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Isoprostanes are chemically stable lipid peroxidation products of
arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of isoprostaglandin F2
type III (iPF2-III), an F2-isoprostane, in patients with
pulmonary hypertension (PHT) in comparison with healthy controls. The secondary objective was to test whether baseline iPF2-III levels correlate to the reversibility of pulmonary hypertension in
response to inhaled NO challenge. Urinary iPF2-III levels were
measured by gas chromatography-mass spectrometry in 25 patients with PHT, 14 of whom were investigated for response to inhaled NO challenge. Urinary iPF2-III levels in PHT patients (225 ± 27 pmol/mmol creatinine) were 2.3 times as high as in controls (97 ± 7 pmol/mmol creatinine, p < 0.001). The mean pulmonary
arterial pressure variation and the pulmonary vascular resistance
variation in response to inhaled NO were correlated to basal iPF2-III levels. This study shows that oxidative stress is increased in patients with pulmonary hypertension. Furthermore, iPF2-III levels
inversely correlate to pulmonary vasoreactivity. These observations are consistent with the hypothesis that free radical generation is involved in PHT pathogenesis.
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Keywords: hypertension; isoprostane; lipid peroxidation; oxidative stress; pulmonary
Precapillary pulmonary hypertension (PHT), a syndrome common to a variety of lung diseases, leads to an increased load to the right ventricle. The elevated vascular resistance is a result of an increase in both vascular tone and vascular wall remodeling. The pulmonary vasoreactivity can be evaluated by short-acting vasodilators such as nitric oxide (NO) in order to identify patients who are likely to respond to long-term vasodilator therapy (1, 2). Although chronic PHT is caused by different factors, the mechanism leading to vasoconstriction and structural remodeling is a common phenomenon. Indeed, although a large variety of molecules appear to be involved in PHT, the primary stimulus as well as their exact interplay remain unclear to date. Experimental data suggest that free radicals play an important role in the development of pulmonary hypertension (3). They may lead to pulmonary vascular wall injury and as such may initiate the process of vascular proliferation and structural remodeling. However, no strong evidence is available to date in humans because of the lack of reliable markers of oxidant injury in vivo (4).
Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo
(5). Among these isoprostanes, isoprostaglandin F2 type III (iPF2-III, also named 15-F2t-isoP [6, 7]) can be measured in
biological fluids and tissues. This compound is a stable and specific product of lipid peroxidation (5), and has been used to
investigate lipid peroxidation in pulmonary diseases such as asthma (8), chronic obstructive pulmonary disease (11),
cystic fibrosis (12), interstitial lung disease (15), acute respiratory distress syndrome (16), and respiratory failure (17).
Besides reflecting an ongoing process of enhanced lipid peroxidation, iPF2-III is a potent constrictor of systemic and pulmonary vessels through thromboxane A2/prostaglandin H2
(PGH2) receptor stimulation (18), which may be relevant in pathophysiology.
The main objective of this study was to quantify the urinary
levels of iPF2-III, as a marker of lipid peroxidation, in patients with PHT in comparison with healthy control subjects. The secondary objective was to test whether baseline iPF2-III levels correlate with the reversibility of pulmonary hypertension in response to inhaled NO challenge.
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Patients
Twenty-five white patients (16 women and 9 men, median age 58 yr,
range 14-78 yr) referred to the Département de Médecine Aiguë Spécialisée (Grenoble University Hospital, Grenoble, France) were included in the study between February and December 2000. Precapillary PHT was defined after right heart catheterization by a baseline
mean pulmonary arterial pressure > 25 mm Hg and a pulmonary artery occlusive pressure < 12 mm Hg (19). The classification as primary or secondary hypertension was performed according to World
Health Organization standards (20). All patients underwent, within
48 h of the right heart catheterization, blood gas determination and
respiratory function testing, and the 6-min walking distance was measured. Complete echocardiographic examinations were performed in
all patients in order to exclude patients with left ventricular systolic
dysfunction. Other exclusion criteria included potential confounding
factors associated with increased F2-isoprostane production: current
cigarette smoking (21), hypercholesterolemia (22), and diabetes (23).
An age (± 5 yr)- and sex-paired sample of 25 healthy volunteers selected from the general population was used as a control group (16 women and 9 men, median age 55 yr, range 19-76 yr, nonsmokers,
free of previously diagnosed diabetes or hypercholesterolemia). Urine
samples (20 ml) were collected between 8 and 10 AM in polyethylene
tubes, immediately refrigerated and transferred to the laboratory, and
aliquoted and stored at 
20° C. This study conformed to the principles outlined in the Declaration of Helsinki, including informed consent.
The daily variation of urinary iPF2-III levels in healthy volunteers
is low (24, 25) (median interday coefficient of variation in our healthy
subjects was 5%, unpublished data). However, the daily variation of
urinary iPF2-III levels in patients with PHT remains unknown. To assess the interday variation of urinary iPF2-III levels, urine samples
(20 ml) were collected between 8 and 10 AM on two consecutive days
from five patients during hospitalization. The median interday coefficient of variation was 7%.
NO Administration
(See online data supplement.)
Of the 25 patients, 14 were investigated for response to inhaled NO challenge (up to 20 ppm). Heart rate; systolic, mean, and diastolic pulmonary arterial pressures; and central venous and pulmonary artery occlusive pressures were measured. Urine samples (20 ml) were collected immediately before a Swan-Ganz catheter was introduced. Another urine sample (20 ml) was collected after completion of the test (median, 30 min; range, 20-50 min).
Urinary iPF2-III Measurements
Urinary iPF2-III was measured by gas chromatography/electronic impact mass spectrometry as previously described and validated (26).
Values were expressed as picomoles per millimole of creatinine.
Statistical Analysis
Sample size calculations were based on the main objective to detect a
difference of at least 30 pmol/mmol between patients and healthy controls, with 
= 0.05 and a power (1 
) = 0.8. iPF2-III levels were
expressed as means ± SEM. The data were analyzed by nonparametric methods to avoid assumption about the distribution of the measured variables: analysis of variance (ANOVA) (Kruskal-Wallis
method) or Mann-Whitney tests were used for statistical comparisons. Paired comparisons were performed with the Wilcoxon test. The
relationship between continuous variables was evaluated by the
Spearman rank correlation test. Values of p < 0.05 were considered significant.
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Subject Characteristics
The demographic, clinical, and baseline cardiorespiratory data of the patients are listed in Table 1. The hemodynamic responses to NO inhalation of the 14 patients who underwent a challenge test are listed in Table 2.
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Main Objective
Urinary iPF2-III levels in patients with PHT (225 ± 27 pmol/
mmol creatinine) were 2.3 times as high as those in control subjects (97 ± 7 pmol/mmol creatinine, p < 0.001; Figure 1).
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Secondary Objectives
No significant correlation was found between basal urinary
iPF2-III levels and PaO2, KCO (transfer factor corrected for
alveolar volume), mean pulmonary arterial pressure, and pulmonary vascular resistance. A subgroup analysis showed that
urinary iPF2-III levels in patients with primary PHT as well as
secondary PHT were elevated compared with control subjects
(267 ± 42 vs. 186 ± 38 vs. 97 ± 7 pmol/mmol creatinine, respectively; ANOVA, p < 0.001).
Mean pulmonary arterial pressure variation and pulmonary vascular resistance variation in response to inhaled NO
were correlated with basal iPF2-III levels (Figure 2). Urinary
iPF2-III levels were not modified after NO challenge (212 ± 31 pmol/mmol creatinine at baseline vs. 218 ± 32 pmol/mmol
creatinine after NO challenge, n = 14; NS).
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MPAP; A) and maximal percentage of variation of pulmonary vascular resistance (max % | |
DISCUSSION |
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This is the first study showing that lipid peroxidation, as reflected by urinary iPF2-III levels, is increased in patients with
PHT in comparison with healthy subjects. Furthermore, iPF2-III levels inversely correlate with the reversibility of pulmonary hypertension.
The study of the role of oxidant injury in human diseases
has been limited by the lack of indices of this process in vivo. In the present study, iPF2-III was used as a reliable marker of
lipid peroxidation in vivo. F2-isoprostanes have many advantages, reviewed by Roberts and Morrow (5): they are specific,
stable, detectable products of lipid peroxidation, not modulated by the lipid content of the diet (27, 28). It is convenient
to measure iPF2-III in urine because the procedure is noninvasive, and because sample handling and storage are easy in
comparison with plasma or tissues, concerning which artifactual formation must be avoided (5). The interday coefficient
of variation is low in healthy subjects (24, 25), as well as in patients with PHT (personal data in METHODS). Urinary iPF2-III
reflects systemic rather than renal formation of this compound
(29). iPF2-III quantification has been shown to be elevated in humans with such physiological and pathological conditions as cigarette smoking (21), hypercholesterolemia (22), and diabetes (23). Patients and control subjects presenting these potential confounding factors conditions were not included in the
present study.
iPF2-III levels in patients with primary as well as secondary PHT were elevated compared with control subjects, suggesting that increased lipid peroxidation was not correlated
with PHT etiology. Our observations are in line with the hypothesis that the mechanism leading to vasoconstriction and
structural remodeling is a common phenomenon in both primary and secondary PHT. Chronic obstructive pulmonary diseases are associated with increase levels of iPF2-III in urine
(11) and breath condensate (30), whereas an increased level of
iPF2-III was observed in breath condensate in interstitial diseases (15). In these studies, secondary PHT could participate
in the F2-isoprostane elevation. Indeed, the elevated levels observed in patients with primary PHT strongly advocate a link
between PHT and lipid peroxidation. We showed enhanced
lipid peroxidation in patients with systemic sclerosis (31), a
disease that may be associated with PHT. No patient with systemic sclerosis was present in this study, excluding this potential bias.
We studied a heterogeneous group of patients with primary and secondary PHT. In secondary PHT, hypoxemia is pre- existing and is a triggering factor for PHT. On the other hand, hypoxemia occurs as a consequence of primary PHT. Thus, the lack of any correlation between F2-isoprostane levels and clinical parameters including the 6-min walking distance, PaO2, KCO, and mean pulmonary arterial pressure that we observed was not surprising.
F2-isoprostane elevation is not specific, and is observed in other pulmonary diseases in which free radical generation is suspected, such as chronic obstructive pulmonary diseases (11, 30) and cystic fibrosis (12). As a consequence, whereas the development of F2-isoprostane quantification in PHT has strong pathophysiological value and may have prognostic value, it is not likely to screen patients susceptible to the development of PHT.
Precapillary PHT can occur either as a primary or secondary disease following pulmonary diseases. In all cases, vascular
remodeling occurs in the resistance vessels associated with
both fixed and reversible obstruction that can be detected in
response to inhaled NO (1). We observed that the basal iPF2-III level correlated with the variation in mean pulmonary artery pressure and with variation in pulmonary vascular resistance. These observations strongly suggest that the basal lipid
peroxidation level is inversely correlated with the reversibility
of pulmonary hypertension, and are consistent with the hypothesis that free radical generation is involved in PHT pathogenesis. There is currently no way to predict from patient demographic or hemodynamic characteristics those likely to
respond to vasodilators (32, 33). It is tempting to suggest from
the present data that F2-isoprostane quantification could be a
candidate marker to discriminate patients likely to respond to
vasodilators. However, this observation was a secondary objective of the study, performed with a limited number of patients. Whether F2-isoprostane quantification could discriminate patients likely to respond to vasodilators needs to be
further studied with a large number of patients.
Whether oxidative stress is the cause or the result of PHT
cannot be elucidated from our observations. However, reactive oxygen species can stimulate endothelial cell proliferation
(34) and induce vasoconstriction (35). In addition, besides reflecting increased lipid peroxidation, local production of
F2-isoprostanes is likely to contribute to PHT pathogenesis.
iPF2-III is a vasoconstrictor in most vascular beds (18), with a
potency similar to that of prostaglandin F2. This vasoconstrictor activity has been demonstrated in rat (36) and rabbit
(40) pulmonary arteries. Furthermore, isolated human pulmonary arteries have been shown to be able to release iPF2-III
(41, 42), which in turn may induce rapid adhesion of neutrophils (43) and alter pulmonary artery endothelial cell function
(44). These data open new areas of research to determine
whether F2-isoprostane overproduction observed in PHT may in
turn participate in vasoconstriction and structural remodeling.
Nitric oxide is a potent electron donor that in the presence
of oxygen and superoxide forms nitrogen dioxide and peroxynitrite, the production of which has been suggested to be involved in NO toxicity, mediated by lipid peroxidation (2).
F2-isoprostanes are formed minutes after membrane oxidation
(5), and are subsequently released in free forms. In a canine
model of coronary thrombosis, urinary iPF2-III are increased
15 min after reperfusion (45). In clinical conditions of acute
oxidative stress such as ischemia-reperfusion in patients undergoing cardiac surgery, myocardial reperfusion after aortic
clamping was associated with increased urinary iPF2-III excretion 15 min later that remained elevated 30 min after surgery (45). In accordance with the latter data, the 30-min median delay for urine sampling after completion of the NO
challenge was optimal to detect any urinary iPF2-III variations. Our observation clearly shows that NO inhalation (up to
20 ppm) does not lead to a systemic increase in lipid peroxidation, in agreement with previous studies (46).
In conclusion, this study shows that oxidative stress is increased in patients with pulmonary hypertension, as reflected
by an increase in urinary iPF2-III levels. Furthermore, iPF2-III levels inversely correlate with pulmonary vasoreactivity.
These observations are consistent with the hypothesis that
free radical generation is involved in PHT pathogenesis.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Jean-Luc Cracowski, MD, PhD, Laboratoire de Pharmacologie, CHU de Grenoble, BP 217, 38043 Grenoble Cedex 09, France. E-mail: Jean-Luc.Cracowski{at}ujf-grenoble.fr
(Received in original form April 6, 2001 and in revised form May 22, 2001).
This article has on online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors acknowledge the technical assistance of Annie Boudol and Jocelyne Truchet.
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DISCUSSION
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 J. B. Snow, V. Kitzis, C. E. Norton, S. N. Torres, K. D. Johnson, N. L. Kanagy, B. R. Walker, and T. C. Resta Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity J Appl Physiol, January 1, 2008; 104(1): 110 - 118. [Abstract] [Full Text] [PDF]
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C. Liu, T. Tazzeo, and L. J. Janssen Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca2+ handling and Rho/ROCK signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1177 - L1184. [Abstract] [Full Text] [PDF]
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C. Kantores, P. J. McNamara, L. Teixeira, D. Engelberts, P. Murthy, B. P. Kavanagh, and R. P. Jankov Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L912 - L922. [Abstract] [Full Text] [PDF]
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 A. Ogawa, K. Nakamura, H. Matsubara, H. Fujio, T. Ikeda, K. Kobayashi, I. Miyazaki, M. Asanuma, K. Miyaji, D. Miura, et al. Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension Circulation, September 20, 2005; 112(12): 1806 - 1812. [Abstract] [Full Text] [PDF]
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R. E. Girgis, H. C. Champion, G. B. Diette, R. A. Johns, S. Permutt, and J. T. Sylvester Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension: Response to Bosentan Therapy Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 352 - 357. [Abstract] [Full Text] [PDF]
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 T. Higenbottam Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease: A Case for Treatment Proceedings of the ATS, April 1, 2005; 2(1): 12 - 19. [Abstract] [Full Text] [PDF]
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L. G. Wood, M. L. Garg, J. L. Simpson, T. A. Mori, K. D. Croft, P. A. B. Wark, and P. G. Gibson Induced Sputum 8-Isoprostane Concentrations in Inflammatory Airway Diseases Am. J. Respir. Crit. Care Med., March 1, 2005; 171(5): 426 - 430. [Abstract] [Full Text] [PDF]
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I. R. Preston, G. Tang, J. U. Tilan, N. S. Hill, and Y. J. Suzuki Retinoids and Pulmonary Hypertension Circulation, February 15, 2005; 111(6): 782 - 790. [Abstract] [Full Text] [PDF]
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 J.-L. Cracowski and O. Ormezzano Isoprostanes, emerging biomarkers and potential mediators in cardiovascular diseases Eur. Heart J., October 1, 2004; 25(19): 1675 - 1678. [Full Text] [PDF]
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 A. Peacock, R. Naeije, N. Galie, and J.T. Reeves End points in pulmonary arterial hypertension: the way forward Eur. Respir. J., June 1, 2004; 23(6): 947 - 953. [Abstract] [Full Text] [PDF]
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R. Bowers, C. Cool, R. C. Murphy, R. M. Tuder, M. W. Hopken, S. C. Flores, and N. F. Voelkel Oxidative Stress in Severe Pulmonary Hypertension Am. J. Respir. Crit. Care Med., March 15, 2004; 169(6): 764 - 769. [Abstract] [Full Text] [PDF]
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J. Belik, R. P. Jankov, J. Pan, M. Yi, I. Chaudhry, and A. K. Tanswell Chronic O2 exposure in the newborn rat results in decreased pulmonary arterial nitric oxide release and altered smooth muscle response to isoprostane J Appl Physiol, February 1, 2004; 96(2): 725 - 730. [Abstract] [Full Text] [PDF]
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J. D. Morrow and L. J. Roberts The Isoprostanes: Their Role as an Index of Oxidant Stress Status in Human Pulmonary Disease Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): S25 - 30. [Abstract] [Full Text] [PDF]
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S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot Pathobiology of pulmonary arterial hypertension Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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 M. C. Walters, A. W. Nienhuis, and E. Vichinsky Novel Therapeutic Approaches in Sickle Cell Disease Hematology, January 1, 2002; 2002(1): 10 - 34. [Abstract] [Full Text]
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