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Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Neonatal rats exposed to 60% O2 for 14 days develop lung changes compatible with human bronchopulmonary dysplasia and pulmonary hypertension. Our aim was to evaluate and compare the newborn and adult rat pulmonary vascular and airway smooth muscle force generation and relaxation potential after exposure to 60% O2 for 14 days. Vascular and airway intrapulmonary rings 100 µm in diameter were mounted on a myograph and bathed in Krebs-Henseleit solution bubbled with air- 6% CO2 at 37°C. Significant age-dependent changes in intrapulmonary arteries and their neighboring airway muscle properties were observed. Whereas hyperoxia enhanced force in neonatal vascular and airway muscle, the opposite was seen in adult samples. No changes in endothelium-dependent vascular relaxation were observed at either age, but the dose response to an endothelium-independent NO donor was altered. In the newborn experimental animals, the relaxation was reduced, whereas, in their adult counterparts, it was enhanced. After O2 exposure, the bronchial muscle relaxation response to epithelium-dependent and -independent stimulation was not altered in either age group, whereas the epithelium-dependent response was decreased only in the adult. The antioxidant Trolox, or an endothelin-A and -B receptor antagonist, reversed the vascular and airway muscle's hyperoxia-induced changes. We conclude that chronic O2 exposure in the newborn rat results in enhanced lung vascular and airway muscle contraction potential via a mechanism involving reactive oxygen species and the endothelin pathway. The present findings also suggest that the newborn is more susceptible to airway hyperresponsiveness after chronic O2 exposure.
pulmonary hypertension; airway reactivity; chronic hyperoxia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CHRONIC O2 exposure induces pulmonary vascular remodeling and pulmonary hypertension in the newborn rat (26). The mechanisms responsible for these changes are not fully understood, but recent evidence from our laboratory indicates that endothelin-1 and possibly 8-isoprostane are involved in its pathogenesis (20, 21). Inhibition of macrophage influx, or combined blockade of endothelin-A and -B receptors, prevented right ventricular hypertrophy and pulmonary vascular remodeling in this model. However, it had no effect on the O2-induced lung parenchymal changes (20), suggesting that the two pathological processes have a distinct inducing mechanism.
Aside from their putative role in the process of vascular remodeling, isoprostanes (22, 23) and endothelin-1 (12, 13, 40) are potent constrictors of pulmonary vessels and airways. This potential dual effect raises the question of whether the maintenance of a high pulmonary vascular resistance in the chronic hyperoxia-induced pulmonary hypertensive newborn rat is secondary to pulmonary vascular muscle contraction or remodeling.
In this respect, the lung histological findings of increased vascular smooth muscle in the newborn rat exposed to chronic hyperoxia are not necessarily indicative of a greater potential for vasoconstriction. In the ligated ductus arteriosus fetal sheep model of pulmonary hypertension, where muscle hypertrophy is observed, our laboratory showed that the pulmonary arterial smooth muscle had a reduced potential for contraction and endothelium-independent abnormal relaxation properties (3). Similar findings have also been described for the monocrotaline-induced adult rat model of pulmonary hypertension (1).
We reasoned that exposure to chronic hyperoxia may also induce airway smooth muscle changes. Our laboratory has previously reported that newborn rats exposed to chronic hyperoxia for 14 days have histological evidence of a bronchopulmonary dysplasia-like lung morphology (16). In human infants with bronchopulmonary dysplasia, an increased incidence of airway hyperresponsiveness has been described (29). Furthermore, an association between pulmonary hypertension and airway hyperresponsiveness has been reported in children (41) but not adults.
Little is known about the effect of 60% O2 exposure for 14 days in the adult rat. The only reported study utilizing this concentration and duration of O2 exposure was limited to evaluating the animal lungs at 7 days, and only minimal histological changes were observed and mostly limited to the vascular endothelium (18). Adult primates exposed for 14 days to this O2 concentration were reported to only develop chronic lung epithelial injury (11), but the functional properties of the vascular and airway smooth muscle were not studied.
In this study, we chose to evaluate and compare the pulmonary arterial and airway smooth muscle mechanical properties of the newborn and adult rat after 60% O2 exposure for 14 days. We hypothesized that chronic exposure to 60% O2 induces pulmonary vascular and airway muscle mechanical property changes via reactive oxygen species (ROS) formation, and these are of greater magnitude in the newborn, compared with the adult, rat. In addition, we hypothesized that chronic hyperoxia alters the endothelium- and epithelium-dependent nitric oxide production.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Institutional review. All procedures involving animals were conducted according to criteria established by the Canadian Council for Animal Care. Approval for the study was obtained from the Animal Care Review Committee of the University Health Network, Toronto Western Hospital, and Hospital for Sick Children Research Institute.
Exposure system. Pathogen-free, timed-pregnant, or nonpregnant female adult Sprague-Dawley rats (250-275 g) were obtained from Charles River (St. Constant, Quebec). Experiments were conducted as paired exposures, with one chamber receiving 60% O2 and the other receiving air. O2 and CO2 concentrations, temperature, and humidity were continuously monitored, recorded, and regulated by a computer with the use of customized software (AnaWin2 Run-Time, version 2.2.18, Watlow-Anafaze, St. Louis, MO). Gas delivery was regulated by customized hardware (Oxycycler model A84XOV, Biospherix, Redfield, NY) and software (AnaWin2 Run-Time, Watlow-Anafaze) to maintain an O2 concentration within 0.1% of the set point. O2 sensors were calibrated weekly. On the anticipated day of delivery, each dam was placed in a 80 × 60 × 50-cm plastic chamber with 12:12-h light-dark cycles and with the temperature maintained at 25 ± 1°C, humidity ~50%, and CO2 concentration <0.5%. Equal litter sizes (10-12 pups) were maintained between paired chambers. Food and water were available ad libitum. Dams were exchanged daily between chambers to prevent maternal O2 toxicity. Pups were maintained in the chambers (air and O2) for a 14-day exposure period. Adult rats were subjected to the same above-described protocol of chronic hyperoxia. Air-treated animals served as controls. At the termination of each exposure period, animals were killed by an overdose of pentobarbital sodium (40 mg/kg ip).
Organ bath studies. Fourth- or fifth-generation (adult) left lung intralobar bronchi and neighboring pulmonary arterial ring segments (average diameter 100 µm and length 2 mm) were dissected free and mounted in a wire myograph (Danish Myo Technology). Isometric changes were digitized and recorded on-line (Myodaq, Danish Myo Technology). Tissues were bathed in Krebs-Henseleit buffer (115 mM NaCl, 25 mM NaHCO3, 1.38 mM NaHPO4, 2.51 mM KCl, 2.46 mM MgSO4 · 7H2O, 1.91 mM CaCl2, and 5.56 mM dextrose) bubbled with air-6% CO2 and maintained at 37°C.
After 1 h of equilibration, the optimal resting tension of the tissue was determined by repeated stimulation with 128 mM KCl until maximum active tension was reached. All subsequent force measurements were obtained at optimal resting tension. Pulmonary vascular muscle force generation was evaluated by stimulating with KCl and the thromboxane mimetic U-46619. Similarly, the bronchial muscle was stimulated with KCl, U-46619, and acetylcholine (ACh). Contractile responses were normalized to the tissue cross-sectional area as (width × diameter) × 2 and expressed in milli-Newtons per millimeter squared. For the acute hyperoxia studies, the pulmonary arteries were dissected, mounted, and studied on Krebs-Henseleit buffer bubbled with 94% O2-6% CO2 and maintained at 37°C. The relaxant response to sodium nitroprusside (SNP), ACh (vascular), and adenosine triphosphate (bronchi) was determined by precontracting the pulmonary and bronchial muscle with U-46619 (10
6 M)
and ACh (104 M), respectively. The antioxidant Trolox
(104 M) and the endothelin-receptor antagonist SB-217242
(105 M) were used to evaluate the effect of ROS and
endothelin, respectively, on the smooth muscle contraction and
relaxation potential.
Drugs. Trolox was obtained from Hoffman-La Roche. SB-217242 was generously provided by Dr. Douglas Hay (SmithKline Beecham Pharmaceuticals, King of Prussia, PA). All other chemicals were obtained from Sigma Chemical (Oakville, ON) and dissolved in Krebs-Henseleit buffer.
Heart measurements. To assess for the presence of pulmonary hypertension in the experimental animals, we evaluated the degree of right ventricular hypertrophy by measuring the right ventricular weight-to-left ventricular + septum weight ratio (14).
Histology. Newborn lungs were removed immediately after death and immersed in 4% paraformaldehyde in a 0.2 M sodium phosphate buffer (pH 7.4). The tissue was postfixed at 4°C for 4-20 h, dehydrated in a graded series of ethanols, and cleared in xylene. The fixed tissue was embedded in molten paraffin in a heating incubator at 54°C for 2-3 days. After tissues were embedded, the paraffin block containing the tissue was trimmed and mounted on a rotary microtome (model 45, Lipshaw, Detroit, MI) equipped with a standard knife holder and a forward-moving block. The tissue was orientated to allow for the cutting of transverse sections (6-µm thickness) at midlung level to allow for visualization of bronchi and pulmonary artery of similar generation as used for the organ bath studies. Sections were mounted on gelatin-subbed microscope slides and immersed in xylene for 15 min to remove wax before staining. The dewaxed sections were dehydrated through a graded series of ethanols, stained with Gill's hematoxylin for 2 min for nuclear staining, and rinsed with distilled water. The sections were then stained for 1 min with eosin for cytoplasmic staining.
Data analysis.
Data were evaluated by the Student's t-test or two-way
ANOVA, with multiple comparisons obtained by the Newman-Keuls test when
appropriate. Statistical significance was accepted if P < 0.05. Power analysis (
= 0.05) was performed for small-size
samples (n = 4) to calculate the probability of
rejecting a false null hypothesis. All statistical analyses were
performed with the Number Cruncher Statistical System (NCSS, Kaysville,
UT). Data are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hyperoxia induced pulmonary hypertension in the newborn and adult
animals, as evidenced by the increased weight of the right ventricle
(RV) relative to the weight of the left ventricle (LV) and septum
[RV/LV + septum (Table 1)]. Figure
1 illustrates low- and high-power
magnifications of the newborn's bronchi
and pulmonary artery of similar generations as those utilized for
functional studies. No obvious difference in the vascular and airway
muscle layer thickness was noted between the control and oxygen-treated newborn animals.
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After 2 wk of hyperoxia, pulmonary arterial smooth muscle force
generation in response to KCl and U-466190 stimulation was significantly increased (P < 0.01) in the newborn and
decreased (P < 0.01) in the adult (Fig.
2). Relaxation of previously constricted arteries was similar after endothelium-dependent stimulation with ACh
(Fig. 3). In contrast,
endothelium-independent relaxation in response to SNP was significantly
reduced (P < 0.01) in the O2-exposed
newborn but enhanced in the adult animals (Fig. 3). The ACh- and
SNP-induced relaxation of control and experimental vessels was
completely inhibited by the endothelial nitric oxide synthase
antagonist NG-nitro-L-arginine
methyl ester and soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one,
respectively (Fig. 3).
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Addition of a ROS scavenger (Trolox), or a combined endothelin-A and
-B-receptor antagonist (SB-217242), to the media abrogated the chronic
hyperoxia-induced changes in the newborn pulmonary arterial muscle
force and relaxation potential (Figs. 4 and
5). The probability
of rejecting a false null hypothesis
(power), given the groups' small sample size (n = 4),
was 0.5 for the endothelin-receptor blocker and 0.63 for Trolox.
Neither compound had an effect on the reduced pulmonary arterial muscle
force but markedly decreased the SNP-induced relaxation
(P < 0.01) in the adult experimental vessels (Figs. 4
and 5).
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Airway smooth muscle mechanical properties were also altered after
hyperoxia in an age-dependent manner that mirrored the changes observed
for the vascular muscle. In the newborn experimental animals, the
bronchial muscle showed a greater (P < 0.01) force generation in response to ACh (data not shown) and U-46619 stimulation (Fig. 6). In contrast, a significant
reduction (P < 0.01) in ACh (data not shown) and
U-46619-induced force generation was documented in the adult
experimental animals (Fig. 6). Trolox or the endothelin-A and
-B-receptor blocker abolished the U-46619-induced bronchial muscle
force increase in the chronic O2-exposed newborn, but not adult, animals (Fig. 6).
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The epithelium-independent (SNP) relaxation of the prestimulated airway
smooth muscle was not altered by hyperoxia at either age (Fig.
7). In contrast, the epithelium-dependent
(adenosine triphosphate) relaxation was reduced (P < 0.01) in the chronic O2-exposed adult, but not newborn,
airway tissue (Fig. 7).
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To evaluate the acute effect of O2 exposure on the
pulmonary vascular muscle, we compared the contraction and relaxation
responses at two different muscle bath PO2
values (air: PO2 = 140 Torr and oxygen:
PO2 = 450 Torr). The higher bath
PO2 increased (P < 0.01) KCl-induced force generation in the newborn and adult pulmonary arterial tissue (Fig. 8). The muscle bath
PO2 did not alter the endothelium-dependent
relaxation dose response. In contrast, the endothelium-independent
SNP-induced response at higher O2 concentration was reduced
(P < 0.01) in the adult but not newborn (Fig.
9).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The factors leading to the development of pulmonary hypertension after chronic O2 exposure are not completely understood. In previous studies, our laboratory has shown that lung tissue ROS formation, thromboxane A2-receptor stimulation, possibly via local release of 8-isoprostane (19), and upregulation of endothelin-1 (20, 21) are involved in the process.
In this study, we evaluated 100-µm third- to fourth-generation pulmonary arteries and adjacent airways. On histology, the pulmonary arteries did not exhibit the increased muscularization that characterizes the more peripheral lung vessels of the chronic hyperoxic newborn animals (26). However, significant changes in their muscle mechanical properties were observed. This response was evident as early as 7 days after O2 exposure (4), when no peripheral pulmonary vascular remodeling was present on lung histology.
Acutely, an increased PO2 in the bath resulted in enhanced force generation in the newborn and adult, as well as reduced SNP-dependent relaxation in the adult pulmonary arterial muscle. In the bovine retina, SNP relaxation was also reported to be O2 dependent (15). Although the bath PO2 in air (145 Torr) was significantly higher than the pulmonary arterial PO2, this does not necessarily result in tissue hyperoxia. In vivo, the vascular wall oxygenation is provided by the vasa vasorum, whereas, in the muscle bath, the oxygen has to diffuse across the tissue to reach the smooth muscle layer.
Trolox abrogated the chronic hyperoxia-induced increase in force development and relaxation to SNP. Trolox is a water-soluble derivative of vitamin E that penetrates biomembranes, protects mammalian cells from oxidative damage, and scavenges superoxide anion formed by smooth muscle cells (27). This suggests that chronic O2 exposure-induced changes in the lung smooth muscle properties are related to ROS formation.
ROS are required for vascular smooth muscle contraction and cell growth signaling. Inositol 1,4,5-trisphosphate-induced Ca2+ release from vascular smooth muscle is selectively stimulated by ROS (45) and may enhance the degree of muscle contraction. ROS increase muscle force generation and/or contraction in rat aorta (43), and xanthine oxidase-derived O2 ROS are involved in the pathogenesis of salt-induced hypertension (46, 49). Catalase, an H2O2 scavenger, abolishes the arterial smooth muscle contraction elicited by H2O2 in rats (39), suggesting that this phenomenon is directly dependent on the presence of ROS. Lastly, exposure to H2O2 causes smooth muscle contractions and dysfunction in isolated rat pulmonary arteries and activation of tyrosine kinases (24).
There is also mounting evidence that oxidative stress is responsible for systemic hypertension via a mechanism that involves the endothelin pathway (48). Our laboratory has previously reported that, in the chronic hyperoxia newborn rat model (21), lung endothelin-1 expression and content are increased. In this study, we demonstrated that SB-217242 abolished the newborn rat hyperoxia-induced altered response of pulmonary and airway smooth muscle contraction and relaxation. SB-217242 is an endothelin-A and -B-receptor antagonist that has been shown to be effective in human and animal pulmonary vascular tissue (28, 31).
This evidence strongly suggests that ROS and endothelin contribute to
the enhanced force and reduced NO-induced relaxation of pulmonary
vascular smooth muscle after chronic exposure of newborn rats to
O2. Likely, these factors interact in a rather complex
manner. Although endothelin-1 is produced by endothelial cells, recent
evidence points to ROS having a stimulant effect on its release from
endothelial, as well as pulmonary vascular (47), and other
smooth muscle cells (25). Figure
10 illustrates a possible mechanism for
the chronic O2-induced changes in smooth muscle contraction
and relaxation responses.
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Our present data demonstrate that, developmentally, the newborn rat pulmonary vascular muscle has a lower potential for force generation compared with the adult. We have reported similar findings for the sheep pulmonary and systemic vascular smooth muscle (5). To our knowledge, there are no published studies comparing the mechanical properties of newborn and adult pulmonary vascular smooth muscle in animal models of pulmonary hypertension. However, there is evidence that the newborn is more susceptible to pulmonary hypertension than the adult. In the chronically hypoxic rat, the degree of pulmonary vascular remodeling and of pulmonary hypertension vary according to age (8, 32, 36). Newborn hypoxic animals exhibit greater residual elevated pressure and structural lung abnormalities after a return to normoxia, compared with adult rats (36).
We have shown that pulmonary arterial muscle force generation is decreased in two animal models of fetal pulmonary hypertension: the ductus-arteriosus ligation-induced sheep (3), and the nitrofen-induced congenital diaphragmatic hernia in rats (2). In the present study, we have documented that pulmonary arterial muscle force generation was also reduced in the chronically O2-exposed adult, but not newborn, rat. Others have also reported a reduced pulmonary vascular smooth muscle force in the pulmonary hypertensive adult rat (1, 8).
The endothelium-independent relaxation responses of the pulmonary, but not airway, muscle were found to be distinct for the newborn and adult experimental animals compared with control rats. Significant changes in relaxation properties have also been documented in the pulmonary hypertensive adult rat exposed to chronic hypoxia. In these, endothelium-dependent relaxation of pulmonary arterial smooth muscle was reported to increase in several (37, 38) studies and to decrease in at least one other study (9).
Our laboratory recently documented that the lungs of newborn rats exposed to 60% O2 for 14 days have an increased nitrotyrosine content (marker of peroxynitrite formation) but unaltered peroxynitrite-independent nitric oxide release (unpublished observations). Adult rat pulmonary arteries dilate in response to peroxynitrite (reaction product of NO and superoxide anions), and this compound potentiates the dilatory response of SNP (10). This is the most plausible explanation for the potentiation of the SNP-induced relaxation in the O2-treated pulmonary arteries obtained from the adult rats in this study.
We documented that the endothelium-independent, but not -dependent, relaxation was affected by chronic O2 treatment. Similar observations were made by other investigators. Endothelium-independent dilations of bovine pulmonary arteries induced by SNP are impaired by oxidized lipoprotein, whereas forskolin-induced dilator responses were unaffected (33). In fifth-generation pulmonary arteries isolated from lambs with persistent pulmonary hypertension of the newborn, pretreatment with superoxide dismutase significantly enhanced vascular relaxation in response to a NO donor (44). Thus this evidence suggests that, in our study, the relaxation potential of the pulmonary arterial smooth muscle is not affected by chronic O2 exposure, and the discrepancy between hyperoxia-induced changes in the ACh- and SNP-mediated relaxation is related to a direct effect of ROS and/or O2 on the latter response.
Alternatively, the altered SNP-induced relaxation of the chronic O2-exposed animals and the difference in response between the newborn (decreased) and adult (increased relaxation) are possibly related to the pulmonary arterial soluble guanylyl cyclase content. This enzyme responsible for cGMP production was found to be decreased (6, 30) or increased (7) in animal models of pulmonary hypertension.
In the present study, 60% O2 exposure for 14 days induced significant changes in airway smooth muscle mechanical properties in an age-dependent pattern that mimics that observed for the pulmonary arterial muscle. Similarly, to the vascular endothelium, the airway epithelium is capable of producing ROS (17). In the adult horse, H2O2 (one of the ROS products) alters the tracheal smooth muscle mechanical properties in a concentration-dependent manner (35). ROS products also appear to have distinct in vitro effects on airway smooth muscle. In the cat, H2O2 results in an increase in airway muscle tone and enhancement of contraction after supraelectrical stimulation, whereas superoxide inhibits muscle tone. The observed increase in the bronchial force generation in the O2-exposed newborn rat suggests that newborn airway muscle responds to O2 exposure and ROS formation in a unique way, compared with the adult.
Increased airway resistance is a common finding in neonates with bronchopulmonary dysplasia (29, 34) and is believed to be related to the supplemental O2 and ventilatory support required by these infants. Increased airway resistance has also been clinically reported in children with postoperative pulmonary hypertension (42). This suggests that cross talk between the vascular and airway compartments exists and may modulate the behavior of the airway when pulmonary hypertension is present.
In summary, we have demonstrated that 60% O2 treatment for 14 days results in vascular and airway smooth muscle property changes in an age-dependent manner. Oxygen toxicity in the newborn rat results in enhanced potential for vascular and airway smooth muscle contraction and reduced vascular endothelium-independent relaxation through a mechanism that involves ROS and the endothelin pathway. This uniquely distinct response of the newborn muscle to O2 exposure likely renders them more susceptible to pulmonary hypertension and increased airway hyperresponsiveness.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Canadian Institute for Health and Research. A. K. Tanswell holds the Hospital for Sick Children Women's Auxiliary Chair in Neonatal Medicine. R. P. Jankov is supported by Postdoctoral Research Awards from the Canadian Institutes of Health Research and the Canadian Lung Association, as well as a Clinician-Scientist Training Fellowship from the Hospital for Sick Children Research Institute.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Belik, Professor of Pediatrics, Univ. of Toronto, Division of Neonatology, Hospital for Sick Children, Rm. 3886, 555 Univ. Ave., Toronto, Ontario, Canada M5G 1X8 (E-mail: Jaques.Belik{at}SickKids.ca).
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. Section 1734 solely to indicate this fact.
First published January 31, 2003;10.1152/japplphysiol.00820.2002
Received 9 September 2002; accepted in final form 22 January 2003.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Altiere, RJ,
Olson JW,
and
Gillespie MN.
Altered pulmonary vascular smooth muscle responsiveness in monocrotaline-induced pulmonary hypertension.
J Pharmacol Exp Ther
236:
390-395,
1986
2.
Belik, J,
Davidge S,
Zhang W,
Pan J,
and
Greer J.
Airway smooth muscle changes in the nitrofen-induced congenital diaphragmatic hernia rat model.
Pediatr Res
53:
1-7,
2003[ISI].
3.
Belik, J,
Halayko AJ,
Rao K,
and
Stephens NL.
Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes.
Circ Res
72:
588-596,
1993
4.
Belik, J,
Jankov R,
Pan Jingyi,
and
Tanswell AK.
Rat pulmonary vascular and airway smooth muscle mechanical properties following neonatal chronic hyperoxia (Abstract).
Pediatr Res
51:
332A,
2002.
5.
Belik, J,
and
Stephens NL.
Developmental differences in vascular smooth muscle mechanics in pulmonary and systemic circulations.
J Appl Physiol
74:
682-687,
1993
6.
Berkenbosch, JW,
Baribeau J,
and
Perreault T.
Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia-induced pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol
278:
L276-L283,
2000
7.
Black, SM,
Sanchez LS,
Mata-Greenwood E,
Bekker JM,
Steinhorn RH,
and
Fineman JR.
sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol
281:
L1051-L1057,
2001
8.
Bonnet, S,
Belus A,
Hyvelin JM,
Roux E,
Marthan R,
and
Savineau JP.
Effect of chronic hypoxia on agonist-induced tone and calcium signaling in rat pulmonary artery.
Am J Physiol Lung Cell Mol Physiol
281:
L193-L201,
2001
9.
Carville, C,
Raffestin B,
Eddahibi S,
Blouquit Y,
and
Adnot S.
Loss of endothelium-dependent relaxation in proximal pulmonary arteries from rats exposed to chronic hypoxia: effects of in vivo and in vitro supplementation with L-arginine.
J Cardiovasc Pharmacol
22:
889-896,
1993[ISI][Medline].
10.
Chabot, F,
Mitchell JA,
Quinlan GJ,
and
Evans TW.
Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase.
Br J Pharmacol
121:
485-490,
1997[ISI][Medline].
11.
Crapo, JD,
Hayatdavoudi G,
Knapp MJ,
Fracica PJ,
Wolfe WG,
and
Piantadosi CA.
Progressive alveolar septal injury in primates exposed to 60% oxygen for 14 days.
Am J Physiol Lung Cell Mol Physiol
267:
L797-L806,
1994
12.
Deuchar, GA,
Docherty A,
MacLean MR,
and
Hicks MN.
Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin-1 in the control of pulmonary vascular tone.
Br J Pharmacol
135:
1060-1068,
2002[ISI][Medline].
13.
Dupuis, J.
Endothelin-receptor antagonists in pulmonary hypertension.
Lancet
358:
1113-1114,
2001[ISI][Medline].
14.
Fulton, RM,
and
Hutchinson EC.
Ventricular weight in cardiac hypertrophy.
Br Heart J
14:
413-420,
1952
15.
Haefliger, IO,
Chen Q,
and
Anderson DR.
Effect of oxygen on relaxation of retinal pericytes by sodium nitroprusside.
Graefes Arch Clin Exp Ophthalmol
235:
388-392,
1997[ISI][Medline].
16.
Han, RN,
Buch S,
Tseu I,
Young J,
Christie NA,
Frndova H,
Lye SJ,
Post M,
and
Tanswell AK.
Changes in structure, mechanics, and insulin-like growth factor-related gene expression in the lungs of newborn rats exposed to air or 60% oxygen.
Pediatr Res
39:
921-929,
1996[ISI][Medline].
17.
Hay, DW,
Van Scott MR,
and
Muccitelli RM.
Characterization of endothelin release from guinea-pig tracheal epithelium: influence of proinflammatory mediators including major basic protein.
Pulm Pharmacol Ther
10:
189-198,
1997[ISI][Medline].
18.
Hayatdavoudi, G,
O'Neil JJ,
Barry BE,
Freeman BA,
and
Crapo JD.
Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days.
J Appl Physiol
51:
1220-1231,
1981
19.
Jankov, RP,
Belcastro R,
Ovcina E,
Lee J,
Massaeli H,
Lye SJ,
and
Tanswell AK.
Thromboxane A2 receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism.
Am J Respir Crit Care Med
166:
208-214,
2002
20.
Jankov, RP,
Luo X,
Belcastro R,
Copland I,
Frndova H,
Lye SJ,
Hoidal JR,
Post M,
and
Tanswell AK.
Gadolinium chloride inhibits pulmonary macrophage influx and prevents O2-induced pulmonary hypertension in the neonatal rat.
Pediatr Res
50:
172-183,
2001[ISI][Medline].
21.
Jankov, RP,
Luo X,
Cabacungan J,
Belcastro R,
Frndova H,
Lye SJ,
and
Tanswell AK.
Endothelin-1 and O2-mediated pulmonary hypertension in neonatal rats: a role for products of lipid peroxidation.
Pediatr Res
48:
289-298,
2000[ISI][Medline].
22.
Janssen, LJ.
Isoprostanes: an overview and putative roles in pulmonary pathophysiology.
Am J Physiol Lung Cell Mol Physiol
280:
L1067-L1082,
2001
23.
Janssen, LJ,
Premji M,
Netherton S,
Coruzzi J,
Lu-Chao H,
and
Cox PG.
Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinase in human and canine pulmonary vascular smooth muscles.
Br J Pharmacol
132:
127-134,
2001[ISI][Medline].
24.
Jin, N,
and
Rhoades RA.
Activation of tyrosine kinases in H2O2-induced contraction in pulmonary artery.
Am J Physiol Heart Circ Physiol
272:
H2686-H2692,
1997
25.
Kaehler, J,
Sill B,
Koester R,
Mittmann C,
Orzechowski HD,
Muenzel T,
and
Meinertz T.
Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species.
Clin Sci (Lond) 103, Suppl
48:
176S-178S,
2002.
26.
Koppel, R,
Han RN,
Cox D,
Tanswell AK,
and
Rabinovitch M.
Alpha 1-antitrypsin protects neonatal rats from pulmonary vascular and parenchymal effects of oxygen toxicity.
Pediatr Res
36:
763-770,
1994[ISI][Medline].
27.
Kugi, M,
Matsunaga A,
Ono J,
Arakawa K,
and
Sasaki J.
Antioxidative effects of fluvastatin on superoxide anion activated by angiotensin II in human aortic smooth muscle cells.
Cardiovasc Drugs Ther
16:
203-207,
2002[ISI][Medline].
28.
MacLean, MR,
Docherty CC,
McCulloch KM,
and
Morecroft I.
Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries.
Pulm Pharmacol Ther
11:
147-149,
1998[ISI][Medline].
29.
Mallory, GB, Jr,
Chaney H,
Mutich RL,
and
Motoyama EK.
Longitudinal changes in lung function during the first three years of premature infants with moderate to severe bronchopulmonary dysplasia.
Pediatr Pulmonol
11:
8-14,
1991[ISI][Medline].
30.
Mathew, R,
Yuan N,
Rosenfeld L,
Gewitz M,
and
Kumar AH.
Effects of monocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs.
Heart Dis
4:
152-158,
2002[Medline].
31.
Medbo, S,
Tollofsrud PA,
and
Saugstad OD.
Pulmonary hemodynamics in newborn piglets during hypoxemia and reoxygenation: blocking of the endothelin-1 receptors.
Pediatr Res
46:
514-522,
1999[ISI][Medline].
32.
Meyrick, B,
and
Reid L.
Normal postnatal development of the media of the rat hilar pulmonary artery and its remodeling by chronic hypoxia.
Lab Invest
46:
505-514,
1982[ISI][Medline].
33.
Mohazzab, KM,
Fayngersh RP,
Kaminski PM,
and
Wolin MS.
Potential role of NADH oxidoreductase-derived reactive O2 species in calf pulmonary arterial PO2-elicited responses.
Am J Physiol Lung Cell Mol Physiol
269:
L637-L644,
1995
34.
Northway, WH, Jr,
Moss RB,
Carlisle KB,
Parker BR,
Popp RL,
Pitlick PT,
Eichler I,
Lamm RL,
and
Brown BW, Jr.
Late pulmonary sequelae of bronchopulmonary dysplasia.
N Engl J Med
323:
1793-1799,
1990[Abstract].
35.
Olszewski, MA,
Robinson NE,
Yu MF,
and
Derksen FJ.
Effects of hydrogen peroxide on isolated trachealis muscle of horses.
Am J Vet Res
56:
1479-1485,
1995[ISI][Medline].
36.
Rabinovitch, M,
Gamble WJ,
Miettinen OS,
and
Reid L.
Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery.
Am J Physiol Heart Circ Physiol
240:
H62-H72,
1981
37.
Resta, TC,
and
Walker BR.
Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation.
Am J Physiol Heart Circ Physiol
270:
H888-H896,
1996
38.
Rodman, DM.
Chronic hypoxia selectively augments rat pulmonary artery Ca2+ and K+ channel-mediated relaxation.
Am J Physiol Lung Cell Mol Physiol
263:
L88-L94,
1992
39.
Rodriguez-Martinez, MA,
Garcia-Cohen EC,
Baena AB,
Gonzalez R,
Salaices M,
and
Marin J.
Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved.
Br J Pharmacol
125:
1329-1335,
1998[ISI][Medline].
40.
Rubens, C,
Ewert R,
Halank M,
Wensel R,
Orzechowski HD,
Schultheiss HP,
and
Hoeffken G.
Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension.
Chest
120:
1562-1569,
2001[ISI][Medline].
41.
Schindler, MB,
Bohn D,
Cox PN,
McCrindle BW,
Jarvis A,
Edmonds J,
and
Barker G.
Outcome of out-of-hospital cardiac or respiratory arrest in children.
N Engl J Med
335:
1473-1479,
1996
42.
Schindler, MB,
Bohn DJ,
Bryan AC,
Cutz E,
and
Rabinovitch M.
Increased respiratory system resistance and bronchial smooth muscle hypertrophy in children with acute postoperative pulmonary hypertension.
Am J Respir Crit Care Med
152:
1347-1352,
1995[Abstract].
43.
Shen, JZ,
Zheng XF,
and
Kwan CY.
Differential contractile actions of reactive oxygen species on rat aorta: selective activation of ATP receptor by H2O2.
Life Sci
66:
L291-L296,
2000.
44.
Steinhorn, RH,
Albert G,
Swartz DD,
Russell JA,
Levine CR,
and
Davis JM.
Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension.
Am J Respir Crit Care Med
164:
834-839,
2001
45.
Suzuki, YJ,
and
Ford GD.
Redox regulation of signal transduction in cardiac and smooth muscle.
J Mol Cell Cardiol
31:
345-353,
1999[ISI][Medline].
46.
Swei, A,
Lacy F,
Delano FA,
Parks DA,
and
Schmid-Schonbein GW.
A mechanism of oxygen free radical production in the Dahl hypertensive rat.
Microcirculation
6:
179-187,
1999[ISI][Medline].
47.
Wedgwood, S,
Dettman RW,
and
Black SM.
ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species.
Am J Physiol Lung Cell Mol Physiol
281:
L1058-L1067,
2001
48.
Wilcox, CS.
Reactive oxygen species: roles in blood pressure and kidney function.
Curr Hypertens Rep
4:
160-166,
2002[ISI][Medline].
49.
Yang, ZW,
Zheng T,
Zhang A,
Altura BT,
and
Altura BM.
Mechanisms of hydrogen peroxide-induced contraction of rat aorta.
Eur J Pharmacol
344:
169-181,
1998[ISI][Medline].
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