited By ~ 12

Author(s):

K.-D. Chen ◽

L.-W. Hsu ◽

S. Goto ◽

K.-T. Huang ◽

T. Nakano ◽

...

Keyword(s):

Stem Cell ◽

Cell Therapy ◽

Liver Regeneration ◽

Heme Oxygenase ◽

Stem Cell Therapy ◽

Heme Oxygenase 1

Download Full-text

Deceleration of Liver Regeneration by Knockdown of Heme Oxygenase-1 is Associated With Impairment of Liver Injury Recovery After Reduced-Size Liver Transplantation in Rats

Transplantation Proceedings ◽

10.1016/j.transproceed.2019.11.051 ◽

2020 ◽

Vol 52 (3) ◽

pp. 1001-1006

Author(s):

Bing Cheng ◽

Hua Xie ◽

Junjun Jia ◽

Man Wu ◽

Junling Guo ◽

...

Keyword(s):

Liver Transplantation ◽

Liver Injury ◽

Liver Regeneration ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Injury Recovery

Download Full-text

Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.2.h643 ◽

2000 ◽

Vol 278 (2) ◽

pp. H643-H651 ◽

Cited By ~ 245

Author(s):

James E. Clark ◽

Roberta Foresti ◽

Padmini Sarathchandra ◽

Harparkash Kaur ◽

Colin J. Green ◽

...

Keyword(s):

Infarct Size ◽

Heme Oxygenase ◽

Myocardial Function ◽

Myocardial Dysfunction ◽

Protoporphyrin Ix ◽

Heme Oxygenase 1 ◽

Heme Oxygenase Activity ◽

Oxygenase Activity ◽

Tin Protoporphyrin

Bilirubin is a potent antioxidant generated intracellularly during the degradation of heme by the enzyme heme oxygenase. The purpose of this study was to determine the role of increased cardiac bilirubin in protection against postischemic myocardial dysfunction. Rat hearts were isolated and perfused according to the Langendorff technique to evaluate the recovery of myocardial function after 30 min of global ischemia and 60 min of reperfusion. We found that upregulation of the inducible isoform of heme oxygenase (HO-1) by treatment of animals with hemin 24 h before ischemia ameliorated myocardial function and reduced infarct size (tetrazolium staining) on reperfusion of isolated hearts. Tin protoporphyrin IX, an inhibitor of heme oxygenase activity, completely abolished the improved postischemic myocardial performance observed after hemin-mediated HO-1 induction. Likewise, cardiac tissue injury was exacerbated by treatment with tin protoporphyrin IX. Increased cardiac HO-1 expression and heme oxygenase activity were associated with enhanced tissue bilirubin content and an increased rate of bilirubin release into the perfusion buffer. Furthermore, exogenously administered bilirubin at concentrations as low as 100 nanomolar significantly restored myocardial function and minimized both infarct size and mitochondrial damage on reperfusion. Our data provide strong evidence for a primary role of HO-1-derived bilirubin in cardioprotection against reperfusion injury.

Download Full-text

HbG200-mediated preinduction of heme oxygenase-1 improves bile flow and ameliorates pericentral downregulation of Bsep and Mrp2 following experimental liver ischemia and reperfusion

Biological Chemistry ◽

10.1515/hsz-2012-0153 ◽

2013 ◽

Vol 394 (1) ◽

pp. 97-112 ◽

Cited By ~ 7

Author(s):

Markus G. Donner ◽

Stefan A. Topp ◽

Patricia Cebula ◽

Anna Krienen ◽

Thor Gehrmann ◽

...

Keyword(s):

Heme Oxygenase ◽

Bile Flow ◽

Protoporphyrin Ix ◽

Transport Systems ◽

Heme Oxygenase 1 ◽

Reperfusion Period ◽

Tin Protoporphyrin ◽

Experimental Liver ◽

Hepatocellular Cholestasis ◽

Transporter Expression

Abstract We studied the downregulation of hepatobiliary transport systems and the effect of pharmacological heme oxygenase-1 (HO-1) preinduction by Hemoglobin-Glutamer 200 (HbG200) in cold ischemia-reperfused rat liver (I/R). Cold I/R reduced bile flow in the reperfusion period from 3.10±0.10 ml/3 h to 0.54±0.20 ml/3 h (p<0.05) and biliary taurocholate excretion from 45.9±13.81 μmol/3 h to 1.87±0.46 μmol/3 h (p<0.05). Mrp2, Bsep and Ntcp peak immunofluorescence in pericentral hepatocytes decreased to 79.0±2.6% (p<0.001), 80.6±8.4% (p<0.05) and 65.8±5.0% (p<0.01), respectively. Pre-induction of HO-1 by HbG200 was largely confined to pericentral hepatocytes. HO-1 induction attenuated the decreased bile flow (0.91±0.16 ml/3 h, p<0.05) and canalicular taurocholate secretion (4.33±1.71 μmol/3 h, p<0.05). Bsep and Mrp2 peak immunofluorescence in pericentral hepatocytes was largely restored. Activation of JNK and Fyn by cold I/R was significantly attenuated by HO-1. Inhibiting HO activity by tin protoporphyrin IX after HbG200 administration reversed the effect on bile flow and canalicular transporter expression. In conclusion, pericentral downregulation of Bsep and Mrp2 following cold I/R is ameliorated by inducing HO-1 and was associated with diminished hepatocellular JNK and Fyn signaling. HO-1 may serve as a therapeutic target to attenuate hepatocellular cholestasis following I/R injury.

Download Full-text