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Departments of 1 Molecular and Integrative Physiology and 2 Pediatrics, University of Kansas Medical Center, Kansas City, Kansas 66160
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
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DISCUSSION
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We recently demonstrated that systemic hypoxia during reduced inspired PO2 produces a rapid increase in leukocyte adherence to rat mesenteric venules. Evidence suggests that the mechanism of this response involves decreased nitric oxide (NO) levels. One possible pathway for NO depletion could involve increased reactive oxygen species (ROS) generation resulting in inactivation of NO. The overall goal of the present study was to examine the role of ROS in promoting leukocyte-endothelial adherence during systemic hypoxia. Experiments were designed to 1) evaluate changes in ROS generation in the mesenteric microcirculation during systemic hypoxia, 2) determine how the ROS signal changes when PO2 levels return to normal after a period of systemic hypoxia, 3) assess the effect of antioxidants on ROS generation during hypoxia, and 4) utilize antioxidants to examine the functional relationship between ROS generation and leukocyte adherence during hypoxia. The major findings from this study are that systemic hypoxia increases ROS generation within the mesenteric microcirculation and that antioxidants prevent the increase in leukocyte-endothelial adhesive interactions observed in hypoxia.
antioxidants; superoxide dismutase/catalase; lipoic acid; dihydrorhodamine 123; nitric oxide; acute hypoxia; mesenteric microcirculation; reactive oxygen species
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WE RECENTLY DEMONSTRATED that systemic hypoxia caused by a reduction in inspired PO2 produces a rapid increase in leukocyte adherence to rat mesenteric venules (29). Our results obtained in vivo are consistent with numerous in vitro studies showing increased leukocyte-endothelial interaction during hypoxia. A reduction in PO2, in the absence of other changes in the composition of the medium, increased adherence of leukocytes to cultured endothelial cells (1) and incubated umbilical vein cells (3). In addition, hypoxia was shown to increase leukocyte sequestration within isolated perfused hearts (8). These data from in vitro and in vivo studies indicate that a decrease in PO2 alone can initiate events that lead to proadhesive changes, which may result in microvascular damage.
Several lines of evidence suggest that the mechanism of enhanced leukocyte-endothelial adhesive interactions during hypoxia involves decreases in nitric oxide (NO) levels. NO is formed from L-arginine within endothelial cells and has several important roles in regulation of microvascular function, including one as an anti-inflammatory mediator by preventing leukocyte-endothelial adhesion (10, 18, 21). Recent studies have shown that hypoxia decreases NO formation in endothelial cells in vitro (28) and in an isolated lung preparation (16). Furthermore, we found that increasing tissue NO levels, by administering either an NO donor (spermine NONOate) or the NO substrate L-arginine, reduced the number of adherent leukocytes during hypoxia (29). Taken together, these studies support a role for NO depletion in the microvascular response to acute hypoxia. Furthermore, the fact that L-arginine reduced leukocyte-endothelial adherence suggests that NO formation was not completely inhibited during hypoxia.
Reduced NO levels may result from impaired synthesis or from enhanced degradation. Evidence from in vitro studies supports both possibilities. For example, reduced NO formation during hypoxia could result directly from decreased O2 availability because O2 is a substrate for NO formation (28). Another possible pathway for NO depletion could involve increased reactive oxygen species (ROS) generation resulting in inactivation of NO, since superoxide radical combines with NO to form peroxynitrite (2) and other potentially toxic reactive nitrogen oxide species (12).
In support of the latter possibility, several studies have shown that hypoxia alone results in formation of ROS. For example, graded hypoxia causes dose-related increases in ROS generation in isolated cardiac myocytes (6, 22) as well as other types of cells (4). In addition, hypoxia has been shown to reduce the levels of several antioxidants in cultured endothelial cells (23) as well as in the liver in vivo (7), which was attributed to ROS formation during low O2. Antioxidants have also been recently reported to improve contractile function of the diaphragm under hypoxic conditions (19). An emerging concept in this respect is that reductive stress can result from buildup of reducing equivalents that cannot be transferred to O2 at the mitochondrial cytochrome oxidase in conditions of reduced cellular respiration due to hypoxia (19).
The overall goal of the present study was to examine the role of ROS in promoting leukocyte-endothelial adherence during systemic hypoxia. We hypothesized that ROS involvement in this phenomenon would be supported by demonstrating 1) generation of ROS during systemic hypoxia and 2) prevention of leukocyte-endothelial adherence during hypoxia by administration of antioxidants. Intravital microscopy was utilized to examine the mesenteric microcirculation of rats in which systemic hypoxia was induced by lowering inspired PO2. Dihydrorhodamine 123 (DHR) (24), an oxidant-sensitive fluorescent probe, was used to measure ROS generation in vivo. Experiments were designed to 1) evaluate changes in ROS generation in the mesenteric microcirculation during systemic hypoxia, 2) determine how the ROS signal changes when PO2 levels return to normal after a period of systemic hypoxia, 3) assess the effect of antioxidants on ROS generation during hypoxia, and 4) utilize antioxidants to examine the functional relationship between ROS generation and leukocyte adherence during hypoxia.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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All surgical and experimental procedures were approved by the Animal Care and Use Committee of the University of Kansas Medical Center. The University of Kansas is accredited by the American Association for the Accreditation of Laboratory Animal Care. Guidelines set by the National Institutes of Health and the Public Health Service Policy on the humane use and care of laboratory animals were followed at all times.
Surgical Preparation
As described previously (29), male Sprague-Dawley rats (~225-350 g) were anesthetized by an intramuscular injection of urethan (1.5 g/kg) after an overnight fast with free access to water. During all procedures, the animal's temperature was maintained at 36-38°C by using a homeothermic blanket system (Harvard Apparatus, Natick, MA) connected to an intrarectal temperature probe. Polyethylene cannulas (PE-50) were inserted into a jugular vein and a carotid artery. Lactated Ringer solution was infused via the jugular vein (2 ml/h) while blood pressure was continuously measured by using the carotid artery cannula connected to a digital blood pressure monitor (Micro-Med, Louisville, KY). A tracheotomy was performed, and the trachea was intubated by using polyethylene tubing (PE-240).Intravital Microscopy: Adherence of Circulating Leukocytes With Mesenteric Venules
The abdomen was opened along the midline by using a radiocautery (Harvard Apparatus), and the animal was then positioned on a Plexiglas sheet on top of the stage of a Zeiss Axiovert inverted microscope as previously described (29). A section of the small intestine was carefully removed from the abdomen and positioned over a glass coverslip on a Plexiglas sheet to view a mesenteric venule. The mesentery was covered with a piece of Saran wrap to prevent drying of the tissue and to minimize the effect of ambient oxygen on the mesenteric venules. Mesenteric venules were selected for experiments by using the following criteria: 1) straight, unbranched vessels at least 100 µm in length; 2) diameters of 20-40 µm; 3) fewer than two adherent leukocytes observed within a 100-µm segment of the venule during control periods; and 4) no lymphatic vessels adjacent to the venule. The mesentery was superfused (2 ml/min) with phosphate-buffered saline (37°C, pH 7.4) to keep the tissue moist and warm. Images of mesenteric venules (×40 objective) were recorded on a videocassette recorder with a time-date generator (Panasonic S-VHS) by using a Panasonic video camera.Venular diameter was measured by using a video caliper (Microcirculation Research Institute, College Station, TX) either on-line or off-line during playback of videotapes. An optical Doppler velocimeter (Microcirculation Research Institute) was used to measure centerline red blood cell velocity in venules. Average red blood cell velocity was calculated as centerline velocity/1.6 (5). Wall shear rate, which represents the physical force generated at the vessel wall due to movement of blood, was calculated as 8 × (average red blood cell velocity/venular diameter) (15). During analysis of video recordings of the experiments, the number of adherent leukocytes was determined for each minute of every experimental period by counting the number of leukocytes that remained stationary for longer than 30 s (29).
Measurement of ROS Generation in the Mesenteric Microcirculation by Using DHR
DHR, an oxidant-sensitive probe, was used to assess ROS generation in the mesenteric microcirculation. Oxidation of DHR primarily by hydrogen peroxide-dependent reactions forms rhodamine 123, which fluoresces. Rhodamine 123 binds to the inner mitochondrial membrane, which is a major site of ROS generation in endothelial cells during hypoxia (4). We slightly modified the procedures described previously (14, 17) to use DHR for measurement of oxidant stress in the mesenteric microcirculation. After a stabilization period, DHR was injected intravenously (iv) into the animal, and 30 min were allowed for the probe to equilibrate within endothelial cells before experiments were begun. Fluorescence was visualized by using an intensified charged-coupled device camera (Hamamatsu Photonics, Shizouka, Japan). The intensity of the fluorescent signal was later measured from video recordings of experiments by using image analysis (NIH Image 1.61). The fluorescence intensity was measured in five contiguous areas along the vessel (total length ~80-100 µm) and then averaged to obtain a single estimate of the DHR signal during the normoxic control period, the hypoxic period, and the normoxic recovery period for each animal. The field of view was maintained throughout the entire experiment so that measurements of DHR fluorescence were obtained in the same section of the venule under each experimental condition. Values for DHR fluorescence were expressed relative to values observed during the normoxic control period, which were arbitrarily defined as 100%.Drugs and Chemicals
Phosphate-buffered saline, bovine serum albumin, lipoic acid, superoxide dismutase (SOD), catalase, and other chemicals were purchased from Sigma Chemical (St. Louis, MO). Lidocaine hydrochloride and heparin sodium from porcine intestinal mucosa were purchased from Elkins-Sinn (Cherry Hill, NJ). DHR was purchased from Molecular Probes (Portland, OR). All solutions were prepared freshly on the day of the experiment.Experimental Protocols
Series 1: Changes in ROS generation in the mesenteric microcirculation during systemic hypoxia and the normoxic recovery period. The animals spontaneously breathed room air or hypoxic gas mixtures through a two-way valve (2384 series, Hans Rudolph, Kansas City, MO) that had been attached to the tracheal tube before the beginning of the experiment. The protocol consisted of a 10-min period in which the animal breathed room air, a 30-min period after administration of DHR, followed by a 10-min period of hypoxia, and finally a 10-min recovery period while the animal breathed room air again. Hypoxia was produced by having the animal breathe from a bag containing a mixture of 10% O2-90% N2, which resulted in an inspired PO2 of ~70 Torr. The O2 concentration in the gas mixture was determined with an Applied Electrochemistry oxygen analyzer (9).
Recordings of DHR fluorescence were made during brief intervals (~15 s) to avoid light-induced damage to the tissue. The results for DHR fluorescence represent values obtained in all animals of the group at each of the following times: at the end of the 30-min normoxic equilibration period and at the end of the 10-min hypoxia and normoxic recovery periods.Series 2: Effect of SOD/catalase on ROS generation during acute hypoxia. The protocol of these experiments was the same as described for series 1 except that SOD and catalase were administered after DHR. The doses of these antioxidants were 0.5 and 50 mg/kg iv for SOD and catalase, respectively, in a bolus of 1 ml. Administration of SOD/catalase was begun 15 min after DHR was injected and completed within 5 min so that the antioxidants were given 10-15 min before systemic hypoxia was produced. DHR fluorescence was recorded as described for series 1 during the normoxic control period, hypoxia, and normoxic recovery periods.
Series 3: Effect of antioxidants on leukocyte-endothelial adherence during hypoxia. Animals were randomly assigned to the following groups: control group, saline-treated; SOD/catalase-treated group (0.5/50 mg/kg iv bolus); and lipoic acid-treated group (2 mg/kg iv bolus in 2 ml). The experimental protocol was the same as described in series 1, with the antioxidants given at least 10 min before systemic hypoxia was produced. The number of adherent leukocytes was measured during each minute of the 10-min normoxia period immediately before the reduction of inspired PO2, the 10-min hypoxia period, and the 10-min normoxic recovery period.
Statistical Analysis
Means and SEs were calculated for all values from each treatment group. The statistical significance of observed differences was evaluated by using a statistical analysis program (Statistix 4.0, Analytical Software, St. Paul, MN). Analysis of variance with Bonferroni's pairwise comparison of means, Student's t-test, and paired t-test were used to compare groups. Values of P < 0.05 were considered to be statistically significant.| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Series 1: Changes in ROS Generation in the Mesenteric Microcirculation During Systemic Hypoxia and the Normoxic Recovery Period
Figure 1 shows a series of representative photographs from one experiment in which DHR was used to measure ROS generation in the mesenteric circulation. The intensity of DHR fluorescence was extremely low during room air breathing (left) but increased markedly during hypoxia (middle). When the animal returned to room air breathing during the normoxic recovery period, the fluorescence intensity began to progressively decrease as illustrated in Fig. 1, right. The cumulative results from these experiments are shown in Fig. 2, where changes in DHR fluorescence are expressed relative to control values. These results represent values obtained in all animals of the group under each experimental condition: normoxic control, 10% O2-90% N2 breathing (hypoxia), and normoxic recovery. By 10 min of hypoxia, DHR fluorescence had increased by nearly 200% above control values (P < 0.01; mean ± SE, 272 ± 44%; range, 152-375%). On the other hand, when animals returned to room air breathing, no further increase in DHR fluorescence was observed. In fact, the intensity of the signal progressively decreased such that, by the end of the 10-min recovery period, DHR fluorescence intensity was not significantly different from control but was significantly lower compared with the hypoxia period (P < 0.01).
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Series 2. Effect of SOD/Catalase on ROS Generation During Acute Hypoxia
Figure 3 shows typical examples of the effect of antioxidants on DHR fluorescence during hypoxia. Figure 3, left, which represents the response to systemic hypoxia in an untreated animal is the same photograph shown in Fig. 1, middle. Figure 3, right, is from an animal pretreated with SOD/catalase before hypoxia and shows that the antioxidants markedly reduced the intensity of DHR fluorescence during hypoxia. Cumulative results from this series of experiments are shown in Fig. 4, where DHR fluorescence intensity is presented as percentage of the control values. In contrast to untreated animals (Fig. 2), there was no significant increase in DHR fluorescence during hypoxia in antioxidant-treated animals (mean ± SE, 88 ± 8%; range, 67-105%). There was also no change in the DHR signal during the normoxic recovery period compared with control or to the hypoxia values in the rats given SOD/catalase.
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Series 3: Effect of Antioxidants on Leukocyte-Endothelial Adherence During Hypoxia
Figure 5 shows the cumulative results from experiments that examined the effect of antioxidants on the microvascular response to hypoxia. SOD/catalase completely prevented leukocyte adherence during hypoxia (P < 0.01 vs. untreated animals). These results demonstrate that ROS generation during hypoxia is functionally related to these microvascular responses. There were no differences in shear rate between groups, which demonstrates that the reduced leukocyte adherence in the SOD/catalase-treated group was not secondary to a greater force at the vessel wall that physically opposes adhesive interactions.
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To further ensure that these protective effects of SOD/catalase were related to their antioxidant actions, we examined the responses to another compound. Lipoic acid, a potent lipid antioxidant (20), is structurally different from SOD and catalase, which are proteins. However, as shown in Fig. 5, pretreatment with lipoic acid markedly reduced leukocyte adherence during systemic hypoxia. These beneficial actions were again unrelated to changes in shear rate because there was no statistically significant difference in this parameter between untreated rats and lipoic acid-treated rats during the entire period of hypoxia. The higher shear rate observed during the first few minutes after lipoic acid administration during normoxia is likely to be due to the hemodynamic effects of the initial bolus. Although it was significantly higher than baseline values immediately after lipoic acid was given, shear rate progressively decreased and was not significantly different from that of the untreated and SOD/catalase-treated groups during the 5 min before hypoxia.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings from this study are that systemic hypoxia increases ROS generation within the mesenteric microcirculation and that antioxidants prevent the increase in leukocyte-endothelial adhesive interactions observed in hypoxia. These results support the conclusion that the increased leukocyte-endothelial adherence observed during systemic hypoxia is the result of ROS generation.
The conclusion that ROS are generated during hypoxia is based on results obtained by using a complementary experimental approach, namely, direct measurement of ROS generation as well as effects of antioxidants on the intensity of the fluorescence signal. The fluorescence intensity of DHR was increased more than twofold during hypoxia. Although this probe and others have been used to assess oxidant stress in many systems (4, 6, 17), a potential limitation of this approach is specificity of the fluorochrome. In fact, recent studies have extended the use of DHR to detect generation of reactive nitrogen intermediates (27). We addressed this issue by evaluating the effect of antioxidants on hypoxia-induced DHR fluorescence, which showed that pretreatment with SOD/catalase completely blocked the increase in DHR signal during hypoxia. These results strongly support the notion that hypoxia results in oxidant stress and, to our knowledge, represent the first direct demonstration of this phenomenon during hypoxia in intact animals. These results support previous observations of ROS generation by cultured cells during reductions in PO2 (4, 6) and indicate that systemic hypoxia-induced oxidant stress also occurs in the more physiological setting of the intact animal.
A particularly important point is the pattern of ROS generation observed in this study. We observed that ROS generation increased during hypoxia, when O2 delivery to the tissues decreased, and decreased rapidly during the recovery period, when O2 delivery to the tissues returned to control values. This pattern is in distinct contrast to that observed with ischemia-reperfusion, in which the strength of DHR fluorescence increases only on reintroduction of O2 during reperfusion (11, 13). These results may reflect fundamental differences in the mechanisms responsible for ROS generation during reductions in inspired PO2 vs. ischemia-reperfusion. Evidence suggests that mitochondria are a major site of ROS production in response to reduced PO2 because of impairment of the electron transport chain (4). In contrast, xanthine oxidase, a cytosolic enzyme formed from xanthine dehydrogenase during prolonged ischemia, is the major source of ROS production immediately on reperfusion of ischemic tissue (11, 13). Further studies will be needed to define the pathways of ROS production during systemic hypoxia.
The second major finding from the present study is that ROS formed during hypoxia are functionally related to subsequent leukocyte-endothelial adherence. This interpretation is based on the efficacy of antioxidants to reduce both DHR fluorescence and the number of adherent leukocytes during hypoxia. The possible role of ROS as initiating agents of hypoxia-induced endothelial response was studied by comparing the effects of different antioxidants: the combination of SOD/catalase on one hand and lipoic acid on the other. The use of antioxidants of vastly different chemical nature minimizes possible nonspecific effects unrelated to the antioxidant effect. In addition, lipoic acid has several advantageous characteristics: it is lipophilic so it readily enters cells and also is a naturally occurring compound. Lipoic acid is a cofactor involved in mitochondrial electron transport; it is unclear whether this action contributed its effects in attenuating the hypoxia-induced endothelial response. To our knowledge, this is the first demonstration of an effect of lipoic acid in attenuating leukocyte-endothelial adhesive interactions under any conditions.
In this study, the antioxidants were infused iv, which raises the possibility that the reduction in leukocyte adherence was due not to a local action within the mesenteric microcirculation but to a systemic action. For example, hypoxia is well known to cause a modest fall in arterial pressure, even in conscious animals. If antioxidants moderated this fall in arterial pressure, leukocyte adherence could also be reduced as a result of higher shear rate at the venular wall. This is unlikely to be the case: as shown in Fig. 5, there were no significant differences in shear rate between the untreated, SOD/catalase-treated, and lipoic acid-treated groups at any time during hypoxia.
ROS generation within the mesenteric microcirculation during hypoxia may have implications that extend beyond a possible mechanism of initiation of a vascular endothelial response. Although a marked microvascular inflammatory response occurs in nonacclimatized rats when inspired PO2 is reduced to 70 Torr, we have recently shown that rats acclimatized to the same inspired PO2 for 3 wk show no evidence of leukocyte-endothelial adherence and tolerate decreases in inspired PO2 to ~50 Torr without an increase in leukocyte endothelial adherence (29). Our previous results suggested that upregulation of inducible NO synthase contributes to this greater vascular tolerance to hypoxia in acclimatized rats. Recent studies have proposed that intracellular ROS generation (4, 25) is one of the promoters of hypoxia inducible factor-1, a nuclear protein expressed in endothelial cells that activates gene transcription and results in multiple cellular changes. These responses include expression of inducible NO synthase, heme oxygenase-1, and vascular endothelial growth factor within endothelial cells (25). ROS generation has also been proposed as the signal responsible for vascular remodeling in various conditions (26). On the basis of the emerging concept of ROS playing a role as signaling elements rather than simply as toxic molecules, an intriguing prospect is that ROS generated during hypoxia not only cause acute microvascular injury but also initiate the mechanisms responsible for microvascular acclimatization.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants ES/HL-09293 (J. G. Wood) and HL39443 (N. C. Gonzalez) as well as by American Heart Association, Kansas Affiliate, Grant KS-97-GB-73 (J. G. Wood).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. G. Wood, Dept. of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, KS 66160.
Received 22 April 1999; accepted in final form 14 July 1999.
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 E. L. Bell, T. A. Klimova, J. Eisenbart, P. T. Schumacker, and N. S. Chandel Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia Mol. Cell. Biol., August 15, 2007; 27(16): 5737 - 5745. [Abstract] [Full Text] [PDF]
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J.-S. Wang, H.-Y. Lin, M.-L. Cheng, and M.-K. Wong Chronic intermittent hypoxia modulates eosinophil- and neutrophil-platelet aggregation and inflammatory cytokine secretion caused by strenuous exercise in men J Appl Physiol, July 1, 2007; 103(1): 305 - 314. [Abstract] [Full Text] [PDF]
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 N. C. Gonzalez, J. Allen, E. J. Schmidt, A. J. Casillan, T. Orth, and J. G. Wood Role of the renin-angiotensin system in the systemic microvascular inflammation of alveolar hypoxia Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2285 - H2294. [Abstract] [Full Text] [PDF]
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A. J. Thomson, G. B. Drummond, W. S. Waring, D. J. Webb, and S. R. J. Maxwell Effects of short-term isocapnic hyperoxia and hypoxia on cardiovascular function J Appl Physiol, September 1, 2006; 101(3): 809 - 816. [Abstract] [Full Text] [PDF]
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T. Orth, J. A. Allen, J. G. Wood, and N. C. Gonzalez Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules J Appl Physiol, July 1, 2005; 99(1): 290 - 297. [Abstract] [Full Text] [PDF]
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T. A. Orth, J. A. Allen, J. G. Wood, and N. C. Gonzalez Exercise training prevents the inflammatory response to hypoxia in cremaster venules J Appl Physiol, June 1, 2005; 98(6): 2113 - 2118. [Abstract] [Full Text] [PDF]
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T. Altay, E. R. Gonzales, T. S. Park, and J. M. Gidday Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase J Appl Physiol, March 1, 2004; 96(3): 1223 - 1230. [Abstract] [Full Text] [PDF]
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R. Dix, T. Orth, J. Allen, J. G. Wood, and N. C. Gonzalez Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules J Appl Physiol, December 1, 2003; 95(6): 2495 - 2502. [Abstract] [Full Text]
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A. D. Ray, A. J. Roberts, S. D. Lee, G. A. Farkas, C. Michlin, D. I. Rifkin, P. T. Ostrow, and J. A. Krasney Exercise delays the hypoxic thermal response in rats J Appl Physiol, July 1, 2003; 95(1): 272 - 278. [Abstract] [Full Text] [PDF]
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A. J. Casillan, N. C. Gonzalez, J. S. Johnson, D. R. S. Steiner, and J. G. Wood Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4 J Appl Physiol, June 1, 2003; 94(6): 2313 - 2322. [Abstract] [Full Text] [PDF]
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S. Shah, J. Allen, J. G. Wood, and N. C. Gonzalez Dissociation between skeletal muscle microvascular PO2 and hypoxia-induced microvascular inflammation J Appl Physiol, June 1, 2003; 94(6): 2323 - 2329. [Abstract] [Full Text] [PDF]
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D. R. S. Steiner, N. C. Gonzalez, and J. G. Wood Mast cells mediate the microvascular inflammatory response to systemic hypoxia J Appl Physiol, January 1, 2003; 94(1): 325 - 334. [Abstract] [Full Text] [PDF]
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 C. Schroedl, D. S. McClintock, G. R. S. Budinger, and N. S. Chandel Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L922 - L931. [Abstract] [Full Text] [PDF]
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D. R. S. Steiner, N. C. Gonzalez, and J. G. Wood Interaction between reactive oxygen species and nitric oxide in the microvascular response to systemic hypoxia J Appl Physiol, October 1, 2002; 93(4): 1411 - 1418. [Abstract] [Full Text] [PDF]
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D. R. S. Steiner, N. C. Gonzalez, and J. G. Wood Leukotriene B4 promotes reactive oxidant generation and leukocyte adherence during acute hypoxia J Appl Physiol, September 1, 2001; 91(3): 1160 - 1167. [Abstract] [Full Text] [PDF]
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 P. MOLLER, S. LOFT, C. LUNDBY, and N. V. OLSEN Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans FASEB J, May 1, 2001; 15(7): 1181 - 1186. [Abstract] [Full Text] [PDF]
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J. G. Wood, J. S. Johnson, L. F. Mattioli, and N. C. Gonzalez Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats J Appl Physiol, October 1, 2000; 89(4): 1561 - 1568. [Abstract] [Full Text] [PDF]
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 N. S. Chandel, D. S. McClintock, C. E. Feliciano, T. M. Wood, J. A. Melendez, A. M. Rodriguez, and P. T. Schumacker Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1alpha during Hypoxia. A MECHANISM OF O2 SENSING J. Biol. Chem., August 11, 2000; 275(33): 25130 - 25138. [Abstract] [Full Text] [PDF]
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