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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The pathogenesis of severe pulmonary hypertension seems to be
related to inflammatory response in diseased sites. Monocyte chemoattractant protein-1 (MCP-1) has been reported to play a role
in the development of congestive heart failure. In this immunological response, activation and migration of leukocytes including
macrophages to the inflammatory region are important factors.
We hypothesized that the severity of pulmonary hypertension may
be related to MCP-1, which is thought to be upregulated by blood
pressure or shear stress in pulmonary vasculature as well as by immunological and inflammatory reactions in chronic thromboembolic pulmonary hypertension (CTEPH). Circulating levels of MCP-1,
interleukin-1
(IL-1), and tumor necrosis factor-
(TNF-) were
measured by sandwich ELISA in 14 patients with CTEPH. The
plasma level of MCP-1 was significantly correlated with pulmonary
vascular resistance. In IL-1 and TNF-, on the other hand, there
was no correlation between cytokines and pulmonary hemodynamics. Pathological specimens obtained from the patients with
CTEPH undergoing thromboendarterectomy demonstrated immunoreactivity of MCP-1 in endothelium, smooth muscle cells, and
macrophages within neointima in the hypertensive large elastic
pulmonary artery. We conclude that MCP-1 is upregulated in the
remodeling of pulmonary arteries in close association with increased pulmonary vascular resistance in CTEPH.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pathological studies of human hypertensive pulmonary arteries suggest that vascular remodeling is a common abnormality regardless of etiology. Generally, vascular remodeling in the large elastic pulmonary artery is thought to be an adaptive response to increased pressure in human severe pulmonary hypertension (1). The specific mechanisms, however, underlying both large and small vessel remodeling in human primary pulmonary hypertension (PPH) are still unknown. In chronic pulmonary thromboembolism, on the other hand, it is known that a varying degree of precapillary pulmonary hypertension is involved. In case of chronic thromboembolic pulmonary hypertension (CTEPH), the prognosis is quite poor if pulmonary hypertension is severe enough to resist medical treatment (4, 5). Recently, pulmonary thromboendarterectomy was reported as a beneficial surgical treatment that clearly improves mortality in CTEPH (6). However, the pathogenesis and molecular mechanisms of vascular remodeling causing CTEPH have so far not been well clarified.
It has been reported that chemokines or proinflammatory cytokines play a pivotal role in the pathogenesis of PPH (10). Monocyte chemoattractant and activating factor /monocyte chemoattractant protein-1 (MCAF/MCP-1), for examples, is a C-C chemokine that possesses potent chemotactic and activating effects for monocytes/macrophages in vitro (11, 12). MCP-1 acts as a pathogenic mediator in the development of congestive heart failure (CHF) in humans as well as in experimental animal models (13, 14). Aukrust and coworkers reported that the plasma level of MCP-1 was elevated in patients suffering from CHF, and that MCP-1 levels were inversely correlated with left ventricular ejection fractions (13). In addition, they suggested that monocytes/macrophages migrating into the heart are crucial sources for producing MCP-1 protein (13). Shioi and coworkers also reported that left ventricular hypertrophy and heart failure caused by pressure overload induce macrophage infiltration and MCP-1 mRNA gene expression as well as protein synthesis at the interstitium around hypertrophied cardiac myocytes in rats (14).
It has been elucidated that interleukin-1 (IL-1) and
macrophage inflammatory protein-1 (MIP-1) play an important role in vascular remodeling of PPH (15, 16). Elevated
circulating levels of interleukin-1 (IL-1) and IL-6 were also
observed in patients with pulmonary hypertension associated
with mixed connective tissue disease (MCTD), suggesting that
they may act as chemical mediators in vascular remodeling
caused by autoimmune-induced inflammatory reaction (17).
Furthermore, we also demonstrated that MCP-1 protein
synthesis takes place in monocytes/macrophages around pulmonary arterioles in the lung parenchyma in the monocrotaline-induced pulmonary hypertension model (18). We proposed that MCP-1 acts as a mediator via autocrine and/or
paracrine mechanisms to induce migration and activation of
monocytes/macrophages in the lung (18). It is conceivable that
monocytes/macrophages activated by excessive secretion of
MCP-1 participate in pulmonary vascular remodeling, in which
various kinds of growth factors such as transforming growth
factor- (TGF-) (19), MIP-1 (16), and vascular endothelial growth factor (VEGF) (10) are also involved. Moreover, it is known that MCP-1 and IL-1 possess actions to induce muscular hypertrophy and angiogenesis by themselves (20, 21). It
is widely recognized that patients with a diagnosis of antiphospholipid syndrome with positive lupus anticoagulants occasionally suffer from CTEPH (22, 23). These findings indicate
that immunological and inflammatory mechanisms play roles
in the pathogenesis of CTEPH. We hypothesized that the severity of pulmonary hypertension may be related to MCP-1,
which is thought to be upregulated by blood pressure or shear
stress in pulmonary vasculature as well as by immunological
and inflammatory reactions in CTEPH. In our hypothesis,
monocytes/macrophages activated by excessive secretion of
MCP-1 may induce vascular cell proliferation and matrix protein synthesis via autocrine or paracrine mechanisms. To test
this hypothesis, we performed a hemodynamic and pathological study in combination with the measurement of various
kinds of immunological parameters or cytokines/chemokines
including MCP-1, which may play a role in vascular remodeling in CTEPH.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
CTEPH was diagnosed in 14 patients (2 males and 12 females) aged
from 28 to 66 yr (50.5 ± 10.6 yr; mean ± SD) by right cardiac catheterization during a clinically stable period. CTEPH was defined as
mean pulmonary artery pressure (
) of more than 25 mm Hg and
pulmonary capillary wedge pressure (Ppc, we) of less than 12 mm Hg,
indicating precapillary pulmonary hypertension. Clinical features of
the patients are summarized in Table 1. All patients had a history of
dyspnea on exertion for more than 6 mo prior to admission.
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Pulmonary perfusion scan with 99mTc-macroaggregated albumin (MAA) revealed segmental or larger defects. Ventilation scan with krypton-81m (81mKr), on the other hand, revealed no abnormality in any of the patients. Pulmonary angiography following right cardiac catheterization also supported the clinical diagnosis. No patient in this study was medicated with thrombolytic therapy (urokinase or tissue plasminogen activator), antiinflammatory drugs (corticosteroid, etc.), or vasodilating drugs including orally administered prostacyclin analogue (Veraprost). Anti-coagulant warfarin potassium (Warfarin) was discontinued for 72 h before right cardiac catheterization. One female patient (Case 3) underwent right cardiac catheterization twice before and after pulmonary thromboendarterectomy.
Patients were prospectively divided into two groups as follows: central predominant type (Cpred.) and peripheral predominant type (Ppred.), according to location of thromboemboli in pulmonary angiography (24) and imaging by spiral computed tomography (CT) scan with a bolus injection of contrast medium. Cpred. and Ppred. were defined as thromboemboli located in the lobar arteries or proximal in Cpred. and in segmental arteries or distal in Ppred. Pulmonary thromboendarterectomy was performed in six patients, four of Cpred. and two of Ppred. Representative cases of Cpred. and Ppred. are presented in Figures 1 and 2, respectively.
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Informed consent was obtained from all patients, and the protocols were approved by the institutional review board.
Hemodynamics
To evaluate the pulmonary hemodynamics, and cardiac output
(CO) were measured using the thermodilution method from patients breathing room air. Cardiac index (CI) was calculated as CO divided by body surface area. Pulmonary vascular resistance (PVR) was obtained by the following equation:
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Pulmonary function tests and arterial blood gas analyses were also performed in all patients (Table 1).
Cytokine/Chemokine Measurement
Levels of MCP-1 in plasma, and IL-1 and tumor necrosis factor-
(TNF-) in serum were measured by sandwich enzyme-linked immunosorbent assay (ELISA) using the samples from peripheral venous
blood. The detecting limits of MCP-1, IL-1 and TNF- were 25.0, 2.0, and 15.6 pg/ml, respectively. First, to analyze correlation between
the cytokine/chemokine level and pulmonary hemodynamics, a regression line was drawn using the least-squares method, and the coefficient of correlation was calculated in each cytokine. Second, the
cytokine/chemokine level was compared with serological immunoglobulins (IgG, IgM, and IgA) and complements (C3, C4, and CH50).
Each sample was extracted from peripheral blood on the same day.
Histology and Immunohistochemistry
Pathological specimens of pulmonary arterial thrombi and lung tissue
were obtained from two patients with Cpred. undergoing pulmonary
thromboendarterectomy at Chiba University Hospital. Immediately
following surgical resection, thrombus and lung tissue were fixed in
4% neutro-buffered formaldehyde for 24 h at room temperature and
subsequently dehydrated in sequential 30%, 50%, and 70% ethanol
washes. Tissues were embedded in paraffin and transverse slices of specimens were cut into 5-µm-thick sections. Hematoxylin and eosin (HE)
and Elastica-van Gieson (EVG) stain were used for pathological observation. The same specimens were prepared for immunoperoxidase
staining using a Histamine SAB-PO (R, M) kit (Nichirei Co. Ltd., Tokyo, Japan) as described previously (25). Endogenous peroxidase was
blocked with 0.3% (vol/vol) H2O2 in methanol for 20 min at room
temperature. Nonspecific immunoglobulin binding sites were blocked
with 10% goat serum. Sections were subsequently incubated for 2 h at
4° C with rabbit polyclonal anti-human MCP-1 antibody (26). The
specimens were also incubated for 2 h at 4° C with mouse monoclonal
anti-human alveolar macrophage (HAM56) or anti-human -smooth
muscle actin (-SMA) antibodies (DAKO Co. Ltd., Carpinteris, Denmark). Appropriate preimmune 10% serum served as negative controls. Sections were then incubated for 20 min with affinity-purified
biotin-conjugated goat anti-rabbit immunoglobulin G (IgG) or rabbit
anti-mouse IgG, IgM complex (10 µg/ml), washed, and incubated for
20 min with horseradish peroxidase-streptavidin (100 g/ml). Immunoglobulin complexes were visualized by incubation with 3,3'-diaminobenzidine (0.03 mmol/L in Tris-HCl, pH 7.4), 0.6% H2O2 and
NiCl2. Sections were washed, counterstained with Meyer's hematoxylin,
dehydrated, mounted in Permount, and examined by light microscopy.
Statistical Analysis
All data are presented as mean ± SD. Spearman's correlation was used to analyze the relationship between cytokines/chemokines and hemodynamic parameters as well as cytokines/chemokines and immunologic parameters. A p value less than 0.05 was considered significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamics
was elevated (42.5 ± 13.6 mm Hg) and CI was decreased
(2.86 ± 0.64 L/min/m2) in patients with CTEPH. PVR was elevated, as a result, ranging from 302 to 1467 (mean PVR; 733.4 ± 330.3) dyne · s/cm5, suggesting increased pulmonary hemodynamics in CTEPH. PVR in Cpred. (792 ± 374 dyne · s/cm5; n = 8) tended to be elevated rather than that in PPred. (655 ± 273 dyne · s/cm5; n = 6) (Table 1).
Pulmonary Function and Arterial Blood Gases
Spirometry demonstrated normal pulmonary function in patients with CTEPH except for one case of restrictive ventilatory disturbance (%VC; 75.0%) and two cases (FEV1%; 64.3% and 56.1%) of obstructive ventilatory disturbance. Hypoxemia combined with hypocapnia was observed in almost all subjects; mean PaO2 and PaCO2 were 57.1 ± 11.8 and 35.3 ± 4.2 mm Hg, respectively. The acid-base balance was slightly but significantly shifted to alkalosis (pH; 7.436 ± 0.026) in patients with CTEPH (Table 1).
Cytokine/Chemokine Level
The plasma MCP-1 level ranged widely from 25 to 799 (mean
173.4 ± 202.9 pg/ml). Mean concentrations of IL- and TNF-
were 164.5 ± 279.3 (2.0-932.0 pg/ml) and 40.1 ± 44.8 (15.6-
183.0 pg/ml), respectively. Regression analysis revealed no significant coefficient of correlation between MCP-1 and
(0.268; p > 0.1) and between MCP-1 and CI (
0.393; p > 0.1).
On the other hand, the coefficient of correlation was significant between MCP-1 and PVR (0.692; p < 0.01) (Figure 3).
When it was analyzed in the subpopulation of Cpred. patients,
the coefficient of correlation became much higher (r = 0.805),
suggesting that the correlation became more prominent between
MCP-1 and PVR in response to the type of thromboemboli. Case 3, a case of Cpred. in which pulmonary hemodynamics
were evaluated before and after pulmonary thromboendarterectomy, revealed that PVR was dramatically decreased (1023 to 292 dyne · s/cm5) in conjunction with a parallel change in
the MCP-1 plasma level (118 to 50 pg/ml). No significant relationship was demonstrated in the coefficients of correlation between CI and MCP-1 or and MCP-1. Similarly, no relationships were observed between pulmonary hemodynamics and
other cytokines.
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The mean values of serum immunoglobulins IgG, IgA, and IgM were 1666.6 ± 443.4 (1064-2660), 379.4 ± 246.5 (194- 1105), and 199.8 ± 132.7 (66-500) mg/dl. C3, C4, and CH50 exhibited 81.6 ± 19.4 (59-128), 29.6 ± 9.4 (15-48) mg/dl, and 41.9 ± 8.3 (32.7-64.7) U/ml, respectively. The coefficients of correlation between circulating cytokines/chemokines and serum immunoglobulins or complements are summarized in Table 2. There was no significant correlation between cytokine level and serum immunoglobulins/complements.
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Pathology and Immunohistochemistry
Neointimal formation was observed in an endarterectomized specimen, an inner part of the hypertensive large elastic pulmonary artery (Figure 4). Neointimal formation was also observed in small pulmonary arterioles in the lung parenchyma (Figure 5). Immunoreactivity of MCP-1 was demonstrated not only in endothelial cells (Figure 4C and 4D) but also in mononuclear cells (Figure 4D) and smooth muscle cells (Figure 4E) in a fibrinous portion adjacent to the vascular lumen in endarterectomized tissue. Mononuclear cells producing MCP-1 were confirmed as macrophages by HAM56 anti-human alveolar macrophage antibody (Figure 4F). In a preliminary study before this project, no immunoreactivity of MCP-1 was demonstrated in either endothelial cells or smooth muscle cells in the pulmonary arteries obtained from the patient undergoing pneumonectomy (data not shown).
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Both physiological and pathological results suggest that increased pulmonary hemodynamics potentially activate pulmonary arterial endothelial cells or monocytes/macrophages to upregulate MCP-1 protein synthesis and induce neointimal formation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that MCP-1 may participate in the vascular response to injury caused by pressure overload or shear stress in the pulmonary vasculature in CTEPH. In our hypothesis, monocytes/macrophages activated by excessive secretion of MCP-1 may induce endothelial or smooth muscle cell growth and differentiation factors, which act via autocrine or paracrine mechanisms to stimulate vascular cell proliferation and matrix protein synthesis. In our data, the circulating level of MCP-1 was well correlated with PVR in patients with CTEPH. The fact that MCP-1 decreased in parallel with the decrease of PVR after pulmonary thromboendarterectomy in one case also supported our hypothesis. However, the plasma MCP-1 level was not correlated with pulmonary arterial pressure or cardiac index. These results indicate that the elevated pulmonary vascular resistance per se may cause MCP-1 secretion from the vascular wall in the diseased site but myocardial stretch by right ventricle pressure overload may not. MCP-1 secreted from macrophages induced macrophage migration and activation via an autocrine or paracrine mechanism to cause pulmonary vascular remodeling as we previously reported (18).
It is likely that MCP-1 secretion from endothelial cells, smooth muscle cells, and macrophages increases in response to shear stress caused by increased PVR. The immunoreactivity of MCP-1 demonstrated in vascular endothelial cells, smooth muscle cells, and macrophages also supported this paradigm. The coefficient of correlation between MCP-1 and pulmonary vascular resistance became greater when the subjects were limited to the subgroup exhibiting the Cpred. pattern, suggesting that patients with the Ppred. pattern seemed to have difficulty in responding to shear stress, and that intact endothelial cell functions at the level of the peripheral portion of pulmonary arteries/arterioles are considered to be essential to secrete MCP-1. It is also conceivable that MCP-1 synthesis is a kind of compensatory phenomenon that maintains pulmonary circulation normally through negative inotropic action of the myocardium. We are hardly able to discuss the involvement of a systemic inflammatory factor in vascular remodeling of CTEPH because no chemical mediators except MCP-1 seem to be correlated with hemodynamic parameters as far as could be determined in the present study.
Endothelial cells of hypertensive pulmonary arteries/arterioles must be consistently exposed to high blood pressure sustained with strong shear stress in the patients with severe pulmonary hypertension. Shear stress itself plays a key role in
inducing various kinds of cytokine gene expressions including
MCP-1 (27, 28). The same mechanisms may be involved in the
upregulation of MCP-1 protein synthesis in CTEPH. It is reported that macrophages participate in pulmonary vascular
remodeling in the hypertensive large elastic pulmonary artery
in human PPH (29). This mechanism is also supported by evidence that macrophages produce TGF- and colocalize with
extracellular matrix mRNA in the atherosclerotic large elastic
pulmonary artery in human PPH (30, 31).
It has been proposed that local regulatory factors in the
failing myocardium could clarify the pathogenesis of congestive heart failure (13, 14, 32, 33). This concept suggests another possibility
that MCP-1 elevation is ascribed to right ventricular hypertrophy, which is derived from the same process as reported previously (14). Shioi and coworkers (14)
demonstrated that chemokine gene expression and protein
synthesis such as MCP-1 and IL-1 take place in close association with macrophage infiltration in the left ventricular myocardium in the animal model of cardiac hypertrophy chronically induced by mechanical overload. Leukocyte activation
and migration from blood to the injured area appear to be of
major importance in congestive heart failure (CHF) (32, 33).
It is likely that the same mechanism is present in patients with
CTEPH. Furthermore, the elevation of circulating levels of C-C chemokines was reported in patients with CHF by Aukrust and coworkers (13). They clearly demonstrated that patients with CHF exhibited higher concentrations of MCP-1
and MIP-1 compared with normal subjects and that the cytokine level was inversely correlated with the left ventricular
ejection fraction. The pathological roles of proinflammatory
cytokines, such as IL-1 and TNF-, have been reported as
negative inotropic action in the perfused heart and cultured
myocytes (34, 35). Our data, however, showed no significant
relationship between IL-1 or TNF- and other hemodynamic parameters or serological data. Moreover, there was no
significant relation between MCP-1 and IL-1 or between
MCP-1 and TNF- (data not shown). The discrepancy between the report of Aukrust and coworkers (13) and our data
may be explained, in part, by differences in the mechanism of
MCP-1 protein secretion, although the true mechanism remains unknown.
In conclusion, this is the first report to demonstrate that MCP-1 is upregulated in response to increased pulmonary vascular resistance in CTEPH. We showed evidence of specific site of MCP-1 production by immunohistochemistry. The increase of MCP-1 appears to reflect the deterioration of pulmonary hemodynamics in CTEPH. In addition, MCP-1 protein synthesis seems to be enhanced by mechanical factors such as shear stress, although the involvement of other inflammatory cytokines is not totally ruled out. To explain the true mechanism of vascular response to injury in CTEPH, further study will be necessary including a study of other secretory components such as circulating monocytes in the blood, vascular smooth muscle cells, and cardiac myocytes.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Hiroshi Kimura, M.D., Ph.D., Department of Chest Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: kimura{at}nmu-gw.naramed-u.ac.jp
(Received in original form June 29, 2000 and in revised form December 12, 2000).
Acknowledgments:
Supported in part by a Grant-in-Aid for Scientific Research (C) (12670547) from
the Ministry for Education, Science, Sports and Culture, Japan, and a grant from
the Research Committee, Intractable Respiratory Failure, the Ministry of Health
and Welfare of Japan.
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References |
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ABSTRACT
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METHODS
RESULTS
DISCUSSION
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O. Sanchez, E. Marcos, F. Perros, E. Fadel, L. Tu, M. Humbert, P. Dartevelle, G. Simonneau, S. Adnot, and S. Eddahibi Role of Endothelium-derived CC Chemokine Ligand 2 in Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1041 - 1047. [Abstract] [Full Text] [PDF]
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 N. Galie and N. H. S. Kim Pulmonary Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension Proceedings of the ATS, September 1, 2006; 3(7): 571 - 576. [Abstract] [Full Text] [PDF]
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 P. Joppa, D. Petrasova, B. Stancak, and R. Tkacova Systemic Inflammation in Patients With COPD and Pulmonary Hypertension. Chest, August 1, 2006; 130(2): 326 - 333. [Abstract] [Full Text] [PDF]
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 M. M. Hoeper, E. Mayer, G. Simonneau, and L. J. Rubin Chronic Thromboembolic Pulmonary Hypertension Circulation, April 25, 2006; 113(16): 2011 - 2020. [Full Text] [PDF]
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 P. Herve, E. Fadel, P. Herve, and E. Fadel Systemic neovascularization of the lung after pulmonary artery occlusion: "decoding the Da Vinci code" J Appl Physiol, April 1, 2006; 100(4): 1101 - 1102. [Full Text] [PDF]
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C. Guignabert, B. Raffestin, R. Benferhat, W. Raoul, P. Zadigue, D. Rideau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats Circulation, May 31, 2005; 111(21): 2812 - 2819. [Abstract] [Full Text] [PDF]
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 N. Tanabe, A. Kimura, S. Amano, O. Okada, Y. Kasahara, K. Tatsumi, M. Takahashi, H. Shibata, M. Yasunami, and T. Kuriyama Association of clinical features with HLA in chronic pulmonary thromboembolism Eur. Respir. J., January 1, 2005; 25(1): 131 - 138. [Abstract] [Full Text] [PDF]
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J. K. Damas, K. Otterdal, A. Yndestad, H. Aass, N. O. Solum, S. S. Froland, S. Simonsen, P. Aukrust, and A. K. Andreassen Soluble CD40 Ligand in Pulmonary Arterial Hypertension: Possible Pathogenic Role of the Interaction Between Platelets and Endothelial Cells Circulation, August 24, 2004; 110(8): 999 - 1005. [Abstract] [Full Text] [PDF]
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 U. Maus, S. Henning, H. Wenschuh, K. Mayer, W. Seeger, and J. Lohmeyer Role of endothelial MCP-1 in monocyte adhesion to inflamed human endothelium under physiological flow Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2584 - H2591. [Abstract] [Full Text] [PDF]
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 D. A. Bradbury, R. Newton, Y.-M. Zhu, J. Stocks, L. Corbett, E. D. Holland, L. H. Pang, and A. J. Knox Effect of bradykinin, TGF-beta 1, IL-1beta , and hypoxia on COX-2 expression in pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L717 - L725. [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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