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Oxidant-mediated reperfusion injury of the gut is a major contributor of the systemic inflammatory response in hemorrhagic shock.
Recent studies have suggested that heme-oxygenase-1 (HO-1) represents an endogenous protective mechanism against oxidant stress. We assessed whether HO-1 induction modulates the synthesis of tumor necrosis factor-
(TNF-) in hemorrhagic shock. In
rats submitted to hemorrhagic shock, pretreatment with hemoglobin (Hb) increased HO-1 mRNA expression in macrophages.
This increased expression was associated with a decreased expression of TNF- mRNA, as well as decreased plasma concentrations
of TNF-. These effects of Hb were reduced by the HO-1 inhibitor
tin-protoporphyrin (Sn-PP 20 µmol/kg), while Sn-PP had no effect
in the absence of Hb. In parallel, Hb pretreatment reduced pulmonary edema, vascular injury, and increased mesenteric blood flow,
and these effects were reduced by Sn-PP. Thus, induction of HO-1
is protective in hemorrhagic shock, possibly through its antioxidant properties. Interventions that induce HO-1 may be beneficial
in the treatment of shock states, leading to a reduced systemic inflammatory response.
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Keywords: hemorrhagic shock; ischemia/reperfusion; IL-6; TNF-;
heme-oxygenase; hemoglobin
Multiple organ failure, the leading cause of death in Intensive Care Units (1), is characterized by a generalized inflammatory response (2), that may largely originate from the gut (3). Recently, we have shown that gut ischemia/reperfusion is a major contributor of the systemic inflammatory response which occurs in hemorrhagic shock (4). However, the molecular mechanisms that link gut injury and systemic inflammation are still partly unknown.
Heme-oxygenase (HO) catalyzes the first and rate-limiting step in the oxidative degradation of heme to carbon monoxide (CO), bilirubin, and iron (5). CO is a gas molecule that shares some of the properties of NO, especially the capacity to activate soluble guanylate cyclase (8, 9). Two isoenzymes of HO, HO-1 and HO-2, exist and are the products of two distinct genes (10). HO-2 is expressed constitutively, while HO-1 is highly induced by heme, but also by oxidative stress (14). Such induction may be protective against oxidative stress through the production of bilirubin, a metabolite with antioxidant properties (18, 19). Indeed, HO-1 induction increases antioxidant defenses in rats and decreases mortality in septic shock (20), and also prevents venular leukocyte adhesion after hemorrhage (19). Moreover, CO produced by HO-1 may induce vasodilatation (21), which could also be protective in situations of organ injury. However, whether HO-1 modulates the systemic inflammatory response in situations such as hemorrhagic shock is largely unknown.
Thus, the aim of the study was to investigate whether HO-1
induction modulates the production of tumor necrosis factor-
(TNF-) in rats subjected to hemorrhagic shock.
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Animals
Adult male Wistar rats, weighing 300-320 g each, were kept at 25° C with 12 h light/dark cycles. Animals were fasted 16-20 h before experimentation and allowed water ad libitum.
Preparation of Peritoneal Macrophages
Peritoneal macrophages were harvested by five consecutive washes of the peritoneal cavity with 10 ml of ice cold medium containing 5% fetal calf serum, 100 U/ml penicillin, and 1% glutamine. Cells were washed once with RPMI medium and centrifuged at 280 × g for 15 min at 4° C. The pellet was dispersed and used for RNA extraction.
RNA Isolation and RT-PCR
Total RNA extraction was extracted from peritoneal macrophages according to a one-step method, as described previously (4). Reverse transcription protocols were performed with 2 µg of total RNA in 30 µl (final volume) of reaction buffer. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control. Aliquots of the reverse transcription reaction were amplified with the following rat primers :
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The number of polymerase chain reaction (PCR) cycles was 24 for
TNF- and 30 for HO-1. Products were separated by electrophoresis, and gels were stained with ethidium bromide, illuminated with ultraviolet (UV) light, and measured by quantitative scanning densitometry of autoradiographs. These analyses were normalized to the amount
of amplified GAPDH as an endogenous internal standard.
Production of TNF-
TNF- concentration was measured by immunoassay (Biosource International Cytoscreen Rat TNF- Ultrasensitive Elisa). The plasma was passed through a 0.22-mm filter before use. The minimal detectable dose of TNF- is < 0.7 pg/ml.
Measurement of Mesenteric Blood Flow
Anesthetized rats were subjected to laparotomy under sterile conditions. A Doppler probe (internal diameter 1-1.5 mm) was placed around the mesenteric artery and connected to a Triton System 6 signal processor and a Gould chart recorder, in order to measure mesenteric blood velocity and to calculate mesenteric blood flow (4).
Determination of Fluid Resuscitation Requirement
Animals in all groups with hemorrhagic shock required fluid resuscitation in addition to the reinjection of their shed blood to maintain their mean arterial pressure (MAP) to at least 90% of baseline. The cumulative fluid requirements after 3 h of resuscitation was used as an indicator of vascular injury after shock.
Determination of Lung Wet-weight to Dry-weight Ratio
The changes in pulmonary microvascular permeability were evaluated by the measurement of the lung wet-weight to dry-weight ratio (25). Lung tissus samples were dried at 80° C for 24 h. The dry tissue weight was then determined and wet-weight to dry-weight ratios were calculated as an index of pulmonary edema.
Induction of Hemorrhagic Shock
Rats were anesthetized with 50 mg/kg body weight of pentobarbital intraperitoneally. The carotid arteries and the jugular vein were dissected out using sterile techniques and then cannulated with polyethylene tubing (PE 20). Catheters were inserted into the jugular vein for fluid injection, the left carotid artery for measurement of blood pressure (Millar 2F catheter), and the right carotid for the induction of hemorrhage. Hemorrhage was initiated by bleeding the animal into a heparinized syringe over a period of 30 min to achieve a mean arterial blood pressure of 40 mm Hg. In this model, the rate of blood withdrawal was 0.3 ml/min and the volume of blood withdrawn was 25 ml/kg and was not different between groups. This level of blood pressure was maintained for 60 min by further blood withdrawal or by reinfusing the shed blood. At this point, animals were resuscitated over 20 min by first returning all shed blood, followed by administering warmed NaCl 0.9% in volumes necessary to maintain MAP within 90% of baseline levels. If MAP was < 90% of baseline, 5 ml/kg NaCl 0.9% was infused and MAP was measured again after 5 min. This process was continued until MAP was > 90% of baseline. Fluid resuscitation was continued for 3 h.
At the end of the resuscitation period, the surviving rats were subjected to laparotomy and peritoneal macrophages were harvested for
the measurements of TNF-. Carotid and mesenteric blood samples were collected in syringes containing 5 U heparin. Samples were immediatly centrifuged at 10,000 g for 20 min, and plasma was stored at
80° C until it was used for measurement of TNF- and lactate.
Experimental Protocols
HO-1 induction was obtained by administering rat hemoglobin 50 mg/kg (Sigma Chemical Co, St Louis, MO) in normal saline intravenously, 16 h before resuscitation of hemorrhagic shock. The preparation was made under sterile conditions to be free of lipopolysaccharide (LPS). A 16 h pretreatment was chosen because previous reports have indicated that it corresponds to the peak HO-1 activity in rat tissues (20, 26).
HO-1 mRNA expression in peritoneal macrophages after hemorrhagic shock. Rats (n = 10 per group) were assigned to 12 experimental groups. They were subjected either to sham surgery or to hemorrhagic shock without (time 0) or with 1, 2, or 3 h saline restitution, without or with Hb pretreatment. At the end of each experiment, macrophages were isolated for the measurement of HO-1 mRNA expression.
Effect of hemoglobin on HO-1 mRNA expression in lungs. HO-1 mRNA expression in lungs was studied in rats subjected to hemorrhage alone or hemorrhage followed by 1, 2, or 3 h of saline restitution, without or with hemoglobin pretreatment.
Role of HO-1 induction or inhibition on TNF- production after
hemorrhagic shock.
TNF- concentrations were assessed in the systemic and mesenteric blood 3 h after resuscitation, as this corresponds
to their maximal peak increase in the present experimental conditions (4).
Data Analysis
Data are presented as means ± SD. Results were compared using t test or ANOVA when appropriate, and a p value less than 0.05 was considered significant.
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Survival
All animals survived in the control groups (C). One animal out of 10 in the HS group died within 3 h of resuscitation, whereas all animals survived in the hemorrhagic shock group receiving Hb (HS+Hb and HS+Hb+Sn-PP) or Sn-PP (HS+Sn-PP).
Hemodynamic Parameters
In controls (C), MAP was maintained at 120 mm Hg throughout the experiment. In the group of rats submitted to hemorrhagic shock, MAP decreased significantly to 40 mm Hg during blood withdrawal and was maintained at this level for 60 min. After saline resuscitation, MAP returned to 120 mm Hg within the first 30 min, without significant difference from the control group (Figure 1). No effect of Hb, Sn-PP, or Hb+Sn-PP on MAP was observed at any time point.
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In controls (C), mesenteric blood flow was maintained around 5.6 ml/min/kg throughout the experiment. In the groups of rats submitted to hemorrhage, mesenteric blood flow decreased significantly to 1.7 ± 0.4 ml/min/kg after hemorrhage and returned to 5.1 ± 0.5 ml/min/kg after saline restitution. This level was below baseline level, although this was not significant. In the group of rats submitted to hemorrhagic shock with Hb pretreatment, mesenteric blood flow decreased significantly to 1.7 ± 0.3 ml/min/kg and returned to baseline level, without significant difference with the HS group. In the group of rats submitted to hemorrhagic shock with Sn-PP pretreatment, mesenteric blood flow decreased significantly to 1.8 ± 0.5 ml/min/kg and returned to baseline level, without significant difference with the HS group. Similar results were found with the HS+Hb+Sn-PP group.
Fluid Resuscitation Requirements
In the four groups of rats with hemorrhagic shock followed by saline restitution (HS), either in the absence or presence of hemoglobin (HS+Hb), or tin-proporphyrin (HS+Sn-PP and HS+Hb+Sn-PP), animals required fluid resuscitation in addition to a complete reinfusion of their shed blood to maintain MAP at a value of at least 90% of the baseline. At 1 h, all animals were alive, and the cumulative fluid requirement was 29 ± 3 ml/kg for the saline group (HS), 25 ± 2 ml/kg for the Hb group (HS+Hb), 28 ± 2 ml/kg for the Sn-PP group (HS+Sn-PP), and 29 ± 2 ml/kg for the Hb+Sn-PP group (HS+Hb+Sn-PP). At this early time point of resuscitation, there were no significant differences between the four groups (Figure 2). However, fluid resuscitation requirements were significantly less in the Hb-treated group (HS+Hb) than in untreated hemorrhagic shock rats (HS). This Hb-induced reduction in fluid requirement was prevented by Sn-PP, while Sn-PP had no effect in the absence of Hb. Indeed the cumulative fluid volumes were 88 ± 3 ml/kg for the untreated group (HS), 60 ± 2 ml/kg for the Hb group, 85 ± 3 ml/kg for the Sn-PP group, and 87 ± 4 ml/kg for the Sn-PP+Hb group (Figure 2). It must be noted that the mean value from the untreated group (HS) is underestimated because of the death of one animal before the end of the experiment.
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Lung Wet-weight to Dry-weight Ratio
In the control group, lung wet-weight to dry-weight ratio was 4.33 ± 0.16. This ratio was increased to 6.19 ± 0.28 in the untreated hemorrhagic shock rats (HS). The hemorrhagic shock-induced lung edema was reduced by hemoglobin pretreatment (4.8 ± 0.3). Sn-PP abolished the effect of Hb on lung edema (6.1 ± 0.4), but had no effect in the absence of Hb (6.2 ± 0.2 ).
HO-1 mRNA Expression in Peritoneal Macrophages after Hemorrhagic Shock
As compared with control rats, hemorrhagic shock without resuscitation did not significantly affect HO-1 mRNA in peritoneal macrophages. During saline resuscitation, an increased HO-1 mRNA expression was first observed at 2 h and further increased at 3 h (Figure 3). On the contrary, HO-1 mRNA expression was not modified at the same times in the control groups without hemorrhagic shock.
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Effect of Hb on HO-1 mRNA Expression in Macrophages and in Lungs after Hemorrhage and Resuscitation
The effect of Hb pretreatment on HO-1 mRNA expression is shown in Figures 4 and 5 for macrophages and lungs, respectively. As compared with untreated rats, Hb pretreatment induced a more than 4-fold induction of HO-1 mRNA expression, and a more than 5-fold induction in the lungs.
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Effect of Hb on TNF- mRNA Expression in Macrophages after
Hemorrhage and Resuscitation
In macrophages isolated from the control group, expression of
TNF- mRNA was undetectable (data not shown). In animals
with hemorrhagic shock, pretreatment with Hb markedly reduced the expression of TNF- (Figure 6). These effects of hemoglobin were abolished by Sn-PP.
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Effect of Hb on Plasma Levels of TNF-
TNF- was not detectable in the control group without hemorrhagic shock (data not shown). Hb significantly attenuated
TNF- production in systemic and mesenteric circulation compared with the value obtained with saline resuscitation alone
(Figure 7).
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Sn-PP had no effect in the absence of Hb, but prevented
the Hb-induced reduction in TNF-. Indeeed, Sn-PP administered after Hb significantly increased TNF- in systemic and
mesenteric circulation compared with the value obtained in
the HS+Hb group (Figure 7).
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In our experiments, we observed a high expression of HO-1
mRNA in peritoneal macrophages after hemorrhagic shock in
rats. Furthermore, evidence that early HO-1 induction plays
an important role in mediating protection against inflammatory response and organ injury after hemorrhagic shock was
provided by the following observations. First, hemoglobin
pretreatment 16 h before shock induced mRNA HO-1 expression in peritoneal macrophages, at the end of hemorrhagic
shock (i.e., immediately before resuscitation). Second, the same
treatment was associated with a marked decrease in the synthesis of TNF- after resuscitation, a decrease in fluid resuscitation requirements, and a prevention of pulmonary edema. Third, the protection induced by Hb was abolished by a competitive inhibitor of HO. Thus, our data provide evidence that
HO-1 induction plays a protective role against the inflammatory response observed after hemorrhagic shock.
A number of studies have been performed regarding the role of antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase, in mediating protection against oxidant-induced tissue injury (27). Another potentially important stress response protein is HO-1. Indeed, HO-1 is induced not only by the substrate heme but also by a variety of nonheme substances such as heavy metals, endotoxin, heat shock, cytokines, and prostaglandins. In addition to its role in heme degradation, the induction of HO-1 by a wide variety of factors may play a defensive role against oxidative stress in situations such as inflammation, irradiation, and light (30). The wide distribution of this enzyme in tissues, as well as the biological activities of CO, iron, and bilirubin, make HO-1 a highly attractive and interesting candidate stress response protein.
In agreement with our results, several studies have demonstrated that HO-1 plays a major role in the defense against lethal endototoxic shock or in situations of increased inflammatory responses. Indeed, rats pretreated with Hb 16 h before LPS injection have been shown to survive to a lethal dose of LPS, while treatment with Sn-PP renders the animals more susceptible to a lethal dose of LPS (20). Such Hb-induced protection against LPS is dependent on HO-1 but not on ferritin (35). Moreover, Hayashi and coworkers showed that HO-1 induction by hemin prevents the increased venular adhesion of leukocytes induced by hemorrhagic shock, but also by oxidant stress or NO inhibition (19).
The antioxidant properties of biliverdin/bilirubin, a metabolite of heme degradation, have been proposed as a molecular mechanism mediating the protection seen after induction of HO-1 (36, 37). Indeed, Hayashi and coworkers (19) showed that the effects of HO-1 induction on leukocyte adhesion could be mimicked by bilirubin, suggesting that this product of HO reaction was an important contributor of the antiinflammatory effect.
Another possible mechanism of the protective effects of the increased HO activity is through the degradation of heme. Heme is a potentially damaging species that not only provides a lipophilic form of iron but can directly attack the lipid bilayer, the cytoskeleton, and DNA (38, 39). Recent investigations have shown a link between induction of HO and ferritin synthesis in oxidant stress (40). Incubation of cultured endothelial cells with heme results in marked induction of HO and ferritin as well as an acquired cellular resistance toward oxidant-mediated injury (41). Such resistance is dependent on increased cellular stores of ferritin, which sequester potentially damaging catalytic iron. In a recent study, the resistance to injury conferred by endotoxin in a model of acute renal failure has been shown to involve HO-1 and ferritin synthesis (42).
We have found that Hb pretreatment leads to a rise in mesenteric blood flow during restitution. Although Hayashi and coworkers failed to show any inhibitory effect of CO on leukocyte adhesion (19), the increased intestinal flow might be indirectly related to the antiinflammatory effects of this treatment, or the consequence of the vasodilatory effects of CO (21). In any case, the possible role of CO in the protected effect of HO-1 cannot be excluded in our present experiments.
Gut injury seems to play a major role in the pathogenesis of multiple organ failure. The present study demonstrated a beneficial role of HO-1 induction in regulating the inflammatory response after hemorrhagic shock with gut injury. Thus HO-1 induction could be of great importance in the course of stress response and vascular control in hemorrhagic shock.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. F. Tamion, INSERM E9920, Faculté de Médecine, 22 Bd Gambetta, 76183 Rouen Cedex, France. E-mail: fabienne.tamion{at}chu-rouen.fr
(Received in original form October 12, 2000 and accepted in revised form September 18, 2001).
Acknowledgments:
The authors thank Lacoume Yann for valuable technical assistance.
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References |
|---|
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INTRODUCTION
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REFERENCES
|
|---|
1.
Baue AE.
Multiple organ failure, multiple organ dysfunction syndrome,
and the systemic inflammatory response syndrome
where we do
stand?
Shock
1994;
2:
385-397
[Medline].
2. Deitch DA. Multiple organ failure: pathophysiology and potential future therapy. Ann Surg 1992; 216: 117-134 [Medline].
3.
Dantzker DR.
The gastrointestinal tract, the canary of the body.
JAMA
1993;
270:
1247-1248
4. Tamion F, Richard V, Lyoumi S, Daveau M, Bonmarchand G, Leroy J, Thuillez C, Lebreton JP. Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic and endotoxic shock. Am J Physiol 1997; 36: G314-G321 .
5.
Tenhumen R,
Marver HS,
Schmid RJ.
Microsome heme oxygenase.
J
Biol Chem
1969;
244:
6388-6394
6. Tenhumen R, Marver HS, Schmid RJ. The enzymatic catabolism of hemoglobin: stimulation of microsomol heme oxygenase by hemin. J Lab Clin Med 1970; 75: 410-421 [Medline].
7. Abraham NG, Drummond GS, Lutton JD, Kappas A. The biological significance and physiological role of heme oxygenase. Cell Physiol Biochem 1996; 6: 129-168 .
8.
Verma A,
Hirsch DJ,
Glatt CE,
Ronnett GV,
Snyder SH.
Carbon monoxide: a putative neural messenger.
Science
1993;
259:
381-384
9. Maines MD, Mark JA, Ewing JF. Heme oxygenase, a likely regulator of GMPc production in the brain: induction in vivo of HO-1 compensates for depression in NO synthetase activity. Mol Cell Neurosci 1993; 4: 398-405 .
10.
Maines MD,
Trakshel GM,
Kutty RK.
Characterization of two constitutive forms of rat liver microsomal heme oxygenase.
J Biol Chem
1986;
261:
411-419
11. Cruse I, Maines MD. Evidence suggesting that two forms of heme oxygenase are products of different genes. J Biol Chem 1988; 263: 411-419 .
12.
Trakshel GM,
Maines MD.
Multiplicity of heme oxygenase isoenzymes
HO-1 and HO-2 are different molecular species in rat and rabbit.
J
Biol Chem
1987;
264:
1323-1328
13. McCoubrey WK, Ewing JF, Maines MD. The structure, organization and differential expression of the gene encoding rat heme oxygenase-2. Gene 1994; 139: 155-161 [Medline].
14.
Applegate LA,
Luscher P,
Tyrrell RM.
Induction of heme oxygenase: a
general response to oxidant stress in cultured mammalian cells.
Cancer Res
1991;
51:
974-978
15.
Keyse SM,
Applegate LA,
Tromvouskis Y,
Tyrrell RM.
Oxidant stress
leads to transcriptional activation of the human heme oxygenase gene
in cultured skin fibroblasts.
Mol Cell Biol
1990;
10:
4967-4969
16.
Keyse SM,
Tyrrell RM.
Heme oxygenase is the major 32-kDa stress
protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.
Proc Natl Acad Sci USA
1989;
86:
99-103
17.
Nascimento ALP,
Lusher P,
Tyrell RM.
Ultraviolet A radiation causes
an alteration in the binding of a specific protein/protein complex to
a short region of promoter of the human HO-1 gene.
Nucleic Acids
Res
1993;
21:
1103-1109
18. Yamaguchi T, Tearkado M, Horio F, Aoki K, Tanaka M, Nakajima H. Role of bilirubin as an antioxidant in an ischemia-reperfusion of rat liver and induction of hemeoxygenase. Biochem Biophys Res Commun 1996; 223: 129-135 [Medline].
19.
Hayashi S,
Takamiya R,
Yamaguchi T,
Matsumoto K,
Tojo SJ,
Tamatani T,
Kitajima M,
Makino N,
Ishimura Y,
Suematsu M.
Induction of
heme oxygenase-1 suppresses venular leukocyte adhesion elicited by
oxidative stress: role of bilirubin generated by the enzyme.
Circ Res
1999;
85:
663-671
20. Otterbein L, Sylvester SL, Choi AMK. Hemoglobin provides protection against lethal endotoxemia in rats: the role of hemeoxygenase-1. Am J Respir Cell Mol Biol 1995; 13: 595-601 [Abstract].
21. Suematsu M, Goda N, Sano T, Kashiwagi S, Egawa T, Shinoda Y, Ishimura Y. Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver. J Clin Invest 1995; 96: 2431-2437 .
22.
Wakabayashi Y,
Takamiya R,
Mizuki A,
Kyokane T,
Goda N,
Yamaguchi T,
Takeoka S,
Tsuchida E,
Suematsu M,
Ishimura Y.
Carbon monoxide
overproduced by heme oxygenase-1 causes a reduction of vascular resistance in perfused rat liver.
Am J Physiol
1999;
277:
G1088-G1096
23. Goda N, Suzuki K, Naito M, Takeoka S, Tsuchida E, Ishimura Y, Tamatani T, Suematsu M. Distribution of heme oxygenase isoforms in rat liver. Topographic basis for carbon monoxide-mediated microvascular relaxation. J Clin Invest 1998; 101: 604-612 [Medline].
24. Pannen BHJ, Kohler N, Hole B, Bauer M, Clemens MG, Geiger KK. Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. J Clin Invest 1998; 102: 1220-1228 [Medline].
25. Stephens KE, Ischizaka A, Larrick JW. Tumor necrosis factor causes increased pulmonary permeability and edema. Am Rev Respir Dis 1988; 137: 1364-1368 [Medline].
26. Hershko C. The fate of circulating hemoglobin. Br J Haematol 1975; 29: 199-204 [Medline].
27. Tamion F, Richard V, Lyoumi S, Hiron M, Bonmarchand G, Leroy J, Daveau M, Thuillez C, Lebreton JP. Induction of heme-oxygenase contributes to the synthesis of proinflammatory cytokines in reoxygenated macrophages. Role of cGMP. Cytokine 1999; 11: 326-330 [Medline].
28. Howard MS, Scalea T, Paskanik A, Yang B. Superoxide dismutase prevents hypotension after hemorrhagic shock and aortic cross clamping. Am J Med Sci 1996; 312: 155-159 [Medline].
29. Bernard GR. N-acetylcysteine in experimental and clinical acute lung injury. Am J Med 1991;S3C:54S-59S.
30. Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in rat. J Clin Invest 1992; 90: 267-270 .
31. Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in rat. J Clin Invest 1992; 90: 267-270 .
32. Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inductible protein in oxidant induced lung injury. Am J Respir Cell Mol Biol 1996; 15: 9-19 [Abstract].
33.
Vile GF,
Tyrrell RM.
Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase dependent increase in ferritin.
J Biol Chem
1994;
268:
14678-14681
34.
Vile GF,
Basu-Modak S,
Waltner C,
Tyrrell RM.
Heme oxygenase 1 mediates an adaptative response to oxidative stress in human skin fibroblasts.
Proc Natl Acad Sci USA
1994;
91:
2607-2610
35.
Otterbein L,
Chin BY,
Otterbein SL,
Lowe VC,
Fessler HE,
Choi AM.
Mechanism of hemoglobin-induced protection against endotoxemia in
rats: a ferritin-independent pathway.
Am J Physiol
1997;
272:
L268-L275
36.
Stoker RR,
Yamamoto Y,
McDonagh AF,
Glazer AN,
Anas BN.
Bilirubin is an antioxidant of possible physiological importance.
Science
1987;
235:
1043-1046
37.
Stoker T,
Glazer AN,
Ames BN.
Antioxidant activity of albumin-bound
bilirubin.
Proc Natl Acad Sci USA
1987;
84:
5918-5922
38. Kim E, Sevaniam A. Hematin and peroxide catalyzed peroxidation of phospholipid liposomes. Arch Biochem Biophys 1991; 288: 324-330 [Medline].
39.
Aft R,
Mueller G.
Hemin mediated DNA strand scission.
J Biol Chem
1983;
258:
12069-12072
40. Eisenstein R, Garcia Mayol D, Pettingell W, Muno H. Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc Natl Acad Sci USA 1991;88:688-692.
41.
Balla G,
Jacob H,
Balla J,
Rosenberg M,
Nath K,
Apple F.
Ferritin: a cytoprotective antioxidant stratagem of endothelium.
J Biol Chem
1992;
267:
18148-18153
42. Vogt BA, Alam J, Croatt AJ, Vercellotti GM, Nath KA. Acquired resistance to acute oxidative stress. Possible role of heme oxygenase and ferritin. Lab Invest 1995; 72: 474-483 [Medline].
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 V. Nascimento-Silva, M. A. Arruda, C. Barja-Fidalgo, C. G. Villela, and I. M. Fierro Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells Am J Physiol Cell Physiol, September 1, 2005; 289(3): C557 - C563. [Abstract] [Full Text] [PDF]
|
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 |
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 A. S. Pachori, L. G. Melo, M. L. Hart, N. Noiseux, L. Zhang, F. Morello, S. D. Solomon, G. L. Stahl, R. E. Pratt, and V. J. Dzau Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury PNAS, August 17, 2004; 101(33): 12282 - 12287. [Abstract] [Full Text] [PDF]
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 |
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 P. Philippidis, J.C. Mason, B.J. Evans, I. Nadra, K.M. Taylor, D.O. Haskard, and R.C. Landis Hemoglobin Scavenger Receptor CD163 Mediates Interleukin-10 Release and Heme Oxygenase-1 Synthesis: Antiinflammatory Monocyte-Macrophage Responses In Vitro, in Resolving Skin Blisters In Vivo, and After Cardiopulmonary Bypass Surgery Circ. Res., January 9, 2004; 94(1): 119 - 126. [Abstract] [Full Text] [PDF]
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 D. Morse, S. E. Pischke, Z. Zhou, R. J. Davis, R. A. Flavell, T. Loop, S. L. Otterbein, L. E. Otterbein, and A. M. K. Choi Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1 J. Biol. Chem., September 26, 2003; 278(39): 36993 - 36998. [Abstract] [Full Text] [PDF]
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 F. A. D. T. G. Wagener, H.-D. Volk, D. Willis, N. G. Abraham, M. P. Soares, G. J. Adema, and C. G. Figdor Different Faces of the Heme-Heme Oxygenase System in Inflammation Pharmacol. Rev., September 1, 2003; 55(3): 551 - 571. [Abstract] [Full Text] [PDF]
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F. Tamion, V. Richard, Y. Lacoume, and C. Thuillez Intestinal preconditioning prevents systemic inflammatory response in hemorrhagic shock. Role of HO-1 Am J Physiol Gastrointest Liver Physiol, August 1, 2002; 283(2): G408 - G414. [Abstract] [Full Text] [PDF]
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 M. J. TOBIN Critical Care Medicine in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 565 - 583. [Full Text] [PDF]
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