Expression of Endothelin-1 in the Lungs of Patients with Pulmonary Hypertension
Adel Giaid, Masashi Yanagisawa, David Langleben, Rene P. Michel, Robert Levy, Hani Shennib, Sadao Kimura, Tomoh Masaki, William P. Duguid, and Duncan J. Stewart
Background Pulmonary hypertension is characterized by an increasein vascular tone or an abnormal proliferation of muscle cellsin the walls of small pulmonary arteries. Endothelin-1 is apotent endothelium-derived vasoconstrictor peptide with importantmitogenic properties. It has therefore been suggested that endothelin-1may contribute to increases in pulmonary arterial tone or smooth-muscleproliferation in patients with pulmonary hypertension. We studiedthe sites and magnitude of endothelin-1 production in the lungsof patients with various causes of pulmonary hypertension.
Methods We studied the distribution of endothelin-1-like immunoreactivity(by immunocytochemical analysis) and endothelin-1 messengerRNA (by in situ hybridization) in lung specimens from 15 controlsubjects, 11 patients with plexogenic pulmonary arteriopathy(grades 4 through 6), and 17 patients with secondary pulmonaryhypertension and pulmonary arteriopathy of grades 1 through3.
Results In the controls, endothelin-1-like immunoreactivitywas rarely seen in vascular endothelial cells. In the patientswith pulmonary hypertension, endothelin-1-like immunoreactivitywas abundant, predominantly in endothelial cells of pulmonaryarteries with medial thickening and intimal fibrosis. Likewise,endothelin-1 messenger RNA was increased in the patients withpulmonary hypertension and was expressed primarily at sitesof endothelin-1-like immunoreactivity. There was a strong correlationbetween the intensity of endothelin-1-like immunoreactivityand pulmonary vascular resistance in the patients with plexogenicpulmonary arteriopathy, but not in those with secondary pulmonaryhypertension.
Conclusions Pulmonary hypertension is associated with the increasedexpression of endothelin-1 in vascular endothelial cells, suggestingthat the local production of endothelin-1 may contribute tothe vascular abnormalities associated with this disorder.
Pulmonary hypertension is often a progressive condition, characterizedby a relentless increase in pulmonary vascular resistance thatultimately leads to right-heart failure and death. Althoughthe initiating factors may differ widely in patients with primaryand various secondary causes of pulmonary hypertension, theremay be common pathways of progression that reflect the limitedrange of vascular response to injury. Common to many forms ofpulmonary hypertension is the proliferation of smooth-musclecells in the vascular media and frequently the intima,1 triggeredand perpetuated by as yet unknown mechanisms. The resultingintimal and medial thickening may reduce the caliber of resistancevessels and occlude small vascular channels. Furthermore, vasoconstrictionmay also contribute to inappropriate increases in pulmonaryvascular resistance in many patients with pulmonary hypertension2.
Recently, it has been recognized that the vascular endotheliumplays a crucial part in local regulation of the function ofsmooth-muscle cells3,4. Under physiologic conditions, the endotheliumproduces a variety of vasodilator mediators, which maintainan appropriate level of vascular tone and prevent the proliferationof smooth-muscle cells5,6. Under pathologic conditions, however,the endothelium can be activated to secrete factors that produceprofound vasoconstriction. The most potent of these is the 21-residuepeptide endothelin-1,7 which is also a mitogen for smooth muscle8,9,10and other types of cells in vitro11,12,13. At present, it isnot known whether the functional and morphologic abnormalitiesof small and medium-sized pulmonary arteries in patients withpulmonary hypertension are associated with an increase in thelocal expression and production of this potent vasoconstrictorand mitogenic peptide.
Our previous studies have demonstrated low levels of expressionof endothelin-1 in the normal adult as compared with fetal lungtissue14. Indeed, the normal lung may function to clear endothelin-1from the circulation,15 a concept supported by studies examiningthe gradient of plasma levels across the lung16. However, wehave also shown that in patients with pulmonary hypertension-- particularly primary pulmonary hypertension -- there maybe a net production and release of endothelin-1 into the pulmonarycirculation16. In this report, we provide evidence of increasedvascular expression of endothelin-1 in the lungs of patientswith pulmonary hypertension, evidence consistent with a contributingrole for endothelin-1 in the vascular manifestations of thisdisorder.
Methods
Study Design
The study protocol was approved by the institutional researchand ethics committees of Montreal General Hospital and RoyalVictoria Hospital, Montreal. Lung samples were obtained aftersurgical resection or at autopsy ( 10 hours post mortem). Specimenswere obtained from 28 patients with a clinical diagnosis ofpulmonary hypertension17. The patients were divided into twogroups on the basis of clinical and histopathological characteristics.Group 1 consisted of 11 patients with plexogenic pulmonary arteriopathy(grades 4 through 6),18 of whom 7 had a clinical diagnosis ofprimary pulmonary hypertension according to the criteria ofthe National Heart, Lung, and Blood Institute19 (Table 1). Group2 consisted of 17 patients with secondary causes of pulmonaryhypertension and no more than grade 3 pulmonary arteriopathy18(Table 2). The patients with secondary pulmonary hypertensionwere older than those with plexogenic pulmonary arteriopathyand had significantly lower forced expiratory volumes, diffusingcapacities for carbon monoxide, and hemoglobin levels. However,there were no significant differences in pulmonary arterialpressure and vascular resistance between the two groups. Controlspecimens were obtained from 5 patients (3 men and 2 women,19 to 67 years old [mean, 50]) with pulmonary diseases otherthan idiopathic pulmonary fibrosis or hypertension (e.g., interstitialpneumonitis) and from the unused normal lungs of 10 organ donors(6 female and 4 male donors, 17 to 46 years old [mean, 30]).Tissues were fixed in 10 percent buffered formalin or Bouin'ssolution and embedded in paraffin for routine pathological examinationand immunocytochemical analysis. The method of fixation didnot affect the intensity of immunostaining in five specimensthat were prepared by both methods. For the localization ofendothelin-1 messenger RNA (mRNA), tissues were either snap-frozenin liquid nitrogen or fixed in 4 percent paraformaldehyde inphosphate-buffered saline (0.1 mol of sodium phosphate and 0.15mol of sodium chloride per liter, pH 7.2) and washed in phosphate-bufferedsaline containing 15 percent sucrose and 0.01 percent sodiumazide at 4 °C.
Table 2. Characteristics of the Patients with Secondary Pulmonary Hypertension.
Immunocytochemical Analysis
Two polyclonal antiserums against human endothelin-1 were used:one against the C-terminal of endothelin-1 and the other againstthe C-terminal fragment of big endothelin-1 (big endothelin-122-38).The two endothelin antiserums were raised as previously described20.A commercial antiserum against human endothelin-1 (PeninsulaLaboratories, Belmont, Calif.) was also used. In addition, antiserumto von Willebrand factor (factor VIII-related antigen) (Dako,Santa Barbara, Calif.) was used as an endothelial-cell marker.The avidin-biotin-peroxidase complex method21 was used as previouslydescribed14. Negative controls were prepared with the specificantiserum absorbed with the cross-reactive endothelins or withnonimmune serum instead of primary antiserum, or by omittingsteps in the avidin-biotin-peroxidase procedure.
Three sections were stained with each antiserum and graded semiquantitatively,as previously described22. The light-microscopical sectionswere examined for the localization of endothelin-1-like immunoreactivity,particularly in vascular endothelium and airway epithelium.Staining intensity was graded semiquantitatively from 0 to 4,with 0 representing the absence of any staining and 4 the maximalintensity, corresponding to the intensity of staining with factorVIII. The grading was performed by two of the investigators,without prior knowledge of diagnostic category or clinical information.Additional sections from each specimen were stained with hematoxylinand eosin for pathological grading according to the system ofHeath and Edwards18.
In Situ Hybridization
Ten-microm cryostat sections from paraformaldehyde-fixed tissueswere rehydrated in phosphate-buffered saline, rendered permeablewith proteinase K, and immersed in 4 percent paraformaldehydefor five minutes to stop the reaction. After three washes inphosphate-buffered saline, sections were immersed in a solutionof triethanolamine (0.1 mol per liter) and acetic anhydride(0.25 mol per liter) for 10 minutes, dehydrated in ethanol,and air-dried. Sections were hybridized with a preproendothelin-1complementary RNA (cRNA) probe labeled with sulfur-35 (1 x 106cpm per section) for 16 hours at 42 °C14. Unbound cRNA probewas removed by incubation in RNase solution (20 µg permilliliter) for 30 minutes at 42 °C in 2 x saline sodiumcitrate (SSC; 1 x SSC is 0.15 mol of sodium chloride and 0.015mol of sodium citrate per liter, pH 7). This was followed byfurther washes in graded concentrations of SSC (from 2 x SSCto 0.1 x SSC) at temperatures ranging from 20 °C to 55 °C.Autoradiograms were exposed in light-tight boxes for 5 to 10days at 4 °C, developed in D-19 developer (Kodak, Rochester,N.Y.), fixed, counterstained with hematoxylin, dehydrated, andmounted. Lung sections hybridized with a sense probe or sectionstreated with RNase solution before hybridization were used asnegative controls for determining the specificity of the hybridizationsignals.
Simultaneous Localization of Endothelin-1 mRNA and Peptide
To examine whether endothelin-1-like immunoreactivity was localizedto the cells that expressed the preproendothelin-1 mRNA, cryostatsections were rehydrated in phosphate-buffered saline, renderedpermeable in proteinase K for seven minutes, immersed in 4 percentparaformaldehyde, and washed in phosphate-buffered saline. Subsequently,sections were hybridized with the radiolabeled preproendothelin-1cRNA probe and washed as described above. After the last washin 0.1 x SSC, sections were rinsed in phosphate-buffered salineand immunostained with the endothelin-1 antiserum as describedabove, then processed for autoradiography. The above methodwas a modification of that described by Hoefler et al23.
Northern Blot Analysis
For Northern blot analysis, total RNA was extracted from lungtissue from the patients with plexogenic pulmonary arteriopathy(group 1) and the patients with secondary pulmonary hypertension(group 2), and from the unused normal lung tissue of the organdonors. The RNA extraction and hybridization method has beendescribed elsewhere24.
Statistical Analysis
The results are presented as means ±SE. The significanceof differences between groups was assessed with a two-tailedWilcoxon signed-rank test, and Bonferroni's correction was appliedfor multiple comparisons as appropriate25. Pulmonary vascularresistance was calculated in Wood units (the mean pulmonaryarterial pressure minus the pulmonary-capillary wedge pressurein millimeters of mercury divided by the cardiac output in litersper minute), and total pulmonary resistance was calculated asthe mean pulmonary arterial pressure divided by the cardiacoutput. The correlation between total pulmonary resistance andthe grade of endothelin-1-like immunoreactivity (immunostaining)was assessed with ordinary least-squares linear regression techniques.
Results
Light-microscopical sections of tissue from the patients ingroup 1 revealed arteries with medial and intimal thickening(including onion-skinning), peripheral proliferation of musclecells, and typical plexiform lesions with, in some instances,vasculitis18. Lung tissue from the patients in group 2, whohad secondary pulmonary hypertension, showed changes typicalof their respective underlying diseases and demonstrated variabledegrees of medial thickening and intimal proliferation (i.e.,grades 1 through 3).
Immunocytochemical analysis revealed very little endothelin-1-likeimmunoreactivity in the control subjects (Figure 1A). In contrast,substantial staining was observed in sections from the patientswith pulmonary hypertension (Figure 1B, Figure 1C, Figure 1D,Figure 1E, Figure 1F, Figure 1G, and Figure 1H). The greatestdegree of endothelin-1-like immunoreactivity was seen in theendothelium of muscular pulmonary arteries, particularly overvessels exhibiting severe morphologic changes (Fig. Figure 1B,Figure 1C, and Figure 1D). In addition, vascular immunostainingwas seen in association with plexiform lesions (Figure 1E).The vascular endothelium of bronchial vessels also stained intensely(Figure 1F). Less commonly, endothelin-1-like immunoreactivitywas observed in endothelial cells of capillaries and pulmonaryveins and in neuroendocrine cells (Figure 1F), and in inflammatorycells, pulmonary epithelium, and vascular smooth-muscle cellsof atherosclerotic pulmonary arteries (Figure 1G). In contrast,there was little or no staining in the vasculature of renaland myocardial tissues from the patients with pulmonary hypertension(data not shown).
Figure 1. Endothelin-1-Like Immunoreactivity in Normal Lung Tissue and Lung Tissue from Patients with Plexogenic Pulmonary Arteriopathy (Group 1) and Secondary Pulmonary Hypertension (Group 2).
Panel A shows immunoreactivity (brown staining with antibody to the C-terminal of endothelin-1) in the vascular endothelium of normal lung (arrow) (x600), and Panels B through D immunoreactivity in pulmonary arteries from patients in group 1 (Panel B, x600; Panel C and Panel D, x300). In addition, staining was observed in association with plexiform lesions (Panel E, x600), neuroendocrine cells and the vascular endothelium of bronchial vessels (Panel F, x600), smooth-muscle cells of atherosclerotic pulmonary artery (Panel G, x600), and type II alveolar pneumocytes in lung sections from patients in group 2 (Panel H, x600).
In Figure 2, the degree of endothelin-1-like immunoreactivityin endothelial cells from each vascular region is compared inthe patient groups. The grade of immunostaining was low in thecontrols, with the greatest immunoreactivity observed in elasticand muscular pulmonary arteries (0.4 ±0.2 and 0.2 ±0.1,respectively). This was in sharp contrast to the endothelin-1immunostaining observed in elastic and muscular pulmonary arteriesof the patients in both groups with pulmonary hypertension (2.73±0.22 and 2.74 ±0.15, respectively; P = 0.003);less pronounced increases in immunoreactivity were seen in theother vascular regions.
Figure 2. Mean (±SE) Level of Endothelin-1-Like Immunoreactivity in Vascular Endothelium of Lung Tissue from Two Groups of Controls (Panel A) and Two Groups of Patients with Pulmonary Hypertension (Panel B).
The patients with pulmonary hypertension were further subdivided according to morphologic18 and clinical19 criteria into those with plexogenic pulmonary arteriopathy (group 1) and those with secondary pulmonary hypertension (group 2). Endothelin-1-like immunoreactivity was assessed in the endothelium of elastic and muscular pulmonary arteries, capillaries, pulmonary veins, and bronchial vessels. The level of endothelin-1-like immunoreactivity was significantly greater in the patients with pulmonary hypertension than in the controls in all vessels. The asterisk indicates P = 0.003 for the comparison between groups.
The distribution of vascular endothelin-1-like immunoreactivitywas similar in the patients in groups 1 and 2 (Figure 2B). However,immunostaining was significantly greater in the muscular pulmonaryarteries of the patients with plexogenic pulmonary arteriopathy(group 1) (mean grade, 3.3 ±0.1 vs. 2.4 ±0.2;P = 0.016). Furthermore, linear regression analysis indicateda significant correlation between endothelin-1-like immunoreactivityin muscular pulmonary arteries and total pulmonary resistance(a functional measurement of the severity of the disease) onlyin the patients with plexogenic pulmonary arteriopathy (P =0.008). All four patients with interstitial fibrosis and pulmonaryhypertension had substantial immunostaining for endothelin-1in alveolar epithelial cells (mean grade for type II pneumocytes,2.5 ±0.5) (Figure 1H). This immunostaining was not seenin the controls, and only rare pneumocytes stained in the patientswith pulmonary hypertension without pulmonary fibrosis.
The majority of lung sections from the patients with pulmonaryhypertension stained best with antiserum to endothelin-1 orstained equally well with endothelin-1 and big endothelin-1antiserums. Seven patients, however, had stronger endothelinstaining for the precursor than for the mature peptide (threein group 1 and four in group 2). Experiments with the negativecontrols showed no staining with the respective antiserums (Figure 3G).
Figure 3. Expression of Endothelin-1 mRNA in the Vascular Endothelium of Pulmonary Arteries from Patients with Plexogenic Pulmonary Arteriopathy (Group 1) and Secondary Pulmonary Hypertension (Group 2).
Panel A (dark-field microscopy) and Panel C show expression in the vascular endothelium of pulmonary arteries from patients in group 2, and Panel B expression in a small occluded pulmonary artery from a patient in group 1 (arrow indicates the site of endothelin-1 expression). Panel D shows a section adjacent to that shown in Panel C, hybridized with the endothelin-1 sense probe (negative control). Panel E and Panel F show the expression of endothelin-1-like immunoreactivity and mRNA in the vascular endothelium of muscular pulmonary arteries from patients in group 1. (Panels A through F, x600.) Panel G shows a negative control section adjacent to that shown in Figure 1C, immunostained with normal goat serum instead of the endothelin-1 antiserum. Panel H shows the low expression of endothelin-1 mRNA in normal lung (phase-contrast microscopy). (Panel G and Panel H, x300.).
In situ hybridization revealed the expression of endothelin-1mRNA in the patients with pulmonary hypertension, primarilyin the vascular endothelium, whereas there were only scatteredhybridization signals on autoradiographs from the control subjects(Figure 3H). Clusters of silver grains were found overlyingvascular endothelial cells of pulmonary arteries with medialthickening and intimal fibrosis in lung sections from the patientswith pulmonary hypertension (Figure 3A, Figure 3B, and Figure 3C).The overall distribution of endothelin-1 mRNA relativeto that of endothelin-1 immunostaining was demonstrated on sectionsthat were both hybridized with the endothelin-1 cRNA probe andimmunostained with endothelin-1 antiserums (Figure 3E and Figure 3F).Silver grains indicating the expression of endothelin-1mRNA and the brown color of endothelin-1 immunostaining wereseen mostly in the same cells, but on occasion endothelin-1mRNA and the mature peptide were also expressed independently.There were no specific signals detectable on the negative-controlsections hybridized with the sense probe or treated with RNasebefore hybridization with the endothelin-1 cRNA probe (Figure 3D).In addition, Northern blot analysis showed higher levelsof preproendothelin-1 mRNA in lung tissue from the patientswith plexogenic pulmonary arteriopathy and the patients withsecondary pulmonary hypertension than in normal lung tissue.
Discussion
The present study provides direct evidence of increased localproduction of endothelin-1 in pulmonary hypertension and mayexplain earlier observations of increased circulating endothelin-1levels in patients with this disorder16. Expression of endothelin-1was found in the vessels that were most affected by the morphologicabnormalities of pulmonary hypertension. In addition, expressionof endothelin-1 in alveolar epithelial cells was seen nearlyexclusively in patients with pulmonary fibrosis, raising thepossibility that increased production of endothelin-1 may beinvolved in the pathogenesis of a broad range of pulmonary diseasesassociated with cellular proliferation. Although the expressionof endothelin-1 in the lungs of patients with pulmonary hypertensiondoes not prove a cause-and-effect relation, such a relationis biologically plausible.
Although endothelin-1 immunostaining can only be graded semiquantitatively,the differences between the control group and the patients withpulmonary hypertension were striking. As in a previous report,14there was little expression of endothelin-1 in the normal adultlung or in the pulmonary vasculature of patients with pulmonarydisease but without pulmonary hypertension. This was in sharpcontrast to the prominent endothelin-1-like immunoreactivityin specimens from the patients with pulmonary hypertension.Furthermore, the expression of preproendothelin-1 mRNA in thelungs of the patients with pulmonary hypertension, as demonstratedby in situ hybridization, matched closely the distribution ofendothelin-1-like immunoreactivity, confirming that there islocal production of endothelin-1 by the pulmonary vascular endotheliumin this disorder.
The most intense endothelin-1 immunostaining was found in thevascular endothelium of the patients with plexogenic pulmonaryarteriopathy (grades 4 through 6),18 many of whom had clinicalfindings consistent with a diagnosis of primary pulmonary hypertensionaccording to the criteria of the National Heart, Lung, and BloodInstitute19. This is in agreement with our earlier findings,based on the measurement of endothelin-1 plasma levels, whichdemonstrated the release of endothelin-1 across the pulmonarybed in patients with primary pulmonary hypertension16. Thus,the increased pulmonary vascular production and release of endothelin-1in these patients point to a role for this vasoactive peptidein the functional and morphologic vascular abnormalities characteristicof pulmonary arteriopathy. Although there were no significantdifferences between groups 1 and 2 in pulmonary arterial pressureor pulmonary vascular resistance, only in group 1 was therea significant correlation between the increases in pulmonaryresistance and the degree of endothelin-1-like immunoreactivityin pulmonary vessels. This finding suggests that the patientswith primary pulmonary hypertension had not only a greater degreeof endothelin-1 expression, but also a more specific associationbetween increased local endothelin-1 production and the severityof the disease.
The distribution of endothelin-1-like immunoreactivity in thelung may provide further clues concerning its functional importancein patients with pulmonary hypertension. Regardless of patientgroup, the greatest degree of immunostaining occurred in theendothelium of elastic and muscular pulmonary arteries, whichalso demonstrated severe medial thickening and intimal proliferation,sometimes severe enough to produce luminal occlusion. To a lesserextent, staining was seen in pulmonary capillaries and veinsand bronchial arteries, but no staining was found in systemicvessels in the myocardial and renal tissues of eight patientswith pulmonary hypertension. Endothelin-1-like immunoreactivitywas also seen in association with plexogenic lesions in thepatients in group 1. This specific association of endothelin-1expression with areas of abnormal pulmonary vascular architectureagain supports the view that endothelin-1 contributes to theinitiation or progression of these lesions. In a recent study,Stelzner et al.26 reported an increase in endothelin-1 productionin the lung in rats with idiopathic pulmonary hypertension.Endothelin-1 is not only the most potent vasoconstrictor yetidentified,7 but it has also been shown to stimulate the proliferationof smooth-muscle cells,8,9,10 and in vivo it may act in concertwith other growth factors. Thus, from the standpoint of biologicactivity and tissue distribution, endothelin-1 is a likely mediatorof the functional and morphologic vascular abnormalities ofpulmonary hypertension.
In addition to the vascular endothelium, limited expressionof endothelin-1 was also found in neuroendocrine, inflammatory,and smooth-muscle cells. This is consistent with a previousreport demonstrating the localization of endothelin-1-like immunoreactivityin pulmonary endocrine cells of developing and adult lungs14.Macrophages, mast cells, and polymorphonuclear leukocytes havealso been shown to produce endothelin-1,27,28,29 the biosynthesisof which may be mediated by polymorphonuclear leukocytes29.Furthermore, the production of endothelin-1 in vascular smooth-musclecells has been demonstrated in vitro30,31 and in vivo, particularlyin atherosclerotic arteries32. However, the appearance of endothelin-1-likeimmunoreactivity in the alveolar epithelial cells of patientswith pulmonary fibrosis was an unanticipated and intriguingfinding. This was an extremely rare occurrence in patients withpulmonary hypertension without pulmonary fibrosis and was notseen in the control group. A role for endothelin-1 has beensuggested in progressive systemic sclerosis,33,34 a disordercharacterized by the abnormal production of connective tissueand fibrosis35. Indeed, it has been demonstrated that endothelin-1can induce the proliferation of fibroblasts and increase theproduction of fibrous tissue in vitro33. The demonstration thatalveolar epithelial cells express endothelin-1 in areas closeto foci of fibrous replacement of alveolar structures suggestsa role for this peptide in the pathogenesis of pulmonary fibrosis.
Our finding of striking increases in endothelin-1 mRNA and inthe production of the mature peptide by pulmonary vascular endotheliumprovides compelling new evidence in support of the view thatendothelin-1 contributes to the vascular abnormalities of pulmonaryhypertension. The expression of this mitogenic peptide by alveolarepithelial cells in patients with pulmonary fibrosis raisesthe possibility that endothelin-1 has a broader role in pulmonarydiseases associated with cellular proliferation or fibrosis.Although the precise definition of the pathophysiologic importanceof endothelin-1 in these conditions awaits the availabilityof specific endothelin-1 antagonists or inhibitors for clinicaluse, the present study provides important new information aboutalterations in local pulmonary endothelin-1 synthesis and tissuedistribution in human lung disease, which is an essential prerequisitefor unraveling its biologic importance.
Supported by a grant (MT-11620) from the Medical Research Councilof Canada and the Quebec Lung Association. Dr. Giaid was alsosupported by the Heart and Stroke Foundation of Canada.
We are indebted to Dr. L. Gaspar and the members of the MontrealLung Transplant Program for their cooperation.
Source Information
From the Departments of Pathology (A.G., R.P.M., W.P.D.), Medicine (D.L., R.L., D.J.S.), and Surgery (H.S.), McGill University, Montreal; the Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwest Medical Center, Dallas (M.Y.); Kyoto University, Kyoto, Japan (T.M.); and the Faculty of Medicine, Chiba University, Chiba, Japan (S.K.).
Address reprint requests to Dr. Giaid at the Dept. of Pathology, Montreal General Hospital, 1650 Cedar Ave., Montreal, QC H3G 14A, Canada.
References
Wagenvoort CA. Grading of pulmonary vascular lesions -- a reappraisal. Histopathology 1981;5:595-598. [Medline]
Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958;20:557-570.
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle to acetylcholine. Nature 1980;288:373-376. [CrossRef][Medline]
Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1979;30:293-331. [Medline]
Griffith TM, Lewis MJ, Newby AC, Henderson AH. Endothelium-derived relaxing factor. J Am Coll Cardiol 1988;12:797-806. [Abstract]
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-415. [CrossRef][Medline]
Dubin D, Pratt RE, Kooke JP, Dzau VJ. Endothelin, a potent vasoconstrictor, is a vascular smooth muscle mitogen. J Vasc Biol Med 1989;1:150-4.
Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 1988;238:249-252. [Erratum, FEBS Lett 1989;244:509.] [CrossRef][Medline]
Hirata Y, Takagi Y, Fukuda Y, Marumo F. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 1989;78:225-228. [CrossRef][Medline]
Takuwa N, Takuwa Y, Yanagisawa M, Yamashita K, Masaki T. A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem 1989;264:7856-7861. [Free Full Text]
Simonson MS, Wann S, Mene P, et al. Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression, and mitogenesis in rat mesangial cells. J Clin Invest 1989;83:708-712.
Muldoon LL, Rodland KD, Forsythe ML, Magun BE. Stimulation of phosphotidylinositol hydrolysis, diacylglycerol release, and gene expression in response to endothelin, a potent new agonist for fibroblasts and smooth muscle cells. J Biol Chem 1989;264:8529-8536. [Free Full Text]
Giaid A, Polak JM, Gaitonde V, et al. Distribution of endothelin-like immunoreactivity and mRNA in the developing and adult human lung. Am J Respir Cell Mol Biol 1991;4:50-58.
de Nucci G, Thomas R, D'Orleans-Juste P, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 1988;85:9797-9800. [Free Full Text]
Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-469.
Reeves JT, Groves BM. Approach to the patient with pulmonary hypertension. In: Weit EK, Reeves JT, eds. Pulmonary hypertension. Mount Kisco, N.Y.: Futura, 1984:1-44.
Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958;18:533-547. [Medline]
Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223.
Shinmi O, Kimura S, Yoshizawa T, et al. Presence of endothelin-1 in porcine spinal cord: isolation and sequence determination. Biochem Biophys Res Commun 1989;162:340-346. [CrossRef][Medline]
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577-580. [Abstract]
Michel R, Hakim TS. Increased resistance in postobstructive pulmonary vasculopathy: structure-function relationships. J Appl Physiol 1991;71:601-610. [Free Full Text]
Hoefler H, Childers H, Montminy MR, Lechan RM, Goodman RH, Wolfe HJ. In situ hybridization methods for the detection of somatostatin mRNA in tissue sections using antisense RNA probes. Histochem J 1986;28:597-604.
Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A 1984;81:1991-1995. [Free Full Text]
Shortcuts and nonparametric methods. In: Snedecor GW, Cochran WG. Statistical methods. 7th ed. Ames: Iowa State University Press, 1980:135-48.
Stelzner TJ, O'Brien RF, Yanagisawa M, et al. Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol 1992;262:L614-L620. [Free Full Text]
Ehrenreich H, Anderson RW, Fox CH, et al. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 1990;172:1741-1748. [Free Full Text]
Ehrenreich H, Burd PR, Rottem M, et al. Endothelins belong to the assortment of mast cell-derived and mast cell-bound cytokines. New Biol 1992;4:147-156. [Medline]
Sessa WC, Kaw S, Hecker M, Vane JR. The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 1991;174:613-618. [CrossRef][Medline]
Resink TJ, Hahn AW, Scott-Burden T, Powell J, Weber E, Buhler FR. Inducible endothelin mRNA expression and peptide secretion in cultured human vascular smooth muscle cells. Biochem Biophys Res Commun 1990;168:1303-1310. [CrossRef][Medline]
Kanse SM, Takahashi K, Warren JB, et al. Production of endothelin by vascular smooth muscle cells. J Cardiovasc Pharmacol 1991;17:Suppl 7:S113-S116.
Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325:997-1001. [Abstract]
Kahaleh MB. Endothelin, an endothelial-dependent vasoconstrictor in scleroderma: enhanced production and profibrotic action. Arthritis Rheum 1991;34:978-983. [Medline]
Yamane K, Kashiwagi H, Suzuki N, et al. Elevated plasma levels of endothelin-1 in systemic sclerosis. Arthritis Rheum 1991;34:243-244. [Medline]
Scharffetter K, Lankat-Buttgereit B, Krieg T. Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest 1988;18:9-17. [Medline]
Lai, Y.-J., Pullamsetti, S. S., Dony, E., Weissmann, N., Butrous, G., Banat, G.-A., Ghofrani, H. A., Seeger, W., Grimminger, F., Schermuly, R. T.
(2008). Role of the Prostanoid EP4 Receptor in Iloprost-mediated Vasodilatation in Pulmonary Hypertension. Am. J. Respir. Crit. Care Med.
178: 188-196
[Abstract][Full Text]
Benza, R. L., Rayburn, B. K., Tallaj, J. A., Pamboukian, S. V., Bourge, R. C.
(2008). Treprostinil-Based Therapy in the Treatment of Moderate-to-Severe Pulmonary Arterial Hypertension: Long-term Efficacy and Combination With Bosentan. Chest
134: 139-145
[Abstract][Full Text]
Chin, K. M., Rubin, L. J.
(2008). Pulmonary arterial hypertension.. J Am Coll Cardiol
51: 1527-1538
[Abstract][Full Text]
Dony, E., Lai, Y-J., Dumitrascu, R., Pullamsetti, S. S., Savai, R., Ghofrani, H. A., Weissmann, N., Schudt, C., Flockerzi, D., Seeger, W., Grimminger, F., Schermuly, R. T.
(2008). Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition. Eur Respir J
31: 599-610
[Abstract][Full Text]
National Pulmonary Hypertension Centres of the UK,
(2008). Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart
94: i1-i41
[Full Text]
Ray, L., Mathieu, M., Jespers, P., Hadad, I., Mahmoudabady, M., Pensis, A., Motte, S., Peters, I. R., Naeije, R., McEntee, K.
(2008). Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Exp Physiol
93: 434-442
[Abstract][Full Text]
National Pulmonary Hypertension Centres of the UK,
(2008). Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax
63: ii1-ii41
[Full Text]
Wong, C. M., Cheema, A. K., Zhang, L., Suzuki, Y. J.
(2008). Protein Carbonylation as a Novel Mechanism in Redox Signaling. Circ. Res.
102: 310-318
[Abstract][Full Text]
Dupuis, J., Hoeper, M. M.
(2008). Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J
31: 407-415
[Abstract][Full Text]
Petersen, B., Deja, M., Bartholdy, R., Donaubauer, B., Laudi, S., Francis, R. C. E., Boemke, W., Kaisers, U., Busch, T.
(2008). Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction. Am. J. Physiol. Regul. Integr. Comp. Physiol.
294: R601-R605
[Abstract][Full Text]
Hamidi, S. A., Prabhakar, S., Said, S. I.
(2008). Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J
31: 135-139
[Abstract][Full Text]
Hoeper, M. M., Seyfarth, H. J., Hoeffken, G., Wirtz, H., Spiekerkoetter, E., Pletz, M. W., Welte, T., Halank, M.
(2007). Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J
30: 1096-1102
[Abstract][Full Text]
Liu, H., Liu, Z.-y., Guan, Q.
(2007). Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. ICVTS
6: 608-613
[Abstract][Full Text]
Dupuis, J.
(2007). Endothelin: setting the scene in PAH. ERR
16: 3-7
[Abstract][Full Text]
Barman, S. A.
(2007). Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L472-L479
[Abstract][Full Text]
Jain, S., Ventura, H., deBoisblanc, B.
(2007). Pathophysiology of Pulmonary Arterial Hypertension. SEMIN CARDIOTHORAC VASC ANESTH
11: 104-109
[Abstract]
Merkus, D., Houweling, B., de Beer, V. J., Everon, Z., Duncker, D. J.
(2007). Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction. J. Physiol.
580: 907-923
[Abstract][Full Text]
Zhang, S., Patel, H. H., Murray, F., Remillard, C. V., Schach, C., Thistlethwaite, P. A., Insel, Paul. A., Yuan, J. X.-J.
(2007). Pulmonary artery smooth muscle cells from normal subjects and IPAH patients show divergent cAMP-mediated effects on TRPC expression and capacitative Ca2+ entry. Am. J. Physiol. Lung Cell. Mol. Physiol.
292: L1202-L1210
[Abstract][Full Text]
Dschietzig, T., Richter, C., Asswad, L., Baumann, G., Stangl, K.
(2007). Hypoxic Induction of Receptor Activity-Modifying Protein 2 Alters Regulation of Pulmonary Endothelin-1 by Adrenomedullin: Induction under Normoxia Versus Inhibition under Hypoxia. J. Pharmacol. Exp. Ther.
321: 409-419
[Abstract][Full Text]
Hansmann, G., Wagner, R. A., Schellong, S., de Jesus Perez, V. A., Urashima, T., Wang, L., Sheikh, A. Y., Suen, R. S., Stewart, D. J., Rabinovitch, M.
(2007). Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-{gamma} Activation. Circulation
115: 1275-1284
[Abstract][Full Text]
Ohno, Y., Hatabu, H., Murase, K., Higashino, T., Nogami, M., Yoshikawa, T., Sugimura, K.
(2007). Primary Pulmonary Hypertension: 3D Dynamic Perfusion MRI for Quantitative Analysis of Regional Pulmonary Perfusion. Am. J. Roentgenol.
188: 48-56
[Abstract][Full Text]
Wittbrodt, E. T, Abubakar, A.
(2007). Sitaxsentan for Treatment of Pulmonary Hypertension. The Annals of Pharmacotherapy
41: 100-105
[Abstract][Full Text]
Liu, L., Liu, H., Visner, G., Fletcher, B. S.
(2006). Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats. FASEB J.
20: 2594-2596
[Abstract][Full Text]
Fantozzi, I., Platoshyn, O., Wong, A. H., Zhang, S., Remillard, C. V., Furtado, M. R., Petrauskene, O. V., Yuan, J. X.-J.
(2006). Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
291: L993-L1004
[Abstract][Full Text]
Fox, D J, Khattar, R S
(2006). Pulmonary arterial hypertension: classification, diagnosis and contemporary management. Postgrad. Med. J.
82: 717-722
[Full Text]
Channick, R. N., Olschewski, H., Seeger, W., Staub, T., Voswinckel, R., Rubin, L. J.
(2006). Safety and Efficacy of Inhaled Treprostinil as Add-On Therapy to Bosentan in Pulmonary Arterial Hypertension. J Am Coll Cardiol
48: 1433-1437
[Abstract][Full Text]
Gomberg-Maitland, M.
(2006). Learning to pair therapies and the expanding matrix for pulmonary arterial hypertension: is more better?. Eur Respir J
28: 683-686
[Full Text]
Said, S. I.
(2006). Mediators and modulators of pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.
291: L547-L558
[Abstract][Full Text]
McLaughlin, V. V., McGoon, M. D.
(2006). Pulmonary Arterial Hypertension. Circulation
114: 1417-1431
[Full Text]
Peacock, A., Simonneau, G., Rubin, L.
(2006). Controversies, Uncertainties and Future Research on the Treatment of Chronic Thromboembolic Pulmonary Hypertension. Proc Am Thorac Soc
3: 608-614
[Abstract][Full Text]
Galie, N., Beghetti, M., Gatzoulis, M. A., Granton, J., Berger, R. M.F., Lauer, A., Chiossi, E., Landzberg, M., for the Bosentan Randomized Trial of Endothelin An,
(2006). Bosentan Therapy in Patients With Eisenmenger Syndrome: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. Circulation
114: 48-54
[Abstract][Full Text]
Yin, Z., Wang, Z., Zhu, H., Zhang, R., Wang, H., Li, X.
(2006). Experimental Study of Effect of Fontan Circuit on Pulmonary Microcirculation. Asian Cardiovasc. Thorac. Ann.
14: 183-188
[Abstract][Full Text]
Tan, M.-S., Chai, C.-Y., Wu, J.-R., Yeh, J.-L., Chen, I.-J., Kwan, A.-L., Jeng, A. Y., Yang, H.-Y., Lee, M.-H., Dai, Z.-K.
(2006). Differential Change in Expression of Pulmonary ET-1 and eNOS in Rats After Chronic Left Ventricular Pressure Overload.. Exp. Biol. Med.
231: 948-953
[Abstract][Full Text]
Chou, S.-H., Chai, C.-Y., Wu, J.-R., Tan, M.-S., Chiu, C.-C., Chen, I.-J., Jeng, A. Y., Chang, C.-I, Kwan, A.-L., Dai, Z.-K.
(2006). The Effects of Debanding on the Lung Expression of ET-1, eNOS, and cGMP in Rats with Left Ventricular Pressure Overload.. Exp. Biol. Med.
231: 954-959
[Abstract][Full Text]
Clozel, M., Hess, P., Rey, M., Iglarz, M., Binkert, C., Qiu, C.
(2006). Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats.. Exp. Biol. Med.
231: 967-973
[Abstract][Full Text]
Guignabert, C., Izikki, M., Tu, L. I., Li, Z., Zadigue, P., Barlier-Mur, A.-M., Hanoun, N., Rodman, D., Hamon, M., Adnot, S., Eddahibi, S.
(2006). Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension. Circ. Res.
98: 1323-1330
[Abstract][Full Text]
Barst, R. J., Langleben, D., Badesch, D., Frost, A., Lawrence, E. C., Shapiro, S., Naeije, R., Galie, N., on behalf of the STRIDE-2 Study Group,
(2006). Treatment of Pulmonary Arterial Hypertension With the Selective Endothelin-A Receptor Antagonist Sitaxsentan. J Am Coll Cardiol
47: 2049-2056
[Abstract][Full Text]
Maiya, S, Hislop, A A, Flynn, Y, Haworth, S G
(2006). Response to bosentan in children with pulmonary hypertension. Heart
92: 664-670
[Abstract][Full Text]
Oishi, P., Azakie, A., Harmon, C., Fitzgerald, R. K., Grobe, A., Xu, J., Hendricks-Munoz, K., Black, S. M., Fineman, J. R.
(2006). Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs. Am. J. Physiol. Heart Circ. Physiol.
290: H1922-H1932
[Abstract][Full Text]
Eddahibi, S., Guignabert, C., Barlier-Mur, A.-M., Dewachter, L., Fadel, E., Dartevelle, P., Humbert, M., Simonneau, G., Hanoun, N., Saurini, F., Hamon, M., Adnot, S.
(2006). Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension: Critical Role for Serotonin-Induced Smooth Muscle Hyperplasia. Circulation
113: 1857-1864
[Abstract][Full Text]
Benza, R. L., Rayburn, B. K., Tallaj, J. A., Coffey, C. S., Pinderski, L. J., Pamoukian, S. V., Bourge, R. C.
(2006). Efficacy of bosentan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease.. Chest
129: 1009-1015
[Abstract][Full Text]
Langleben, D., Dupuis, J., Langleben, I., Hirsch, A. M., Baron, M., Senecal, J.-L., Giovinazzo, M.
(2006). Etiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension. Chest
129: 689-695
[Abstract][Full Text]
Wright, J. L., Tai, H., Churg, A.
(2006). Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig. J. Appl. Physiol.
100: 672-678
[Abstract][Full Text]
Oishi, P., Grobe, A., Benavidez, E., Ovadia, B., Harmon, C., Ross, G. A., Hendricks-Munoz, K., Xu, J., Black, S. M., Fineman, J. R.
(2006). Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb. Am. J. Physiol. Lung Cell. Mol. Physiol.
290: L359-L366
[Abstract][Full Text]
Mouthon, L., Guillevin, L., Humbert, M.
(2005). Pulmonary arterial hypertension: an autoimmune disease?. Eur Respir J
26: 986-988
[Full Text]
Stevens, T.
(2005). Molecular and Cellular Determinants of Lung Endothelial Cell Heterogeneity. Chest
128: 558S-564S
[Abstract][Full Text]
Cool, C. D., Groshong, S. D., Oakey, J., Voelkel, N. F.
(2005). Pulmonary Hypertension: Cellular and Molecular Mechanisms. Chest
128: 565S-571S
[Full Text]
Zaiman, A., Fijalkowska, I., Hassoun, P. M., Tuder, R. M.
(2005). One Hundred Years of Research in the Pathogenesis of Pulmonary Hypertension. Am. J. Respir. Cell Mol. Bio.
33: 425-431
[Full Text]
Langer, F., Bauer, M., Tscholl, D., Schramm, R., Kunihara, T., Lausberg, H., Georg, T., Wilkens, H., Schafers, H.-J.
(2005). Circulating big endothelin-1: An active role in pulmonary thromboendarterectomy?. J. Thorac. Cardiovasc. Surg.
130: 1342-1347
[Abstract][Full Text]
Rosenzweig, E. B., Ivy, D. D., Widlitz, A., Doran, A., Claussen, L. R., Yung, D., Abman, S. H., Morganti, A., Nguyen, N., Barst, R. J.
(2005). Effects of Long-Term Bosentan in Children With Pulmonary Arterial Hypertension. J Am Coll Cardiol
46: 697-704
[Abstract][Full Text]
Rubin, L. J., Badesch, D. B.
(2005). Evaluation and Management of the Patient with Pulmonary Arterial Hypertension. ANN INTERN MED
143: 282-292
[Abstract][Full Text]
Galie, N., Badesch, D., Oudiz, R., Simonneau, G., McGoon, M. D., Keogh, A. M., Frost, A. E., Zwicke, D., Naeije, R., Shapiro, S., Olschewski, H., Rubin, L. J.
(2005). Ambrisentan Therapy for Pulmonary Arterial Hypertension. J Am Coll Cardiol
46: 529-535
[Abstract][Full Text]
Nakhoul, F., Yigla, M., Gilman, R., Reisner, S. A., Abassi, Z.
(2005). The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access. Nephrol Dial Transplant
20: 1686-1692
[Abstract][Full Text]
Wright, J L, Levy, R D, Churg, A
(2005). Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax
60: 605-609
[Abstract][Full Text]
Barnes, P. J., Stockley, R. A.
(2005). COPD: current therapeutic interventions and future approaches. Eur Respir J
25: 1084-1106
[Abstract][Full Text]
Pepke-Zaba, J, Morrell, N W
(2005). The endothelin system and its role in pulmonary arterial hypertension (PAH). Thorax
60: 443-444
[Full Text]
Jankov, R. P., Kantores, C., Belcastro, R., Yi, S., Ridsdale, R. A., Post, M., Tanswell, A. K.
(2005). A role for platelet-derived growth factor {beta}-receptor in a newborn rat model of endothelin-mediated pulmonary vascular remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol.
288: L1162-L1170
[Abstract][Full Text]
Sandbo, N., Qin, Y., Taurin, S., Hogarth, D. K., Kreutz, B., Dulin, N. O.
(2005). Regulation of Serum Response Factor-Dependent Gene Expression by Proteasome Inhibitors. Mol. Pharmacol.
67: 789-797
[Abstract][Full Text]
Black, C.
(2005). Pulmonary arterial hypertension: are we doing enough to identify systemic sclerosis patients at high risk of this rare condition?. Rheumatology (Oxford)
44: 141-142
[Full Text]
Task Force members, , Galie, N., Torbicki, A., Barst, R., Dartevelle, P., Haworth, S., Higenbottam, T., Olschewski, H., Peacock, A., Pietra, G., Rubin, L. J., Simonneau, G.
(2004). Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J
25: 2243-2278
[Full Text]
Barnes, P. J.
(2004). Mediators of Chronic Obstructive Pulmonary Disease. Pharmacol. Rev.
56: 515-548
[Abstract][Full Text]
Kunichika, N., Landsberg, J. W., Yu, Y., Kunichika, H., Thistlethwaite, P. A., Rubin, L. J., Yuan, J. X.-J.
(2004). Bosentan Inhibits Transient Receptor Potential Channel Expression in Pulmonary Vascular Myocytes. Am. J. Respir. Crit. Care Med.
170: 1101-1107
[Abstract][Full Text]
Kunichika, N., Yu, Y., Remillard, C. V., Platoshyn, O., Zhang, S., Yuan, J. X.-J.
(2004). Overexpression of TRPC1 enhances pulmonary vasoconstriction induced by capacitative Ca2+ entry. Am. J. Physiol. Lung Cell. Mol. Physiol.
287: L962-L969
[Abstract][Full Text]
Farber, H. W., Loscalzo, J.
(2004). Pulmonary Arterial Hypertension. NEJM
351: 1655-1665
[Full Text]
von der Hardt, K., Kandler, M.A., Chada, M., Cubra, A., Schoof, E., Amann, K., Rascher, W., Dotsch, J.
(2004). Brief adrenomedullin inhalation leads to sustained reduction of pulmonary artery pressure. Eur Respir J
24: 615-623
[Abstract][Full Text]
Langleben, D., Hirsch, A. M., Shalit, E., Lesenko, L., Barst, R. J.
(2004). Sustained Symptomatic, Functional, and Hemodynamic Benefit With the Selective Endothelin-A Receptor Antagonist, Sitaxsentan, in Patients With Pulmonary Arterial Hypertension: A 1-Year Follow-up Study. Chest
126: 1377-1381
[Abstract][Full Text]
Humbert, M., Sitbon, O., Simonneau, G.
(2004). Treatment of Pulmonary Arterial Hypertension. NEJM
351: 1425-1436
[Full Text]
Yu, Y., Fantozzi, I., Remillard, C. V., Landsberg, J. W., Kunichika, N., Platoshyn, O., Tigno, D. D., Thistlethwaite, P. A., Rubin, L. J., Yuan, J. X.-J.
(2004). Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Natl. Acad. Sci. USA
101: 13861-13866
[Abstract][Full Text]
Hachulla, E, Coghlan, J G
(2004). A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Ann Rheum Dis
63: 1009-1014
[Abstract][Full Text]
Fratz, S., Meyrick, B., Ovadia, B., Johengen, M. J., Reinhartz, O., Azakie, A., Ross, G., Fitzgerald, R., Oishi, P., Hess, J., Black, S. M., Fineman, J. R.
(2004). Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure. Am. J. Physiol. Lung Cell. Mol. Physiol.
287: L592-L597
[Abstract][Full Text]
Badesch, D. B., Abman, S. H., Ahearn, G. S., Barst, R. J., McCrory, D. C., Simonneau, G., McLaughlin, V. V.
(2004). Medical Therapy For Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Chest
126: 35S-62S
[Abstract][Full Text]
Dupuis, J.
(2004). Increased endothelin levels in congestive heart failure: does it come from the lungs? Does it matter?. Cardiovasc Res
63: 5-7
[Full Text]
Humbert, M., Morrell, N. W., Archer, S. L., Stenmark, K. R., MacLean, M. R., Lang, I. M., Christman, B. W., Weir, E. K., Eickelberg, O., Voelkel, N. F., Rabinovitch, M.
(2004). Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol
43: 13S-24S
[Abstract][Full Text]
Channick, R. N., Sitbon, O., Barst, R. J., Manes, A., Rubin, L. J.
(2004). Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol
43: 62S-67S
[Abstract][Full Text]
Leuchte, H. H., Holzapfel, M., Baumgartner, R. A., Ding, I., Neurohr, C., Vogeser, M., Kolbe, T., Schwaiblmair, M., Behr, J.
(2004). Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol
43: 764-770
[Abstract][Full Text]
Barst, R. J., Langleben, D., Frost, A., Horn, E. M., Oudiz, R., Shapiro, S., McLaughlin, V., Hill, N., Tapson, V. F., Robbins, I. M., Zwicke, D., Duncan, B., Dixon, R. A. F., Frumkin, L. R.
(2004). Sitaxsentan Therapy for Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med.
169: 441-447
[Abstract][Full Text]
Chu, D., Sullivan, C. C., Du, L., Cho, A. J., Kido, M., Wolf, P. L., Weitzman, M. D., Jamieson, S. W., Thistlethwaite, P. A.
(2004). A new animal model for pulmonary hypertension based on the overexpression of a single gene, angiopoietin-1. Ann. Thorac. Surg.
77: 449-456
[Abstract][Full Text]
Galie, N., Manes, A., Branzi, A.
(2004). The endothelin system in pulmonary arterial hypertension. Cardiovasc Res
61: 227-237
[Abstract][Full Text]
Budhiraja, R., Tuder, R. M., Hassoun, P. M.
(2004). Endothelial Dysfunction in Pulmonary Hypertension. Circulation
109: 159-165
[Full Text]
Fratz, S., Geiger, R., Kresse, H., Roemer, G., Hennig, M., Sebening, W., Hess, J.
(2003). Pulmonary blood pressure, not flow, is associated with net endothelin-1 production in the lungs of patients with congenital heart disease and normal pulmonary vascular resistance. J. Thorac. Cardiovasc. Surg.
126: 1724-1729
[Abstract][Full Text]
Tovar, J. M, Gums, J. G
(2003). Tezosentan in the Treatment of Acute Heart Failure. The Annals of Pharmacotherapy
37: 1877-1883
[Abstract][Full Text]
Rich, S., McLaughlin, V. V.
(2003). Endothelin Receptor Blockers in Cardiovascular Disease. Circulation
108: 2184-2190
[Abstract][Full Text]
Kim, N. H., Channick, R. N., Rubin, L. J.
(2003). Successful Withdrawal of Long-term Epoprostenol Therapy for Pulmonary Arterial Hypertension. Chest
124: 1612-1615
[Abstract][Full Text]
Apostolopoulou, S C, Rammos, S, Kyriakides, Z S, Webb, D J, Johnston, N R, Cokkinos, D V, Kremastinos, D T.
(2003). Acute endothelin A receptor antagonism improves pulmonary and systemic haemodynamics in patients with pulmonary arterial hypertension that is primary or autoimmune and related to congenital heart disease. Heart
89: 1221-1226
[Abstract][Full Text]
Black, S. M., Mata-Greenwood, E., Dettman, R. W., Ovadia, B., Fitzgerald, R. K., Reinhartz, O., Thelitz, S., Steinhorn, R. H., Gerrets, R., Hendricks-Munoz, K., Ross, G. A., Bekker, J. M., Johengen, M. J., Fineman, J. R.
(2003). Emergence of Smooth Muscle Cell Endothelin B-Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow. Circulation
108: 1646-1654
[Abstract][Full Text]
Wagner, F. D., Buz, S., Knosalla, C., Hetzer, R., Hocher, B.
(2003). Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation. Circulation
108: II-278-284
[Abstract][Full Text]
Benjaminov, F S, Prentice, M, Sniderman, K W, Siu, S, Liu, P, Wong, F
(2003). Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut
52: 1355-1362
[Abstract][Full Text]
Kandler, M. A., von der Hardt, K., Mahfoud, S., Chada, M., Schoof, E., Papadopoulos, T., Rascher, W., Dotsch, J.
(2003). Pilot Intervention: Aerosolized Adrenomedullin Reduces Pulmonary Hypertension. J. Pharmacol. Exp. Ther.
306: 1021-1026
[Abstract][Full Text]
Kenyon, K. W, Nappi, J. M
(2003). Bosentan for the Treatment of Pulmonary Arterial Hypertension. The Annals of Pharmacotherapy
37: 1055-1062
[Abstract][Full Text]
Qing, X., Keith, I. M.
(2003). Targeted blocking of gene expression for CGRP receptors elevates pulmonary artery pressure in hypoxic rats. Am. J. Physiol. Lung Cell. Mol. Physiol.
285: L86-L96
[Abstract][Full Text]
Zhao, Y. D., Campbell, A. I.M., Robb, M., Ng, D., Stewart, D. J.
(2003). Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension. Circ. Res.
92: 984-991
[Abstract][Full Text]
Levy, M., Danel, C., Laval, A.-M., Leca, F., Vouhe, P. R., Israel-Biet, D.
(2003). Nitric oxide synthase expression by pulmonary arteries: A predictive marker of Fontan procedure outcome?. J. Thorac. Cardiovasc. Surg.
125: 1083-1090
[Abstract][Full Text]
Yigla, M., Nakhoul, F., Sabag, A., Tov, N., Gorevich, B., Abassi, Z., Reisner, S. A.
(2003). Pulmonary Hypertension in Patients With End-Stage Renal Disease. Chest
123: 1577-1582
[Abstract][Full Text]
10 hours post mortem). Specimens were obtained from 28 patients with a clinical diagnosis of pulmonary hypertension17. The patients were divided into two groups on the basis of clinical and histopathological characteristics. Group 1 consisted of 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6),18 of whom 7 had a clinical diagnosis of primary pulmonary hypertension according to the criteria of the National Heart, Lung, and Blood Institute19 (Table 1). Group 2 consisted of 17 patients with secondary causes of pulmonary hypertension and no more than grade 3 pulmonary arteriopathy18 (Table 2). The patients with secondary pulmonary hypertension were older than those with plexogenic pulmonary arteriopathy and had significantly lower forced expiratory volumes, diffusing capacities for carbon monoxide, and hemoglobin levels. However, there were no significant differences in pulmonary arterial pressure and vascular resistance between the two groups. Control specimens were obtained from 5 patients (3 men and 2 women, 19 to 67 years old [mean, 50]) with pulmonary diseases other than idiopathic pulmonary fibrosis or hypertension (e.g., interstitial pneumonitis) and from the unused normal lungs of 10 organ donors (6 female and 4 male donors, 17 to 46 years old [mean, 30]). Tissues were fixed in 10 percent buffered formalin or Bouin's solution and embedded in paraffin for routine pathological examination and immunocytochemical analysis. The method of fixation did not affect the intensity of immunostaining in five specimens that were prepared by both methods. For the localization of endothelin-1 messenger RNA (mRNA), tissues were either snap-frozen in liquid nitrogen or fixed in 4 percent paraformaldehyde in phosphate-buffered saline (0.1 mol of sodium phosphate and 0.15 mol of sodium chloride per liter, pH 7.2) and washed in phosphate-buffered saline containing 15 percent sucrose and 0.01 percent sodium azide at 4 °C. 
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