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

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.

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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.

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Heme oxygenase-1 attenuates seawater drowning-induced acute lung injury through a reduction in inflammation and oxidative stress

International Immunopharmacology ◽

10.1016/j.intimp.2019.05.019 ◽

2019 ◽

Vol 74 ◽

pp. 105634 ◽

Cited By ~ 5

Author(s):

Xue-qian Sun ◽

Chen Wu ◽

Yu-bao Qiu ◽

Ya-Xian Wu ◽

Jun-liang Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

And Oxidative Stress

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Expression Profiling of microRNAs Related to Heme Oxygenase−1 in a Mouse Model of Hyperoxic Lung Injury

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2013.10.795 ◽

2013 ◽

Vol 65 ◽

pp. S158-S159

Author(s):

Hayato Go ◽

Ping La ◽

Fumihiko Namba ◽

Patrick Amal Fernando ◽

Guang Yang ◽

...

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Heme Oxygenase ◽

Expression Profiling ◽

Heme Oxygenase 1 ◽

Hyperoxic Lung Injury

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Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury.

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.14.6.8652184 ◽

1996 ◽

Vol 14 (6) ◽

pp. 556-568 ◽

Cited By ~ 152

Author(s):

P J Lee ◽

J Alam ◽

S L Sylvester ◽

N Inamdar ◽

L Otterbein ◽

...

Keyword(s):

Lung Injury ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Hyperoxic Lung Injury

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Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.6.l1214 ◽

1999 ◽

Vol 277 (6) ◽

pp. L1214-L1223 ◽

Cited By ~ 6

Author(s):

Funmei Yang ◽

Jacqueline J. Coalson ◽

Heather H. Bobb ◽

Jacqueline D. Carter ◽

Jameela Banu ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Injury ◽

Alveolar Macrophages ◽

Lung Damage ◽

Mouse Lung ◽

Heme Oxygenase 1 ◽

Wild Type ◽

Chronic Pulmonary Diseases ◽

Hyperoxic Lung Injury ◽

Key Participants

Oxidative stress plays a central role in the pathogenesis of acute and chronic pulmonary diseases. Safe sequestration of iron, which participates in the formation of the hydroxyl radical, is crucial in the lung's defense. We used a mouse line defective in the major iron transport protein transferrin to investigate the effect of aberrant iron metabolism on the lung's defense against oxidative injury. The tolerance to hyperoxic lung injury was greater in the hypotransferrinemic than in wild-type mice as documented by histopathology and biochemical indexes for lung damage. There was no increase in the levels of intracellular antioxidants, inflammatory cytokines, and heme oxygenase-1 in the hypotransferrinemic mouse lung compared with those in wild-type mice. However, there were elevated expressions of ferritin and lactoferrin in the lung of hypotransferrinemic mice, especially in the alveolar macrophages. Our results suggest that pulmonary lactoferrin and ferritin protect animals against oxidative stress, most likely via their capacity to sequester iron, and that alveolar macrophages are the key participants in iron detoxification in the lower respiratory tract.

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Inhalation of Hydrogen Reduced Hyperoxic Lung Injury in Rat Through Heme Oxygenase-1 Induction

Journal of Surgical Research ◽

10.1016/j.jss.2011.11.430 ◽

2012 ◽

Vol 172 (2) ◽

pp. 262-263 ◽

Cited By ~ 3

Author(s):

T. Kawamura ◽

C. Huang ◽

K. Masutani ◽

Y. Tanaka ◽

N. Shigemura ◽

...

Keyword(s):

Lung Injury ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Hyperoxic Lung Injury

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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.

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