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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Oxidative stress contributes to the pathophysiology of interstitial lung diseases, such as cryptogenic
fibrosing alveolitis (CFA), fibrosing alveolitis associated with systemic sclerosis (FASSc) and sarcoidosis. F2-isoprostanes are a series of prostaglandin (PG) F2-like compounds produced in vivo independent of cyclooxygenase, as products of the radical-catalyzed lipid peroxidation. Measurement of the
concentrations of F2-isoprostanes has proved to be valuable in assessing oxidative stress in vivo. The
aim of this study was to measure 8-epi-PGF2
concentrations, one of the most abundant F2-isoprostane in humans, in bronchoalveolar lavage (BAL) in normal subjects and to compare them to those
observed in patients with CFA (n = 9), FASSc (n = 8) and sarcoidosis (n = 10). 8-epi-PGF2 was detectable in BAL fluid in normal subjects (9.6 ± 0.8 pg/ml) and its concentrations were increased approximately 5-fold in patients with CFA (47.4 ± 7.0, p < 0.001) and FASSc (43.2 ± 3.3, p < 0.001).
8-epi-PGF2 was also increased in patients with sarcoidosis, although to a lesser extent (12.0 ± 0.70 pg/ml, p < 0.01). No correlation between 8-epi-PGF2 and either lung function tests or BAL cell types
was observed in any group of patients. Our study shows that the level of oxidative stress is enhanced
in patients with interstitial lung diseases as reflected by increased concentrations of 8-epi-PGF2 in
BAL fluid.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Interstitial lung diseases, such as cryptogenic fibrosing alveolitis (CFA) and fibrosing alveolitis associated with systemic sclerosis (FASSc), are characterized by enhanced oxidative stress (1). An imbalance between oxidants and antioxidants may also be important in the pathogenesis of sarcoidosis (6, 7), in which interstitial fibrosis is also present in the more advanced stages of the disease. Alveolar macrophages isolated from patients with both CFA and sarcoidosis produce increased amounts of superoxide anions when cultured in vitro (8). Moreover, indicators of free radical activity are increased in the patients with interstitial lung diseases in both serum (11) and bronchoalveolar lavage (BAL) fluid (12). Isoeicosanoids or isoprostanes are free radical catalyzed products of arachidonic acid which are formed in situ in the cell membrane phospholipids, from which they are cleaved, presumably by phospholipase (s) A2 (13). Measurements of isoprostanes in plasma, urine, or other biological fluids may therefore provide a quantitative index of oxidant stress in vivo (16).
8-epi-prostaglandin F2 alpha (8-epi-PGF2), a member of
the F2-isoprostane class, has been detected in plasma and
urine in humans (15, 17) and 8-epi-PGF2 concentrations are increased in smokers (18), in hepatorenal syndrome and acute paracetamol intoxication (19) when the production of reactive oxygen species (ROS) is increased. Recently, Stein and coworkers reported an increase in urinary 8-epi-PGF2 concentrations in patients with scleroderma (20). The aim of this
study was to investigate whether 8-epi-PGF2 could be detectable in BAL fluid in patients with interstitial lung diseases and
to compare its concentrations in those patients and in healthy
subjects.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients
Nine patients with CFA (mean age ± SEM, 56 ± 2 yr, 5 male) were included in the study on the basis of clinical diagnostic criteria for CFA (21) consisting of bilateral basal or widespread crackles on auscultation of the chest, a restrictive defect or reduction in transfer factor of the lung for carbon monoxide (TLCO) on pulmonary function testing, computed tomography abnormalities compatible with a diagnosis of fibrosing alveolitis (22, 23), and the absence of exposure to a recognized fibrogenic agent. In one of the patients, the diagnosis was confirmed histologically by open lung biopsy. Eight patients with FASSc (53.4 ± 18.9 yr, 3 male) met American Rheumatism Association preliminary criteria for the diagnosis of scleroderma (24), and also fulfilled the criteria for fibrosing alveolitis (21). In two of them the diagnosis was histologically confirmed by transbronchial biopsy. Exclusion criteria were: (a) rheumatological overlap syndrome, (b) pulmonary hypertension, (c) other respiratory disease, (d) respiratory tract infection. The BAL was performed in the middle lobe of all patients. All patients with CFA and FASSc had widespread involvement of the lungs on high-resolution computed tomography (HRCT) scan (one in the CFA group and one in the FASSc group had a predominant upper lobe reticular shadowing; one patient in the FASSc group had a lower lobe reticular pattern). Ten patients with sarcoidosis were included in the study and the diagnosis was made using conventional criteria, including biopsy (transbronchial in 5; Kveim test in 4; lymphonodes in 1) (25). The radiographic stage of sarcoidosis was grade I (bronchial-hilar lymphonode involvement) in two patients, grade II (bronchial-hilar lymphonode involvement and parenchymal disease) in six patients, and grade III (parenchymal disease alone) in two patients.
None of the patients was a current smoker and smoking history was similar in the three disease groups (CFA, FASSc, and sarcoidosis) (Table 1). Two patients with CFA, two patients with FASSc, and three patients with sarcoidosis were on steroid treatment (prednisolone 30 mg/d). One patient with FASSc was treated with penicillamine. In all patients there were no echocardiographic signs of pulmonary hypertension; echocardiography was performed no later than 2 mo before entering the study.
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Pulmonary Function Testing
Pulmonary function tests were performed within 2 wk of the measurement of exhaled nitric oxide (NO). Forced expiratory flow volume curves were obtained using a spirometer (Erich Jaeger, Market Hardborough, UK). Measures of diffusing capacity (TLCO) were performed by single-breath technique (Transfer Factor Erich Jaeger, Market Hardborough, UK). Arterialized capillary blood gases were analyzed using a Corning 248 blood gas analyzer (Ciba Corning, Halstead, UK).
Thin-Section Computed Tomography
CT sections were acquired using a high resolution fast scanner (Imatron Inc., San Francisco, CA). Interspaced 3-mm sections were obtained from the lung apices to the lung bases, with the patients in the supine position. Scans were analyzed by an experienced thoracic radiologist and an assessment made of presence or absence of a pattern consistent with fibrosing alveolitis.
Bronchoscopy and BAL
Bronchoscopy with BAL was performed with the informed consent of the patient on the same day and after exhaled NO measurement. BAL cell counts were assessed as previously reported (26). BAL was considered to be active when any one of the following criteria was met: (1) lymphocytes > 14%, (2) neutrophils > 4%, (3) eosinophils > 3%, each of which indicates abnormal inflammatory cell numbers (27).
Measurement of Immunoreactive
8-epi-PGF2 Concentrations
8-epi-PGF2 concentrations in BAL were measured by a specific enzyme immunoassay (EIA) kit (Cayman Chemical, Ann Arbor, MI).
Samples were centrifuged and the supernatants were collected and
stored at 
70° C until assayed. The assay has been validated to obtain
a high correlation (0.95) between added known amounts of 8-epi-PGF2 and the concentration measured by EIA and has been directly
validated by gas chromatography/mass spectrometry. The antiserum
used in this assay has a 100% cross-reactivity with 8-epi-PGF2, 0.2%
each with PGF2, PGF3, PGE1 and PGE2, 0.1% each with 6-keto-PGF1. The detection limit of the assay is 4 pg/ml. This kit has been
used to measure 8-epi-PGF2 concentrations in rat human urine,
plasma, and BAL (28).
Exhaled NO Measurement
Exhaled NO was measured using a modified chemiluminescence analyzer (model LR2000; Logan Research, Rochester, UK), sensitive to NO from 1 to 5,000 ppb, (by volume), and with a resolution of 0.3 ppb, which was designed for on-line recording of exhaled NO concentration, as previously described (29). The analyzer was calibrated using certified NO mixtures (90 ppb and 436 ppb) in nitrogen (BOC Special Gases, Guilford, UK). Measurements of exhaled NO were made by slow exhalation (5 to 6 L/min) from total lung capacity (TLC) for 20 to 30 s against a resistance (3 ± 0.4 mm Hg).
Statistical Analysis
For parametric data Student's unpaired t test was used to compare
groups, for nonparametric data Mann-Whitney U tests (BAL analysis) were used. Linear regression analysis was used to assess the relationship between 8-epi-PGF2 and BAL cell counts and between exhaled
NO and 8-epi-PGF2. All data were expressed as means ± standard
error of mean. Significance was defined as a p value of < 0.05.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Clinical data and BAL findings of healthy subjects and patients with CFA, FASSc, and sarcoidosis are summarized in
Tables 1 and 2, respectively. 8-epi-PGF2 concentrations were detectable (9.6 ± 0.8 pg/ml) in BAL of normal subjects and
were increased approximately 5-fold in patients with CFA
(47.4 ± 7.0 pg/ml, p < 0.001) and FASSc (43.2 ± 3.3 pg/ml, p < 0.001) (Figure 1). Compared with normal subjects, 8-epi-PGF2
levels were also increased in patients with sarcoidosis, although
to a lesser extent than in patients with CFA and FASSc (12.0 ± 0.7 pg/ml, p < 0.005) (Figure 1). In patients with sarcoidosis,
there is a negative trend between 8-epi-PGF2 concentrations
and absolute number of lymphocytes (r = 0.61, p = 0.061)
and a positive trend with macrophage count was observed in
BAL (r = 0.55, p = 0.102). No correlation between 8-epi-PGF2
levels and the different cell types in BAL was observed in the
patients with CFA and FASSc or between 8-epi-PGF2 concentrations and lung function tests in all groups of patients.
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The highest level of free radical activity as reflected by
8-epi-PGF2 concentrations in BAL was found in the patients with CFA and FASSc. For this reason, we measured exhaled
NO, another potential biomarker of oxidative stress, in the
same study groups. Compared with normal subjects (6.9 ± 0.50 ppb, p < 0.05), exhaled NO was increased in both CFA
(11.8 ± 0.7 ppb, p < 0.05) and FASSc patients (10.7 ± 0.50 ppb, p < 0.05). 8-epi-PGF2 correlated with NO levels in patients with CFA (r = 0.78, p < 0.05) (Figure 2), but no correlation was observed in the patients with FASSc (Figure 3).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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8-epi-PGF2 is the best characterized compound belonging to
the F2- isoprostanes, a group of PGF2 isomers formed by free
radical peroxidation of arachidonic acid, independent of the
action of cyclooxygenase (30). Urinary excretion of 8-epi-PGF2 is enhanced in clinical conditions associated with oxidative stress in vivo (31), including scleroderma (20). For this
reason, 8-epi-PGF2 has been considered as an ideal marker
for the pathophysiology of oxidative injury. Several studies
have shown that 8-epi-PGF2 may also be produced by cyclooxygenase-1 and -2 activity in several cells and tissues (32-
34). However, despite its possible enzymatic synthesis, this
isoprostane is still considered a reliable biomarker of lipid
peroxidation due to ROS (35).
The results of this study show that 8-epi-PGF2 is detectable in BAL fluid of normal subjects and the levels are comparable with those reported in a previous study in which the
same analytical technique was used (27).
Sarcoidosis and fibrosing interstitial lung diseases have different severity and prognosis. 8-epi-PGF2 concentrations were
increased in all patients, but they were almost 4-fold as high in
patients with CFA and FASSc as in patients with sarcoidosis, suggesting a higher level of oxidant stress in the former diseases and consistent with the knowledge that there is greater
lung injury in fibrosing alveolitis than in sarcoidosis. Consistent with our findings, overproduction of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes in urine has recently
been reported in patients with scleroderma (19).
In patients with CFA and FASSc, a pathogenetic role for
ROS was also supported by increased concentrations of exhaled NO, another potential biomarker of oxidative stress.
NO correlated with 8-epi-PGF2 in patients with CFA, but not
in patients with FASSc. Considering that 8-epi-PGF2 is
mainly derived from lipid peroxidation of arachidonic acid in
phospholipids of plasma membranes, whereas NO is primarily
produced during oxidative bursts, it is possible that different
mechanisms of oxidative stress might contribute in CFA and
FASSc. This may be of relevance clinically, in that FASSc carries a better prognosis than CFA even when matched for clinical severity, suggesting that these two types of fibrosing alveolitis have different underlying mechanisms.
The lack of correlation between 8-epi-PGF2 and lung
function tests could be due to different pathophysiological relevance of these biomarkers. Lung function test impairment is
the result of previous lung damage, while the isoprostane levels are likely to reflect the current pathological situation.
8-epi-PGF2 concentrations in BAL might, therefore, be useful as biomarkers of subsequent changes, although further
studies are needed for a complete characterization of the role
of 8-epi-PGF2 as a biomarker of disease progression in patients with interstitial lung diseases.
In conclusion, we have shown that the level of oxidative
stress is enhanced in patients with fibrosing alveolitis and, to a
lesser extent, with sarcoidosis, as reflected by increased concentrations of 8-epi-PGF2 in BAL fluid. This isoprostane
may, therefore, be useful as a quantitative index in vivo of an
important aspect of the pathophysiology of these diseases.
Further studies are needed to investigate whether this isoprostane is measurable in other biological fluid that can be sampled by noninvasive procedures, such as breath condensate,
and to explore whether antioxidant therapy may influence its
concentrations in BAL. Finally, further research is required to
identify the cellular sources of 8-epi-PGF2 and to quantify its
possible enzymatic synthesis.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. Peter J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
(Received in original form March 24, 1998 and in revised form July 15, 1998).
Dr. Paolo Montuschi is the recipient of a Research Fellowship from the National Research Council of Italy.| |
References |
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DISCUSSION
REFERENCES
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P. J. Barnes, I. M. Adcock, and K. Ito Histone acetylation and deacetylation: importance in inflammatory lung diseases Eur. Respir. J., March 1, 2005; 25(3): 552 - 563. [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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 P. MONTUSCHI, P. J. BARNES, and L. J. ROBERTS II Isoprostanes: markers and mediators of oxidative stress FASEB J, December 1, 2004; 18(15): 1791 - 1800. [Abstract] [Full Text] [PDF]
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 A. Catalli and L. J. Janssen Augmentation of bovine airway smooth muscle responsiveness to carbachol, KCl, and histamine by the isoprostane 8-iso-PGE2 Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L1035 - L1041. [Abstract] [Full Text] [PDF]
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 J. R. Kizer, D. A. Zisman, N. P. Blumenthal, R. M. Kotloff, S. E. Kimmel, R. M. Strieter, S. M. Arcasoy, V. A. Ferrari, and J. Hansen-Flaschen Association Between Pulmonary Fibrosis and Coronary Artery Disease Arch Intern Med, March 8, 2004; 164(5): 551 - 556. [Abstract] [Full Text] [PDF]
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K. Psathakis, G. Papatheodorou, M. Plataki, P. Panagou, S. Loukides, N. M. Siafakas, and D. Bouros 8-Isoprostane, a Marker of Oxidative Stress, Is Increased in the Expired Breath Condensate of Patients With Pulmonary Sarcoidosis Chest, March 1, 2004; 125(3): 1005 - 1011. [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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G. E. Carpagnano, S. A. Kharitonov, O. Resta, M. P. Foschino-Barbaro, E. Gramiccioni, and P. J. Barnes 8-Isoprostane, a Marker of Oxidative Stress, Is Increased in Exhaled Breath Condensate of Patients With Obstructive Sleep Apnea After Night and Is Reduced by Continuous Positive Airway Pressure Therapy Chest, October 1, 2003; 124(4): 1386 - 1392. [Abstract] [Full Text] [PDF]
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C. Gessner, S. Hammerschmidt, H. Kuhn, T. Lange, L. Engelmann, J. Schauer, and H. Wirtz Exhaled Breath Condensate Nitrite and Its Relation to Tidal Volume in Acute Lung Injury Chest, September 1, 2003; 124(3): 1046 - 1052. [Abstract] [Full Text] [PDF]
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 E. A. Cowley Isoprostane-Mediated Secretion from Human Airway Epithelial Cells Mol. Pharmacol., August 1, 2003; 64(2): 298 - 307. [Abstract] [Full Text] [PDF]
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K. Kuwano, N. Nakashima, I. Inoshima, N. Hagimoto, M. Fujita, M. Yoshimi, T. Maeyama, N. Hamada, K. Watanabe, and N. Hara Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias Eur. Respir. J., February 1, 2003; 21(2): 232 - 240. [Abstract] [Full Text] [PDF]
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L.G. Wood, P.G. Gibson, and M.L. Garg Biomarkers of lipid peroxidation, airway inflammation and asthma Eur. Respir. J., January 1, 2003; 21(1): 177 - 186. [Abstract] [Full Text] [PDF]
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 L. G Wood, D. A Fitzgerald, A. K Lee, and M. L Garg Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function Am. J. Clinical Nutrition, January 1, 2003; 77(1): 150 - 159. [Abstract] [Full Text] [PDF]
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L. G Wood, D. A Fitzgerald, P. G Gibson, D. M Cooper, and M. L Garg Increased plasma fatty acid concentrations after respiratory exacerbations are associated with elevated oxidative stress in cystic fibrosis patients Am. J. Clinical Nutrition, April 1, 2002; 75(4): 668 - 675. [Abstract] [Full Text] [PDF]
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J.-L. CRACOWSKI, C. CRACOWSKI, G. BESSARD, J.-L. PEPIN, J. BESSARD, C. SCHWEBEL, F. STANKE-LABESQUE, and C. PISON Increased Lipid Peroxidation in Patients with Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1038 - 1042. [Abstract] [Full Text] [PDF]
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G. M. MUTLU, K. W. GAREY, R. A. ROBBINS, L. H. DANZIGER, and I. RUBINSTEIN Collection and Analysis of Exhaled Breath Condensate in Humans Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 731 - 737. [Full Text] [PDF]
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S. A. KHARITONOV and P. J. BARNES Exhaled Markers of Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722. [Full Text] [PDF]
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L. J. Janssen Isoprostanes: an overview and putative roles in pulmonary pathophysiology Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1067 - L1082. [Abstract] [Full Text] [PDF]
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 L. G. Wood, D. A. Fitzgerald, P. G. Gibson, D. M. Cooper, C. E. Collins, and M. L. Garg Oxidative Stress in Cystic Fibrosis: Dietary and Metabolic Factors J. Am. Coll. Nutr., April 1, 2001; 20(2): 157 - 165. [Abstract] [Full Text] [PDF]
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 L. J. Janssen, M. Premji, S. Netherton, A. Catalli, G. Cox, S. Keshavjee, and D. J. Crankshaw Excitatory and Inhibitory Actions of Isoprostanes in Human and Canine Airway Smooth Muscle J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 506 - 511. [Abstract] [Full Text]
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G. CIABATTONI, G. DAVI, M. COLLURA, L. IAPICHINO, F. PARDO, A. GANCI, R. ROMAGNOLI, J. MACLOUF, and C. PATRONO In Vivo Lipid Peroxidation and Platelet Activation in Cystic Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1195 - 1201. [Abstract] [Full Text] [PDF]
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H.-D. HELD and S. UHLIG Mechanisms of Endotoxin-Induced Airway and Pulmonary Vascular Hyperreactivity in Mice Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1547 - 1552. [Abstract] [Full Text] [PDF]
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P. MONTUSCHI, J. V. COLLINS, G. CIABATTONI, N. LAZZERI, M. CORRADI, S. A. KHARITONOV, and P. J. BARNES Exhaled 8-Isoprostane as an In Vivo Biomarker of Lung Oxidative Stress in Patients with COPD and Healthy Smokers Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1175 - 1177. [Abstract] [Full Text]
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N. F. Voelkel and R. Tuder COPD : Exacerbation Chest, May 1, 2000; 117(5_suppl_2): 376S - 379S. [Abstract] [Full Text] [PDF]
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