* Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and Department of Pathology, The Methodist Hospital, Houston, Texas 77030
1 To Whom correspondence should be addressed at Department of Pediatrics, Baylor College of Medicine & Texas Children's Hospital, 6621 Fannin, WT: MC-06104, Houston, TX 77030. Fax: (832) 825-3204. E-mail: Bmoorthy{at}bcm.tmc.edu.
Received March 24, 2005; accepted June 9, 2005
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ABSTRACT |
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Key Words: hyperoxia; cytochrome P450; beta-naphthoflavone.
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INTRODUCTION |
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The CYP enzymes belong to a superfamily of hemeproteins that are involved in the metabolism of exogenous and endogenous chemicals (Guengerich, 1990). It is our hypothesis that various isoforms of the CYP enzyme system, such as CYP 1A1, 1A2, and 2E1, may play a role in the prevention of hyperoxic lung injury, specifically in the elimination of compounds involved in mediating lung injury.
The tissue-specific upregulation of the P4501A system of enzymes by classical inducers such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC), occurs via the aryl-hydrocarbon receptor (AHR)-dependent mechanism (Sinal et al., 1999). The AHR is a cytosolic protein which upon interaction with a chemical ligand, induces a battery of enzymes encoded by the Ah gene locus (Nebert et al., 2000
). These enzymes include CYP1A1, CYP1A2, glutathione S-transferase-
, NAD(P)H quinone reductase-1, UDP glucuronosyl transferase, and aldehyde dehydrogenase. Induction of CYP1A1 by polycyclic aromatic hydrocarbons (PAHs) have been extensively studied (Denison and Helferich, 1998
; Nebert et al., 2004
; Shimada and Fujii-Kuriyama, 2004
; Whitlock, 1999
). The PAHs serve as ligands, and bind to the AHR, after entry into the cells. The PAHAHR complex enters the nucleus and binds to another protein named the arylhydrocarbon nuclear translocator (ARNT). This complex then interacts with Ah-responsive elements (AHREs), located as multiple copies within CYP1A1 gene promoter, leading to enhanced transcription of the CYP1A1 gene. The mechanisms by which hyperoxia induces CYP1A1/1A2 in rodents are not completely understood, although AHR-dependent mechanisms have been suggested (Couroucli et al., 2002
; Jiang et al., 2004
).
Pretreatment of rats (Mansour et al., 1988a) or mice (Mansour et al., 1988b
) with CYP1A inducers protects animals from hyperoxic lung injury. Others have suggested contrary findings, in that lambs treated with cimetidine, a P450 inhibitor, display evidence of attenuated lung injury in a hyperoxic environment. Although cimetidine is a P450 inhibitor, it selectively inactivates a different subset of P450 enzymes, namely CYP2A6 and 2C11, but not CYP1A1/1A2 (Levine et al., 1998
). Cimetidine may also have other effects besides P450 inhibition. In contrast, we earlier reported the potentiation of hyperoxic lung injury by CYP1A-specific inhibitors, such as 1-aminobenzotriazole (ABT). In fact, pretreatment with 1-ABT, an inhibitor of CYP1A in vivo, followed by exposure to hyperoxia, leads to massive inflammation, pleural effusions, and severe lung injury, as evidenced by a disruption of architecture and exudative debris (Moorthy et al., 2000
). These observations further support the idea that CYP1A1/1A2 may play a protective role in oxygen-mediated injury.
Interestingly, animals exposed to hyperoxia are able to upregulate the cytochrome systems such as CYP1A1 and 1A2 for a period of up to 48 h. By 60 h, the animals develop severe respiratory distress (Couroucli et al., 2002). Similarly, when AHR (/) mice are exposed to hyperoxia, they do not display an increase in endogenous CYP1A1 expression as compared to wild-type mice, and are more susceptible to lung injury and inflammation than similarly exposed wild-type mice (Jiang et al., 2004
). Furthermore, we observed that mice deficient in the gene for the liver-specific CYP1A2 are more sensitive to hyperoxic lung injury than wild-type mice, suggesting that extrapulmonary organs such as liver may also contribute to the protection against hyperoxic lung injury (Moorthy et al., in press). These studies led us to the hypothesis that upregulation of the pulmonary and hepatic CYP1A enzyme system, prior to exposure to hyperoxia, would protect animals from developing oxygen-mediated lung injury.
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MATERIALS AND METHODS |
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Animals.
This study was conducted in accordance with the federal guidelines for the human care and use of laboratory animals, and was approved in the Institutional Animal Care and Use Committee of Baylor College of Medicine. Adult Sprague-Dawley rats were obtained from Harlan Sprague-Dawley (Houston, TX) and kept in Texas Children's Hospital animal facility for 24 h before experiments were started. They were fed standard rat food and water ad lib. Animals were maintained in 12-h day/night cycles.
Experiment design.
Animals (eight/group) were injected with ß-NF, (5, 6-benzoflavone) at 80 mg/kg/day, which was dissolved in 2 ml/kg of corn oil (CO), which also served as the vehicle control. The rats were injected once daily for 4 days intraperitoneally before being maintained in either room air (21% oxygen) or exposed to hyperoxic (95100% oxygen) environments for 60 h in a sealed Plexiglass chamber, as previously reported (Gonder et al., 1985). After sealing, the chamber was checked for oxygen concentration by an analyzer (Ventronics, Kenilworth, New Jersey) daily. After 60 h of hyperoxia exposure, the animals were anesthetized with 200 mg/kg of sodium pentobarbital by ip injection, and pleural effusions were measured. Liver and lung tissues were harvested for later analysis of CYP1A parameters.
Preparation of tissues for histology.
Tracheotomy was performed on anesthetized animals, with lung tissue being first perfused with 10 ml of phosphate-buffered saline (GIBCO-Dulbecco's PBS without calcium chloride and without magnesium chloride). Lung tissue was then fixed by intratracheal instillation of 10% zinc formalin at constant pressure (Couroucli et al., 2002). Samples were left in solution for 24 h in formaldehyde, and then transferred to 70% EtOH for long-term storage. Following processing, tissues from three animals from each of the four groups were embedded in paraffin and sectioned at 4 µm on a rotary microtome. To assess lung morphology and injury, six sections were stained with hematoxylin and eosin (H&E) and anti-myeloperoxidase (anti-MPO) antibody (Couroucli et al., 2002
), and then evaluated by a pulmonary pathologist in an unblinded fashion.
Pleural effusions.
Pleural effusions were pooled from both pleural spaces of each animal and measured separately, for volume only by needle thoracotomy, using a 10-ml syringe and 18-gauge slip-tip catheter placed through a ventral incision located above the diaphragm.
Preparation of microsomes.
Lung and liver samples at time of dissection were frozen with liquid nitrogen and maintained at a temperature of 80°C until preparation of microsomes. Liver microsomes were isolated by calcium chloride precipitation and then suspended in buffer. Lung microsomes were isolated by differential centrifugation as previously described (Cinti et al., 1972; Moorthy, 2000
). Protein concentrations were measured by the Bradford dye-binding method (Bradford, 1976
).
Enzyme assays.
Measuring the formation of resorufin from ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) reflects the activities of CYP1A1 and CYP1A2, respectively. The assay methods for EROD and MROD were reported previously (Couroucli et al., 2002; Jiang et al., 2004
; Moorthy et al., 1997
).
Electrophoresis and Western blotting.
Microsomes from liver (2 µg) and lung (20 µg) prepared from individual animals were subjected to SDS-polyacrylamide gel electrophoresis in 7.5% acrylamide gels. The separated proteins were transferred to polyvinylidene difluoride membranes, followed by Western blotting. For the Western analysis, a monoclonal antibody to CYP1A1, which cross-reacts with CYP1A2, and goat anti-mouse IgG conjugated with horseradish peroxidase, were used as primary and secondary antibodies, respectively, as described previously (Jiang et al., 2004; Moorthy, 2000
).
RNA isolation.
RNA was isolated using a modification of the procedure of the Chomczynski method (Chomczynski and Sacchi, 1987). The pellet was resuspended in 100 µl of diethyl pyrocarbonate (DEPC) H2O. Samples were analyzed on agarose gels to confirm the presence of intact RNA.
Northern blotting.
RNA (20 µg/sample) was loaded onto a 1% agarose/formaldehyde denaturing gel, separated by electrophoresis, and transferred to nitrocellulose filters. Northern hybridization was performed by using a 32P-labeled CYP1A1 probe (20 x 106 cpm). After autoradiography of the hybridized membranes, the membranes were stripped by several washes (0.1% sodium dodecyl sulfate in 0.1x sodium citrate and sodium chloride SSC) and reprobed with random prime-labeled glyceraldehyde 3-phosphate (GAPDH) cDNA. GAPDH cDNA probe was used as an internal control to assess RNA transfer, loading, and hybridization (Moorthy et al., 2000).
Densitometry.
Densitometry was performed using Quantity OneTM software package from BioRad. A minimum of three individual RNA and protein samples was analyzed for each experimental group for Northern analyses and Western blot experiments.
Statistical analysis.
Data (pleural effusions, EROD and MROD activity) are expressed as means ± SE, and two-way analysis of variance (ANOVA) was used to test the effect of treatment (corn oil, ß-NF) and condition (room air and hyperoxia) and the interaction between them. If an interaction was detected, then the effect of treatment was assessed separately, by modified post hoc analysis, Tukey test, to assess the effect of hyperoxia; p values <0.05 were considered significant. Linear regression analysis was used to determine an inverse correlation between effusions and pulmonary or hepatic EROD and MROD activity; p values <0.05 were considered significant. Two-way ANOVA was used to analyze mean densitometric data from Western blots and ratios of CYP1A1 or CYP1A2 to GAPDH from Northern Blots, and p values <0.05 were considered significant. Statistical analysis was performed using Mini-Tab software package (Version 13) (State College, PA).
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RESULTS |
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DISCUSSION |
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Pretreatment of rats with ßNF prior to exposure to a hyperoxic environment resulted in a reduction in pleural effusion. Although the effusions are indicative of attenuated inflammation in the lung, simple transudation of fluid in a stressed animal cannot be excluded (Fig. 1). Clearly though, the H&E-stained samples of pulmonary tissue reveal preservation of tissue architecture and evidence of less exudative debris as compared to controls (Fig. 2). As shown in Figure 3, although not quantified, there appear to be fewer neutrophils per high-power field in pulmonary tissue stained with anti-MPO, as compared to controls. The mechanisms by which ß-NF protects rats against hyperoxic lung injury are not completely understood, but it is likely that CYP1A isoforms play a role in this phenomenon.
The 10-fold increase in EROD activities of pulmonary CYP1A1 tissues exposed to ß-NF (p < 0.05) is seen in Figure 4. The apoprotein levels on Western blot correlated well with EROD activity. The overall EROD activity, however, was decreased in pulmonary tissues exposed to hyperoxia, which appears to be an independent effect of hyperoxia. Northern blots of pulmonary tissue (Fig. 8) revealed an increase at the pretranslational level of CYP1A1 in the ß-NF+room air group, but after exposure to hyperoxia for 60 h, the expression declined moderately, as seen in the ß-NF+O2 group. As evidenced by some of our prior experiments (Couroucli et al., 2002; Jiang et al., 2004
), a contributing factor to decreased expression of CYP1A1 by pulmonary cells at the pretranslational level is possibly due to the effect of H2O2 attenuating CYP1A1 gene expression, by an autoregulatory loop mechanism involving the down-regulation of NF-1 (Barouki and Morel, 2001
; Morel and Barouki, 1998
). Recent studies by Morel and colleagues have shown that benzo-[a]-pyrenetreated hepatoma cells produce H2O2 and, accordingly, cause a decrease in NF-1, which is critical to the expression of the CYP1A1 gene at the basal transcription element of the CYP1A1 promoter (Morel et al., 1999
). The possibility that H2O2 can cause CYP1A1 destruction by oxidative degradation cannot be excluded. In addition, studies have shown that CYP1A1 suppression using Hepa1c1c7 cells is possible with tumor necrosis factor-
(TNF-
) and lipopolysaccharide (LPS), via a nuclear factor-
B (NF-
B) pathway, that particularly inhibits the AHR-mediated expression of CYP1A1 (Ke et al., 2001
). Although we did not specifically look at these molecules in particular, they are common inflammatory cytokines associated with hyperoxic lung injury, and it is possible that these molecules may play a role in the suppression of pulmonary CYP1A1.
With respect to hepatic CYP1A1, the 8-fold increase in EROD activity in tissues exposed to ß-NF similarly correlates inversely (p < 0.05) with a decrease in the level of inflammation. Here there is no independent effect of hyperoxia on expression of CYP1A1. Previous experiments from our laboratory have revealed that, with hyperoxic exposure, animals display an increase in pulmonary and hepatic CYP1A1 expression via an AHR-mediated pathway, but the levels decline within 60 h (Couroucli et al., 2002). Pretreatment with ß-NF maintains this expression of CYP1A1 within hepatic tissue, as confirmed by both Western and Northern analysis.
ß-NF induction of hepatic CYP1A2 is demonstrated in Figure 6. A 2.5-fold increase in activity is present in tissues exposed to ß-NF+O2, as compared to hyperoxic controls, CO+O2 (p < 0.05). This correlated inversely with a decrease in the level of pulmonary inflammation. As seen in the CO+O2 group, hyperoxia alone increases the expression of hepatic CYP1A2 as compared to CO+room air controls, suggesting hyperoxia through production of endogenous ligands may induce CYP1A2. Since previous experiments in AHR-null mice show induction of CYP1A2 by hyperoxia, it is possible that hyperoxia in the rat model induces CYP1A2 by AHR independent mechanism as well (Jiang et al., 2004; Guigal et al., 2000
).
The temporal relationship of CYP1A isoforms to hyperoxia suggested to us that pulmonary and hepatic CYP1A1 and, to some extent, hepatic CYP1A2 play a role in conferring protection against hyperoxic lung injury via an AHR-mediated pathway. This correlates with an increase in pulmonary and hepatic CYP1A1 and 1A2 mRNA, protein, and enzyme activity. The molecular mechanism by which this protection is conferred is not completely understood. Phase II antioxidant enzymes such as glutathione S-transferases, NQO1, and SOD, which may have been induced by ß-NF, may have also contributed to the protection against lung injury. In a recent study, we observed protection against oxygen injury in animals that had been pretreated with 3-methylcholanthrene 15 days prior to exposure to hyperoxia (Moorthy et al., 2004). These animals displayed sustained pulmonary CYP1A1, but not phase II enzyme induction, suggesting that phase II enzymes may not have played a major role in attenuating hyperoxic lung injury. It thus appears that CYP1A enzymes play a key role in the protection against lung injury in the ß-NF-treated rats described in the current study.
As mentioned previously, CYP enzymes are primarily involved in eliminating endogenous and exogenous ligands, molecules implicated in the pathogenesis of cellular injury. Several molecules are now being recognized not only as biomarkers of oxidant-induced injury throughout the body, but also mediators of cellular injury (Fessel et al., 2002; Morrow and Roberts, 2002
). The current theory surrounding these molecules states that free radicals are specifically able to oxidize arachidonic acid within the cell membrane and, via a series of reactions, transform lipids into a variety of toxic stereoisomers. The formation of a ringed structure from arachidonic acid, and its subsequent removal from the cell membrane, leads to instability and eventual cellular apoptosis (Janssen, 2001
). These molecules, known collectively as isoprostanes and isofurans, are two groups that have been implicated in exacerbating cellular injury (Zahler and Becker, 1999
). Their presence has also been correlated with the lung injury associated with BPD (Goil et al., 1998
; Saugstad, 1997
). It is our supposition that members of the cytochrome P450 1A family may be intimately involved with the reduction or elimination of these compounds, either before or during the initial inflammatory event. Since CYP1A enzymes appear to protect against oxidative injury, further studies on the mechanisms of regulation of CYP1A by hyperoxia, in relation to hyperoxic lung injury may lead to the development of rational strategies, involving genetic or dietary interventions, which could in turn lead to prevention and/or treatment of chronic lung disease in preterm and term infants undergoing supplemental oxygen therapy.
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ACKNOWLEDGMENTS |
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