Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2.

Dennery, Phyllis A.; Spitz, Douglas R.; Guang, Yang; Tatarov, Arthur; Lee, C. S.; Shegog, Mychelle; Poss, Kenneth D.

doi:10.1172/jci448

Cited by 209 publications

(126 citation statements)

References 52 publications

(47 reference statements)

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“…Nath et al (2,41,42) showed that a decrease in HO activity predisposed rats to marked tubular interstitial inflammation and mortality after repetitive dosing with hemoglobin. It is also in agreement with those who have studied HO-2 deficiency in the heart and lung (43). A lowered HO activity in HO-2 (Ϫ/Ϫ) compared with HO-2 (ϩ/ϩ) mice therefore would diminish ferritin synthesis and increase tissue iron deposits.…”

Section: Discussionsupporting

confidence: 92%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

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Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

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Section: Discussionsupporting

confidence: 92%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

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“…31,49 These include heme oxygenase, 49,50 which recently has been shown to offer protection from the development of atherosclerosis and to reduce oxidation products in HDL. 51,52 Alternatively, the protective effect of HBO treatment may be mediated by the suppression of specific enzymes responsible for lipid oxidation.…”

Section: Discussionmentioning

confidence: 99%

Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits

Kudchodkar

Wilson

Lacko

et al. 2000

ATVB

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Abstract-We studied the effect of hyperbaric oxygen (HBO) treatment on the extent of diet-induced accumulation of lipid oxidation products in rabbit plasma and tissues, on plasma paraoxonase activity, and on the extent of progression and regression of atherosclerotic lesions in the rabbit aorta. HBO treatment of cholesterol-fed rabbits dramatically reduces the development of arterial lesions despite having little or no effect on plasma or individual lipoprotein cholesterol concentrations. Compared with no treatment in cholesterol-fed animals, HBO treatment also substantially reduces the accumulation of lipid oxidation products (conjugated dienes, trienes, and thiobarbituric acid-reactive substances) in plasma, in the low density lipoprotein and high density lipoprotein fractions of plasma, in the liver, and in the aortic tissues. In addition, HBO treatment prevents the decrease in plasma paraoxonase activity observed in rabbits fed cholesterol-rich diets. Similarly, in regression studies, HBO treatment has no effect on the rate of plasma (or lipoprotein) cholesterol decline but significantly accelerates aortic lesion regression compared with no treatment. Direct measures of aortic cholesterol content support these morphological observations. On the basis of these results, we conclude that repeated, but relatively short, exposure to HBO induces an antioxidant defense mechanism(s) that is responsible for retarding the development or accelerating the regression of atherosclerotic lesions.

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“…If iron transport and storage proteins do not rapidly and effectively remove this LMrFe, the argument for HO as an antioxidant becomes flawed. Experiments with HO-2 knock-out mice reveal the accumulation of iron in the lung after hyperoxic exposure ; this occurs without the induction of ferritin [24]. Indeed, the protective effects attributed to HO might actually reside in the induction of ferritin, rather than in HO-1 itself, as was seen in a rodent rhabdomyolysis model [12].…”

Section: Figure 5 Hne Formationmentioning

confidence: 97%

“…There is much debate at present concerning the pro-oxidant or antioxidant nature of HO in various settings [2,[24][25][26]. Haem has pro-oxidant properties, so its removal by HO can be considered an important antioxidant effect [45].…”

Section: Figure 5 Hne Formationmentioning

confidence: 99%

“…The mechanism of protection is unclear, although the removal of pro-oxidant haem, the antioxidant properties of bilirubin in itro [21,22] and the induction of ferritin synthesis, which sequesters redox-active iron [23], are thought to be involved. However, recent evidence suggests that HO-1 induction might not always be beneficial and that the release of redox-active, low-molecular-mass iron (LMrFe) from haem might be responsible for cellular damage [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron

Lamb

Quinlan

Mumby

et al. 1999

Biochemical Journal

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Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.

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Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2.

Cited by 209 publications

References 52 publications

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits

Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron

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