Background Pulmonary hypertension is characterized by abnormalthickening of the pulmonary arteries and increased pulmonaryvascular resistance. Nitric oxide is a potent endothelium-derivedvasorelaxant substance and an inhibitor of smooth-muscle-cellgrowth. Nitric oxide is produced in various cell types by theaction of an enzyme, nitric oxide synthase. We compared theexpression of endothelial nitric oxide synthase in the lungsof control subjects with that in the lungs of patients withpulmonary hypertension.
Methods We investigated the expression of endothelial nitricoxide synthase by histochemical and immunohistochemical analysis,in situ hybridization, and Northern blot analysis in the lungsof 22 patients with plexogenic pulmonary arteriopathy (arteriopathyof grades 4 through 6), 24 patients with secondary pulmonaryhypertension (arteriopathy of grades 1 through 3), and 23 controlsubjects.
Results In the lungs of the control subjects, nitric oxide synthasewas expressed at a high level in the vascular endothelium ofall types of vessels and in the pulmonary epithelium. In contrast,little or no expression of the enzyme was found in the vascularendothelium of pulmonary arteries with severe histologic abnormalities(i.e., plexiform lesions) in patients with pulmonary hypertension.The intensity of the enzyme immunoreactivity correlated inverselywith the severity of histologic changes. There was an inversecorrelation between the arterial expression of the enzyme andtotal pulmonary resistance in patients with plexogenic pulmonaryarteriopathy (r = -0.766, P = 0.004).
Conclusions Pulmonary hypertension is associated with diminishedexpression of endothelial nitric oxide synthase. It is possiblethat decreased expression of nitric oxide synthase may contributeto pulmonary vasoconstriction and to the excessive growth ofthe tunica media observed in this disease.
Pulmonary hypertension is generally characterized by increasedthickening of the walls of pulmonary arteries, narrowing ofthe pulmonary-artery lumen, increased pulmonary vascular resistance,and right-sided heart failure.1,2,3 Clinically, patients haveincreasing dyspnea, cyanosis, precordial discomfort, anginalpain, and cardiomegaly.1,2,3 Histologically, pulmonary arterieswith such resistance, particularly those less than 100 µmin diameter, show various degrees of intimal thickening andmuscular hypertrophy.1,4,5 Pulmonary hypertension can be eitheridiopathic (primary) or due to other disease conditions. A numberof humoral factors have been implicated in the pathogenesisof pulmonary hypertension, but there is no evidence that anycontribute directly to the disorder.
Recently, attention has been given to the endothelium as animportant mediator of pulmonary hypertension by virtue of itsability to produce factors that regulate blood flow and vasculartone.6,7,8 One of the most important factors so produced isthe endothelium-derived relaxing factor nitric oxide,9,10 whichis produced from the guanidino nitrogen of l-arginine by theenzyme nitric oxide synthase.10 There are three isoforms ofthis enzyme. Two, expressed in neurons and endothelial cells,are calcium-dependent,11,12 whereas a third is calcium-independentand is expressed by macrophages and other cells after inductionwith cytokines.13 In addition to its vasodilative effects, nitricoxide acts as a bronchodilator, neurotransmitter, anticoagulant,antiproliferative, and antimicrobial substance.10 Several studieshave shown that nitric oxide plays an important part in thephysiology of the lung,14 particularly in maintaining low pressurein the normal pulmonary circuit.15 Continuous inhalation ofnitric oxide protects against the development of pulmonary hypertensionin chronically hypoxic rats,16 and chronic deprivation of thesubstance in utero produces pulmonary hypertension in newbornlambs.17 Inhalation of nitric oxide reduces pulmonary vascularresistance in patients with pulmonary hypertension.18,19
On the basis of these considerations, we asked whether the endothelialexpression of nitric oxide synthase might be abnormal in thepulmonary vasculature of patients with pulmonary hypertension.To date, there are only a few reports concerning the expressionof nitric oxide synthase in human lungs,20,21 none of whichhas dealt with the expression of the constitutive endothelialisoform. In this study we provide evidence of abundant expressionof endothelial nitric oxide synthase in normal lungs. We alsoshow that the expression of this enzyme is diminished in theendothelium of pulmonary arteries of patients with pulmonaryhypertension and that this diminution correlates inversely withthe total pulmonary resistance in patients with plexogenic pulmonaryarteriopathy.
Methods
Study Patients
The study patients were divided into three groups on the basisof clinical and histologic characteristics. Group 1 consistedof 22 patients with plexogenic pulmonary arteriopathy (Heathand Edwards grades 4 through 6).4 Eighteen of these had a clinicaldiagnosis of primary pulmonary hypertension,22 two had cirrhosis,one had postpartum pulmonary hypertension, and one had systemiclupus erythematosus. Group 2 consisted of 24 patients with pulmonaryhypertension due to various disease conditions (Heath and Edwardsgrades 1 through 3).4 Group 3 consisted of 10 patients withnonspecific pneumonitis. Also included in group 3 were 13 normallungs that were donor organs not used for transplantation. Thecharacteristics of the study patients are shown in Table 1.Specimens of lung tissue were collected during open-lung biopsy,at transplantation, or at autopsy. Multiple pieces of tissuewere fixed in either paraformaldehyde or formalin for routinehistologic diagnosis, immunohistochemical analysis, and in situhybridization. For the Northern blot analysis, fresh sampleswere snap-frozen in liquid nitrogen.
Paraffin and cryostat sections of tissue were immunostainedwith antiserum to human endothelial nitric oxide synthase producedin our laboratory with a modification of the avidin–biotin–peroxidasemethod.23 The specificity of the antiserum used was determinedby Western blotting and by comparison with a commercial antiserum(Transduction Laboratories, Lexington, Ky.). In the immunohistochemicalanalysis, tissue sections were made permeable with Triton X-100,incubated in hydrogen peroxide to block endogenous peroxidaseactivity, and incubated first with normal serum for 30 minutesand then with the primary antiserum for 16 hours at 4°C.Sections were then incubated with biotinylated IgG and stainedwith an immunoperoxidase technique according to the manufacturer'sinstructions (Vectastain ABC Elite Kit, Vector Laboratories,Burlingame, Calif.). The samples of primary antiserum were incubatedwith their respective antigens (1 µg per milliliter ofsolution) before incubation with tissue sections, or sectionswere incubated with the normal serum instead of the primaryantiserum samples and used as negative controls. Antiserum tothe endothelial-cell marker von Willebrand factor (factor VIII)and antiserum to endothelin-1 were also used. Extra sectionsfrom all patients were stained with hematoxylin and eosin andwith Verhoeff–van Gieson stains for the histologic diagnosisof pulmonary hypertension. The intensity of immunostaining wasgraded semiquantitatively as described elsewhere.24
In Situ Hybridization
Cryostat sections of paraformaldehyde-fixed tissues were placedon RNase-free glass slides and hybridized with an RNA probelabeled with sulfur-35 to detect endothelial nitric oxide synthase,12according to a previously described method.24 In brief, tissuesections were made permeable with Triton X-100 and proteinaseK. To reduce background noise, they were treated with aceticanhydride and triethanolamine and with a further solution ofN-ethylmaleimide and iodoacetamide. After overnight incubationwith the radiolabeled probe at 42°C, unhybridized RNA probeswere removed with RNase A and high-stringency washes with 2xto 0.1x saline sodium citrate (SSC; 1x SSC is 0.15 mol of sodiumchloride and 0.015 mol of sodium citrate per liter, ph 7) at22 to 55°C. The sections were then processed for autoradiography.Negative control experiments included lung sections hybridizedwith the sense probe or with the hybridization buffer in theabsence of the labeled antisense probe. Extra sets of sectionswere immunostained with the endothelial nitric oxide synthaseantiserum before they were processed for autoradiography forcolocalization of the mature protein and messenger RNA (mRNA)on the same sections. Another set of sections was hybridizedwith the RNA probe for human endothelin-1 as a positive control.24
The experiments using immunohistochemical analysis and in situhybridization were further complemented by Northern blot analysis25and histochemical staining for NADPH diaphorase.26
Statistical Analysis
Data are presented as means ±SE. Differences betweengroups were assessed by analysis of variance, with Bonferroni'scorrection for multiple comparisons, with a commercial program(Statview). The correlation between immunohistochemical gradesand total pulmonary resistance or the severity of the lesionwas assessed with ordinary least-squares linear regression techniques.27
Results
Histologic analyses of consecutive sections from the patientswith plexogenic pulmonary arteriopathy (group 1), after stainingwith hematoxylin and eosin and the Verhoeff–van giesonstain, revealed pulmonary arteries with morphologic changesof grades 4 through 6 on the Heath and Edwards scale.4 The parenchymashowed no apparent morphologic abnormalities. Specimens frompatients with secondary pulmonary hypertension showed pulmonaryarteries with muscular hypertrophy and intimal fibrosis (grades1 through 3 on the same scale), with various underlying parenchymalchanges, such as interstitial fibrosis, edema, or hemorrhage.
Immunohistochemical analyses revealed strong immunostainingfor endothelial nitric oxide synthase in the pulmonary vascularendothelium and the pulmonary epithelium of the control lungs(group 3) (Figure 1A, Figure 1B, Figure 1C, Figure 1D, Figure 1E,Figure 1F, Figure 1G, and Figure 1H). Dense, diffuse immunostainingwas observed in the endothelial cells of pulmonary arteriesof all sizes (Figure 1C, Figure 1E, and Figure 1G). The endothelialcells of pulmonary veins, bronchial arteries, and microvesselswere also stained. The intensity of the immunoreaction was similarto that of the immunoreaction to von Willebrand factor. Strongimmunoreactivity was observed in the airway epithelium, excludinggoblet cells (Figure 1A). Moderate-to-weak immunoreactivitywas occasionally seen in the serous glands and nerve fibersaround vessels and airways. In comparison, the lungs of patientswith plexogenic pulmonary arteriopathy (group 1) had littleor no endothelial nitric oxide synthase in the pulmonary arterieswith severe morphologic abnormalities (Figure 2A and Figure 2C).In the same specimens, pulmonary arteries with few histologicchanges or none showed weak-to-moderate immunostaining for theenzyme. The immunoreactivity to endothelial nitric oxide synthaseremained strong in the pulmonary epithelium (Figure 2A). Inthe patients with secondary pulmonary hypertension (group 2),there was weak immunoreactivity to endothelial nitric oxidein the endothelium of pulmonary arteries with medial thickeningand intimal proliferation (Figure 2D). In the patients withpulmonary hypertension due to pulmonary fibrosis, moderatelydiffuse staining was also seen in proliferative type II pneumocytes(Figure 2E). In groups 1 and 2, the immunostaining in the endotheliumof pulmonary veins remained relatively unchanged. Consecutivesections immunostained with the endothelin-1 antiserum showedstrong expression of the peptide at sites where endothelialnitric oxide was absent or weak (data not shown). Immunostainingof heart and kidney sections from normal subjects and patientswith pulmonary hypertension showed a strong immunoreaction withinthe vascular endothelium, as well as in the tubular epitheliumof kidney sections from both diseased patients and normal subjects.No staining was seen in sections immunostained with the mixtureof antiserum and antigen or with the nonimmune serum (Figure 1D).
Figure 1. Endothelial Nitric Oxide Synthase–Like Immunoreactivity and mRNA in Normal Lung Tissue.
Immunoreactivity to nitric oxide synthase is shown in the bronchial epithelium (Panel A, x400) and in the vascular endothelium of the elastic (Panel C, x200) and the medium-sized muscular (Panel E, x400) and small muscular (Panel G, x400) pulmonary arteries of normal lungs. Panel D shows a section consecutive to that shown in Panel C, first hybridized with the sense RNA probe and then immunostained with the mixture of antiserum and antigen to serve as a negative control for in situ hybridization and the immunohistochemical analysis (x200). The expression of endothelial nitric oxide synthase mRNA is shown in the bronchial epithelium (Panel B, x400) and in the vascular endothelium of the medium-sized (Panel F, x400) and small (Panel H, x200) muscular pulmonary arteries in normal lungs. Arrows indicate hybridization signals in the bronchial epithelium (Panel B) and the vascular endothelium (Panels F and H).
Figure 2. Endothelial Nitric Oxide Synthase–Like Immunoreactivity and mRNA in the Lungs of Patients with Pulmonary Hypertension.
Panels A, B, and C show sections of lung from patients in group 1, demonstrating strong immunoreactivity to nitric oxide synthase in the bronchiolar epithelium but no staining in the adjacent pulmonary artery (arrow, Panel A) with severe intimal fibrosis and muscular hypertrophy (x200). Panel B shows the absence of hybridization signals in a small pulmonary artery with morphologic changes similar to those in Panel A (the arrow indicates the presence of a few scattered hybridization signals over the occluded vessel; x400). Panel C shows the absence of immunostaining with endothelial nitric oxide synthase in a plexiform lesion of a small pulmonary artery (x400). Panels D and E, showing sections from patients in group 2, demonstrate weak-to-moderate immunoreactivity in the vascular endothelium of a medium-sized pulmonary artery with muscular hypertrophy (Panel D; the arrow shows a weak brown color in the endothelium; x200) and in the alveolar epithelium of a patient with pulmonary hypertension due to idiopathic pulmonary fibrosis (Panel E; x200). Coexisting endothelial nitric oxide synthase–like immunoreactivity and mRNA are shown in the bronchiolar epithelium of a patient with secondary pulmonary hypertension (Panel F, x400). Strong staining for NADPH diaphorase was seen in the pulmonary epithelium, nerve fibers, and vascular endothelium (arrow) of normal lungs (Panel G, x100). No NADPH activity was detected in pulmonary arteries with severe morphologic changes (intimal fibrosis and muscular hypertrophy; the arrow indicates narrowing of the lumen) (Panel H, phase-contrast micrograph, x200).
In situ hybridization revealed the expression of endothelialnitric oxide synthase mRNA at sites similar to those at whichimmunoreactivity was present. Strong hybridization signals wereseen in the endothelium of pulmonary arteries and the pulmonaryepithelium of control lungs (group 3) (Figure 1B, Figure 1F,and Figure 1H). In contrast, only scattered hybridization signalsor none were seen in pulmonary arteries with severe arteriopathy(group 1) (Figure 2B). As was noted in the immunohistochemicalanalyses, pulmonary arteries with mild morphologic abnormalitiesin groups 1 and 2 showed moderate hybridization signals in thevascular endothelium. In general, in the patients with pulmonaryhypertension, small and medium-sized pulmonary arteries hadthe fewest hybridization signals. The intensity of hybridizationsignals in the airway epithelium remained unchanged in all groups(Figure 2F). These observations were further confirmed in thestudy of lung sections that were hybridized with the radiolabeledprobe and then immunostained with antiserum to endothelial nitricoxide synthase (Figure 2F). No hybridization signals were seenin sections hybridized with the sense RNA probe (Figure 1D).Northern blot analysis showed stronger hybridization signalsfor the enzyme in normal lungs than in the lungs of patientswith secondary pulmonary hypertension. The lung samples frompatients with plexogenic pulmonary arteriopathy showed veryweak signals only after a long exposure.
Histochemical staining for NADPH revealed the localization ofnitric oxide synthase–like immunoreactivity in the pulmonaryepithelium, vascular endothelium, and nerve fibers. In general,strong staining was seen in the pulmonary epithelium, vascularendothelium, and nerve fibers of normal lungs (Figure 2G). Incontrast, there was no staining in the endothelium of any ofthe pulmonary arteries with severe morphologic changes (Figure 2H).
Semiquantitative analyses of the immunohistochemical data revealeda significant difference in the arterial expression of endothelialnitric oxide synthase among the study patients. There was significantlymore immunoreactivity to endothelial nitric oxide synthase inthe endothelium of elastic and muscular pulmonary arteries ofall sizes in the control lungs (group 3) than in the lungs ofthe patients with plexogenic pulmonary arteriopathy (group 1)or secondary pulmonary hypertension (group 2) (P<0.001) (Figure 3).Small and medium-sized pulmonary arteries of patients ingroup 2 showed a greater mean (±SE) degree of immunostaining(immunohistochemical grades, 0.6±0.1 and 1.0±0.1,respectively) than those of patients in group 1 (0.2±0.07and 0.6±0.1; P = 0.009 and P = 0.014). Linear regressionanalysis indicated significant inverse correlations betweenthe immunohistochemical grade and the severity of the lesionin all patients with pulmonary hypertension (r = -0.787; 95percent confidence interval, -0.858 to -0.685; P<0.001) (Figure 4)and between arterial expression of nitric oxide synthaseand total pulmonary resistance in patients with plexogenic pulmonaryarteriopathy (group 1; r = -0.766; 95 percent confidence interval,-0.95 to -0.307; P = 0.004).
Figure 3. Mean (+SE) Endothelial Nitric Oxide Synthase–Like Immunoreactivity in the Vascular Endothelium of Pulmonary Arteries in the Two Groups of Patients with Pulmonary Hypertension and the Control Group.
The patients with pulmonary hypertension were subdivided according to morphologic and clinical criteria into the group with plexogenic pulmonary arteriopathy (group 1) and the group with secondary pulmonary hypertension (group 2). Endothelial nitric oxide synthase–like immunoreactivity was assessed in the endothelium of elastic pulmonary arteries (500 µm in diameter) and large (300 to 500 µm), medium-sized (>100 to <300 µm), and small (100 µm) muscular pulmonary arteries. The level of immunostaining was significantly higher in the control group (group 3) than in the patients with pulmonary hypertension (P<0.001 for all artery types). When group 2 was compared with group 1, P = 0.014 for medium-sized pulmonary arteries and P = 0.009 for small pulmonary arteries. Immunohistochemical grades were determined semiquantitatively, as described elsewhere.24
Figure 4. Relation between Immunoreactivity to Endothelial Nitric Oxide Synthase and the Severity of Morphologic Changes in the Pulmonary Arteries of Patients with Pulmonary Hypertension.
Mean (+SE) endothelial nitric oxide synthase–like immunoreactivity was measured semiquantitatively by immunohistochemical methods24 in the vascular endothelium of pulmonary arteries, and histologic changes in the arteries were graded on the Heath and Edwards scale4 in patients with pulmonary hypertension. Arteries with Heath and Edwards grades of 1 or 2 had significantly higher immunoreactivity (P<0.001) than those with grades of 3 or above.
Discussion
In our study, we observed prominent expression of endothelialnitric oxide synthase in the endothelium of pulmonary vesselsand the airway epithelium of normal lungs. In contrast, in patientswith plexogenic pulmonary arteriopathy or secondary pulmonaryhypertension the expression of the enzyme in the endotheliumof pulmonary arteries with abnormal wall morphology was substantiallyreduced. We also observed an inverse correlation between thearterial expression of endothelial nitric oxide synthase andtotal pulmonary resistance in patients with plexogenic pulmonaryarteriopathy. By virtue of its biologic activities, nitric oxideis likely to play an important part in pulmonary pathophysiology.14Indeed, endothelial nitric oxide synthase has been implicatedin the maintenance of low pressure in the normal pulmonary vascularbed.15 Conceivably, constitutive production of nitric oxideby this enzyme is important for the regulation of blood flowand homeostasis and for the maintenance of normal vascular-wallstructure.
Nitric oxide has vasodilative effects on pulmonary vessels,and it inhibits the thrombogenicity and proliferation of vascularsmooth-muscle cells.10,14 Several studies have shown that nitricoxide and l-arginine can reduce pulmonary pressure in patientswith pulmonary hypertension.28,29 Dinh-Xuan et al.15 showedthat in patients with chronic obstructive lung disease therewas a positive correlation between intimal thickening of bloodvessels and the impaired release of nitric oxide. More recently,the same group found that in chronic hypoxia, pretreatment withan excess concentration of l-arginine does not reverse the effectsof Ng-monomethyl-l-arginine, a specific inhibitor of nitricoxide synthase, indicating that uptake of l-arginine into thecell is not affected.30 Muscular pulmonary arteries 100 µmin diameter, those just before the capillary bed, contributemost to the resistance to flow in pulmonary hypertension.31Indeed, they are the most likely arteries to have severe morphologicabnormalities in patients with pulmonary hypertension.4,5 Immunohistochemicalanalysis and in situ hybridization clearly demonstrate abundantexpression of nitric oxide synthase in the vascular endotheliumof pulmonary arteries, veins, and bronchial vessels of normallungs, as compared with very sparse signals for this enzymein the pulmonary arteries of patients with pulmonary hypertension.These observations are confirmed by histochemical staining forNADPH diaphorase and by Northern blot analysis. Our data alsoshowed a significant inverse correlation between the expressionof endothelial nitric oxide synthase and the severity of morphologicchanges in the study patients. Vessels with arteriopathy ofgrades 1 through 3 on the Heath and Edwards scale often hadweak-to-moderate staining, whereas those with arteriopathy ofgrades 4 through 6 often showed no staining. Indeed, the smalland medium-sized pulmonary arteries of patients in group 1 hadsignificantly less immunoreactivity than those of patients ingroup 2. Furthermore, we found a significant inverse correlationbetween the arterial expression of nitric oxide synthase andtotal pulmonary resistance that appeared only in patients withplexogenic pulmonary arteriopathy. These findings suggest thatin patients with pulmonary hypertension, impaired constitutiveexpression of the enzyme by the vascular endothelium of pulmonaryarteries may play a part in either the initiation or the progressionof pulmonary hypertension. Indeed, from the present study itis difficult to determine whether the reduction in the expressionof this enzyme is a cause or an effect of pulmonary hypertension.
Imbalances in the expression of endothelium-derived vasoactivesubstances are thought to contribute to the pathogenesis ofpulmonary hypertension.29 Christman et al.32 reported an imbalancebetween the excretion of thromboxane and that of prostacyclinmetabolites in patients with pulmonary hypertension. We haveelsewhere demonstrated increased expression of the vasoconstrictorpeptide endothelin-1 in the endothelium of pulmonary arterieswith severe arteriopathy in patients with pulmonary hypertension.24In the present study, when colocalization experiments were performedon consecutive sections of tissue, endothelial nitric oxidesynthase and endothelin-1 appeared to have inverse patternsof expression (data not shown). Whereas endothelin-1 was stronglyexpressed by the diseased vessels,24 endothelial nitric oxidesynthase predominated in the normal vascular bed. Both the pharmacologicand the pathological features of pulmonary hypertension indicatethat the initial reduction of pulmonary arterial blood flowresults from vasoconstriction. Shear stress and alteration inflow are known to modulate the production of endothelin-1 andnitric oxide by endothelial cells.33,34 Although we have notdetermined the mechanisms of reduced expression of endothelialnitric oxide synthase in pulmonary hypertension, it is reasonableto postulate that in the normal lung, shear stress and flowmaintain high constitutive expression of the enzyme in the pulmonaryvasculature. Taken together, these considerations suggest thatdown-regulation of the endothelium-derived relaxing and antiproliferativefactors (e.g., nitric oxide) and up-regulation of the endothelium-derivedvasoconstrictor and mitogenic factors (e.g., endothelin-1) contributeto pulmonary hypertension.
The finding that airway and alveolar epithelial cells expressendothelial nitric oxide synthase is interesting. It is knownthat pulmonary epithelial cells produce factors that cause relaxationof smooth-muscle cells.35,36 Nitric oxide, recently shown tobe a product of epithelial cells,20,21,37 has potent bronchodilatoryeffects and regulates ciliary beat.14 All previous reports havedemonstrated the expression of inducible nitric oxide synthaseby either histochemical staining for NADPH or immunostainingwith antiserum to inducible nitric oxide synthase.20,37 Here,we have demonstrated by immunohistochemical analysis that pulmonaryepithelium in vivo produces endothelial nitric oxide synthaseand by in situ hybridization that it expresses the respectivemRNA. The constitutive expression of endothelial nitric oxidesynthase in the pulmonary epithelium and in the pulmonary endotheliummay have similar effects, regulating smooth-muscle tone andhomeostasis of the airway.
In conclusion, the current findings demonstrate that in thenormal lung there is high basal expression of endothelial nitricoxide synthase in the endothelium of pulmonary vessels. In contrast,under pathologic conditions such as primary or secondary pulmonaryhypertension, the expression of this enzyme in the endotheliumof pulmonary arteries with severe morphologic abnormalitiesis reduced. The reduced expression of this enzyme correlatesinversely with increased vascular resistance. Therapy with analoguesof endothelial nitric oxide synthase may provide a new, safe,more widely applicable and comprehensive therapeutic approachto the prevention of pulmonary hypertension.
Supported by the Medical Research Council of Canada, the Heartand Stroke Foundation of Quebec, and the Lung Foundation ofQuebec. Dr. Giaid is a scholar of the Heart and Stroke Foundationof Canada.
We are indebted to Dr. Kenneth D. Bloch for supplying the probefor human endothelial nitric oxide synthase; to Dr. W.P. Duguidfor his continuous support and his review of the manuscript;and to Dr. David Mulder, Dr. Hani Shennib, Dr. Paul Corris,and all physicians who helped collect the clinical informationused in the study.
Source Information
From the Department of Pathology, Montreal General Hospital, and McGill University, Montreal.
Address reprint requests to Dr. Giaid at the Department of Pathology, Montreal General Hospital, 1650 Cedar Ave., Montreal, QC H3G 1A4, 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.
Reeves JT, Groves BM. Approach to the patient with pulmonary hypertension. In: Weir EK, Reeves JT, eds. Pulmonary hypertension. Mount Kisco, N.Y.: Futura Publishing, 1984:1-44.
Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. Circulation 1958;18:533-547. [Medline]
Heath D. The pathology of pulmonary hypertension. Eur Respir Rev 1993;3:555-8.
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by 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]
Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A 1990;87:682-685. [Free Full Text]
Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992;267:14519-14522. [Erratum, J Biol Chem 1992;267:22964.] [Free Full Text]
Lyons CR, Orloff GJ, Cunningham JM. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 1992;267:6370-6374. [Free Full Text]
Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH. Nitric oxide and the lung. Am J Respir Crit Care Med 1994;149:1375-1380. [Medline]
Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991;324:1539-1547. [Abstract]
Kouyoumdjian C, Adnot S, Levame M, Eddahibi S, Bousbaa H, Raffestin B. Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats. J Clin Invest 1994;94:578-584.
Fineman JR, Wong J, Morin FC III, Wild LM, Soifer SJ. Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. J Clin Invest 1994;93:2675-2683.
Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173-1174. [CrossRef][Medline]
Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405. [Free Full Text]
Kobzik L, Bredt DS, Lowenstein CJ, et al. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993;9:371-377.
Hamid Q, Springall DR, Riveros-Moreno V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993;342:1510-1513. [CrossRef][Medline]
Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223.
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577-580. [Abstract]
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-1739. [Free Full Text]
Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A 1984;81:1991-1995. [Free Full Text]
Hope BT, Michael GJ, Knigge KM, Vincent SR. 1991 Neuronal NADPH diaphorase is a nitric oxide synthase. Proc Natl Acad Sci U S A 1991;88:2811-2814. [Free Full Text]
Glantz SA. Primer of biostatistics. 2nd ed. New York: McGraw-Hill, 1987:287-330.
Ivy DD, Wiggins JW, Badesch DB, Kinsella JP, Kelminson LL, Abman SH. Nitric oxide and prostacyclin treatment of an infant with primary pulmonary hypertension. Am J Cardiol 1994;74:414-416. [Medline]
Higenbottam T, Cremona G. Acute and chronic hypoxic pulmonary hypertension. Eur Respir J 1993;6:1207-1212.
Dinh-Xuan AT, Pepke-Zaba J, Butt AY, Cremona G, Higenbottam TW. Impairment of pulmonary-artery endothelium-dependent relaxation in chronic obstructive lung disease is not due to dysfunction of endothelial cell membrane receptors nor to L-arginine deficiency. Br J Pharmacol 1993;109:587-591. [Medline]
Nagasaka Y, Bhattacharya J, Nanjo S, Gropper MA, Staub NC. Micropuncture measurement of lung microvascular pressure profile during hypoxia in cats. Circ Res 1984;54:90-95. [Free Full Text]
Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70-75. [Abstract]
Lamontagne D, Pohl U, Busse R. Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed. Circ Res 1992;70:123-130. [Free Full Text]
Miller VM, Burnett JC Jr. Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries. Am J Physiol 1992;263:H103-H108. [Free Full Text]
Stuart-Smith K, Vanhoutte PM. Heterogeneity in the effects of epithelium removal in the canine bronchial tree. J Appl Physiol 1987;63:2510-2515. [Free Full Text]
Robbins RA, Springall DR, Warren JB, et al. Inducible nitric oxide synthase is increased in murine lung epithelial cells by cytokine stimulation. Biochem Biophys Res Commun 1994;198:835-843. [CrossRef][Medline]
Izikki, M., Raffestin, B., Klar, J., Hatzelmann, A., Marx, D., Tenor, H., Zadigue, P., Adnot, S., Eddahibi, S.
(2009). Effects of Roflumilast, a Phosphodiesterase-4 Inhibitor, on Hypoxia- and Monocrotaline-Induced Pulmonary Hypertension in Rats. J. Pharmacol. Exp. Ther.
330: 54-62
[Abstract][Full Text]
Ghofrani, H. A., Barst, R. J., Benza, R. L., Champion, H. C., Fagan, K. A., Grimminger, F., Humbert, M., Simonneau, G., Stewart, D. J., Ventura, C., Rubin, L. J.
(2009). Future perspectives for the treatment of pulmonary arterial hypertension.. J Am Coll Cardiol
54: S108-S117
[Abstract][Full Text]
Galie, N., Brundage, B. H., Ghofrani, H. A., Oudiz, R. J., Simonneau, G., Safdar, Z., Shapiro, S., White, R. J., Chan, M., Beardsworth, A., Frumkin, L., Barst, R. J., on behalf of the Pulmonary Arterial Hypertension a,
(2009). Tadalafil Therapy for Pulmonary Arterial Hypertension. Circulation
119: 2894-2903
[Abstract][Full Text]
Laumanns, I. P., Fink, L., Wilhelm, J., Wolff, J.-C., Mitnacht-Kraus, R., Graef-Hoechst, S., Stein, M. M., Bohle, R. M., Klepetko, W., Hoda, M. A. R., Schermuly, R. T., Grimminger, F., Seeger, W., Voswinckel, R.
(2009). The Noncanonical WNT Pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension. Am. J. Respir. Cell Mol. Bio.
40: 683-691
[Abstract][Full Text]
Barnes, P. J., Celli, B. R.
(2009). Systemic manifestations and comorbidities of COPD. Eur Respir J
33: 1165-1185
[Abstract][Full Text]
PELED, N., SHITRIT, D., FOX, B. D., SHLOMI, D., AMITAL, A., BENDAYAN, D., KRAMER, M. R.
(2009). Peripheral Arterial Stiffness and Endothelial Dysfunction in Idiopathic and Scleroderma Associated Pulmonary Arterial Hypertension. The Journal of Rheumatology
36: 970-975
[Abstract][Full Text]
Ghofrani, H. A., Grimminger, F.
(2009). Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. ERR
18: 35-41
[Abstract][Full Text]
McGoon, M. D., Kane, G. C.
(2009). Pulmonary Hypertension: Diagnosis and Management. Mayo Clin Proc.
84: 191-207
[Abstract][Full Text]
Davies, R. J., Morrell, N. W.
(2008). Molecular Mechanisms of Pulmonary Arterial Hypertension: Role of Mutations in the Bone Morphogenetic Protein Type II Receptor. Chest
134: 1271-1277
[Abstract][Full Text]
Aytekin, M., Comhair, S. A. A., de la Motte, C., Bandyopadhyay, S. K., Farver, C. F., Hascall, V. C., Erzurum, S. C., Dweik, R. A.
(2008). High levels of hyaluronan in idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.
295: L789-L799
[Abstract][Full Text]
Jennings, B. L., Donald, J. A.
(2008). Neurally-derived nitric oxide regulates vascular tone in pulmonary and cutaneous arteries of the toad, Bufo marinus. Am. J. Physiol. Regul. Integr. Comp. Physiol.
295: R1640-R1646
[Abstract][Full Text]
Mukhopadhyay, S., Lee, J., Sehgal, P. B.
(2008). Depletion of the ATPase NSF from Golgi membranes with hypo-S-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole. Am. J. Physiol. Heart Circ. Physiol.
295: H1943-H1955
[Abstract][Full Text]
Peinado, V. I., Pizarro, S., Barbera, J. A.
(2008). Pulmonary Vascular Involvement in COPD. Chest
134: 808-814
[Abstract][Full Text]
Schermuly, R. T., Stasch, J-P., Pullamsetti, S. S., Middendorff, R., Muller, D., Schluter, K-D., Dingendorf, A., Hackemack, S., Kolosionek, E., Kaulen, C., Dumitrascu, R., Weissmann, N., Mittendorf, J., Klepetko, W., Seeger, W., Ghofrani, H. A., Grimminger, F.
(2008). Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J
32: 881-891
[Abstract][Full Text]
Kumar, S., Sun, X., Wedgwood, S., Black, S. M.
(2008). Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity. Am. J. Physiol. Lung Cell. Mol. Physiol.
295: L370-L377
[Abstract][Full Text]
Frey, R., Muck, W., Unger, S., Artmeier-Brandt, U., Weimann, G., Wensing, G.
(2008). Single-Dose Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Stimulator BAY 63-2521: An Ascending-Dose Study in Healthy Male Volunteers. J Clin Pharmacol
48: 926-934
[Abstract][Full Text]
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]
Peyter, A.-C., Muehlethaler, V., Liaudet, L., Marino, M., Di Bernardo, S., Diaceri, G., Tolsa, J.-F.
(2008). Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice. Am. J. Physiol. Lung Cell. Mol. Physiol.
295: L201-L213
[Abstract][Full Text]
Amabile, N., Heiss, C., Real, W. M., Minasi, P., McGlothlin, D., Rame, E. J., Grossman, W., De Marco, T., Yeghiazarians, Y.
(2008). Circulating Endothelial Microparticle Levels Predict Hemodynamic Severity of Pulmonary Hypertension. Am. J. Respir. Crit. Care Med.
177: 1268-1275
[Abstract][Full Text]
Falk, J. A., Kadiev, S., Criner, G. J., Scharf, S. M., Minai, O. A., Diaz, P.
(2008). Cardiac Disease in Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc
5: 543-548
[Abstract][Full Text]
Wright, J. L., Churg, A.
(2008). Short-term exposure to cigarette smoke induces endothelial dysfunction in small intrapulmonary arteries: analysis using guinea pig precision cut lung slices. J. Appl. Physiol.
104: 1462-1469
[Abstract][Full Text]
Demchenko, I. T., Atochin, D. N., Gutsaeva, D. R., Godfrey, R. R., Huang, P. L., Piantadosi, C. A., Allen, B. W.
(2008). Contributions of nitric oxide synthase isoforms to pulmonary oxygen toxicity, local vs. mediated effects. Am. J. Physiol. Lung Cell. Mol. Physiol.
294: L984-L990
[Abstract][Full Text]
Matouk, C. C., Marsden, P. A.
(2008). Epigenetic Regulation of Vascular Endothelial Gene Expression. Circ. Res.
102: 873-887
[Abstract][Full Text]
Zhang, F., Wu, S., Lu, X., Wang, M., Liu, M.
(2008). Gene Transfer of Endothelial Nitric Oxide Synthase Attenuates Flow-Induced Pulmonary Hypertension in Rabbits. Ann. Thorac. Surg.
85: 581-585
[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]
Sharma, S., Sud, N., Wiseman, D. A., Carter, A. L., Kumar, S., Hou, Y., Rau, T., Wilham, J., Harmon, C., Oishi, P., Fineman, J. R., Black, S. M.
(2008). Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.
294: L46-L56
[Abstract][Full Text]
Frank, D. B., Lowery, J., Anderson, L., Brink, M., Reese, J., de Caestecker, M.
(2008). Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am. J. Physiol. Lung Cell. Mol. Physiol.
294: L98-L109
[Abstract][Full Text]
Skoro-Sajer, N., Mittermayer, F., Panzenboeck, A., Bonderman, D., Sadushi, R., Hitsch, R., Jakowitsch, J., Klepetko, W., Kneussl, M. P., Wolzt, M., Lang, I. M.
(2007). Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension. Am. J. Respir. Crit. Care Med.
176: 1154-1160
[Abstract][Full Text]
Park, J.-Y., Farrance, I. K. G., Fenty, N. M., Hagberg, J. M., Roth, S. M., Mosser, D. M., Wang, M. Q., Jo, H., Okazaki, T., Brant, S. R., Brown, M. D.
(2007). NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives. Am. J. Physiol. Heart Circ. Physiol.
293: H2320-H2327
[Abstract][Full Text]
Lakshminrusimha, S., Wiseman, D., Black, S. M., Russell, J. A., Gugino, S. F., Oishi, P., Steinhorn, R. H., Fineman, J. R.
(2007). The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow. Am. J. Physiol. Heart Circ. Physiol.
293: H1491-H1497
[Abstract][Full Text]
Malerba, M., Radaeli, A., Ragnoli, B., Airo', P., Corradi, M., Ponticiello, A., Zambruni, A., Grassi, V.
(2007). Exhaled Nitric Oxide Levels in Systemic Sclerosis With and Without Pulmonary Involvement. Chest
132: 575-580
[Abstract][Full Text]
Tiev, K. P., Cabane, J., Aubourg, F., Kettaneh, A., Ziani, M., Mouthon, L., Duong-Quy, S., Fajac, I., Guillevin, L., Dinh-Xuan, A. T.
(2007). Severity of scleroderma lung disease is related to alveolar concentration of nitric oxide. Eur Respir J
30: 26-30
[Abstract][Full Text]
Sehgal, P. B., Mukhopadhyay, S.
(2007). Dysfunctional Intracellular Trafficking in the Pathobiology of Pulmonary Arterial Hypertension. Am. J. Respir. Cell Mol. Bio.
37: 31-37
[Abstract][Full Text]
Sehgal, P. B., Mukhopadhyay, S.
(2007). Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?. Am. J. Physiol. Heart Circ. Physiol.
293: H77-H85
[Abstract][Full Text]
Jain, S., Ventura, H., deBoisblanc, B.
(2007). Pathophysiology of Pulmonary Arterial Hypertension. SEMIN CARDIOTHORAC VASC ANESTH
11: 104-109
[Abstract]
Sasaki, A., Doi, S., Mizutani, S., Azuma, H.
(2007). Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats. Am. J. Physiol. Lung Cell. Mol. Physiol.
292: L1480-L1487
[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]
Xu, W., Koeck, T., Lara, A. R., Neumann, D., DiFilippo, F. P., Koo, M., Janocha, A. J., Masri, F. A., Arroliga, A. C., Jennings, C., Dweik, R. A., Tuder, R. M., Stuehr, D. J., Erzurum, S. C.
(2007). Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl. Acad. Sci. USA
104: 1342-1347
[Abstract][Full Text]
Shim, J. K., Choi, Y. S., Oh, Y. J., Kim, D. H., Hong, Y. W., Kwak, Y. L.
(2006). Effect of oral sildenafil citrate on intraoperative hemodynamics in patients with pulmonary hypertension undergoing valvular heart surgery. J. Thorac. Cardiovasc. Surg.
132: 1420-1425
[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]
Steiner, M. K., Preston, I. R., Klinger, J. R., Criner, G. J., Waxman, A. B., Farber, H. W., Hill, N. S.
(2006). Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study.. Chest
130: 1471-1480
[Abstract][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]
Zuckerbraun, B. S., Chin, B. Y., Wegiel, B., Billiar, T. R., Czsimadia, E., Rao, J., Shimoda, L., Ifedigbo, E., Kanno, S., Otterbein, L. E.
(2006). Carbon monoxide reverses established pulmonary hypertension. JEM
203: 2109-2119
[Abstract][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]
Johnson, S. R., Granton, J. T., Mehta, S.
(2006). Thrombotic Arteriopathy and Anticoagulation in Pulmonary Hypertension.. Chest
130: 545-552
[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]
Grobe, A. C., Wells, S. M., Benavidez, E., Oishi, P., Azakie, A., Fineman, J. R., Black, S. M.
(2006). Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase. Am. J. Physiol. Lung Cell. Mol. Physiol.
290: L1069-L1077
[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]
Hoeper, M. M., Rubin, L. J.
(2006). Update in pulmonary hypertension 2005.. Am. J. Respir. Crit. Care Med.
173: 499-505
[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]
Griffiths, M. J.D., Evans, T. W.
(2005). Inhaled Nitric Oxide Therapy in Adults. NEJM
353: 2683-2695
[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]
Galie, N., Ghofrani, H. A., Torbicki, A., Barst, R. J., Rubin, L. J., Badesch, D., Fleming, T., Parpia, T., Burgess, G., Branzi, A., Grimminger, F., Kurzyna, M., Simonneau, G., the Sildenafil Use in Pulmonary Arterial Hypertens,
(2005). Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. NEJM
353: 2148-2157
[Abstract][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]
Oechslin, E., Kiowski, W., Schindler, R., Bernheim, A., Julius, B., Brunner-La Rocca, H. P.
(2005). Systemic Endothelial Dysfunction in Adults With Cyanotic Congenital Heart Disease. Circulation
112: 1106-1112
[Abstract][Full Text]
Girgis, R. E., Champion, H. C., Diette, G. B., Johns, R. A., Permutt, S., Sylvester, J. T.
(2005). Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension: Response to Bosentan Therapy. Am. J. Respir. Crit. Care Med.
172: 352-357
[Abstract][Full Text]
Baker, S. E, Hockman, R. H.
(2005). Inhaled Iloprost in Pulmonary Arterial Hypertension. The Annals of Pharmacotherapy
39: 1265-1274
[Abstract][Full Text]
Nandi, M., Miller, A., Stidwill, R., Jacques, T. S., Lam, A. A.J., Haworth, S., Heales, S., Vallance, P.
(2005). Pulmonary Hypertension in a GTP-Cyclohydrolase 1-Deficient Mouse. Circulation
111: 2086-2090
[Abstract][Full Text]
Vonk-Noordegraaf, A., van Wolferen, S. A., Marcus, J. T., Boonstra, A., Postmus, P. E., Peeters, J. W. L., Peacock, A. J.
(2005). Noninvasive assessment and monitoring of the pulmonary circulation. Eur Respir J
25: 758-766
[Abstract][Full Text]
Yuan, J. X.-J., Rubin, L. J.
(2005). Pathogenesis of Pulmonary Arterial Hypertension: The Need for Multiple Hits. Circulation
111: 534-538
[Full Text]
Baraldi, E., Bonetto, G., Zacchello, F., Filippone, M.
(2005). Low Exhaled Nitric Oxide in School-Age Children with Bronchopulmonary Dysplasia and Airflow Limitation. Am. J. Respir. Crit. Care Med.
171: 68-72
[Abstract][Full Text]
Guazzi, M., Tumminello, G., Di Marco, F., Fiorentini, C., Guazzi, M. D.
(2004). The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol
44: 2339-2348
[Abstract][Full Text]
Farber, H. W., Loscalzo, J.
(2004). Pulmonary Arterial Hypertension. NEJM
351: 1655-1665
[Full Text]
Humbert, M., Sitbon, O., Simonneau, G.
(2004). Treatment of Pulmonary Arterial Hypertension. NEJM
351: 1425-1436
[Full Text]
Humbert, M., Barst, R.J., Robbins, I.M., Channick, R.N., Galie, N., Boonstra, A., Rubin, L.J., Horn, E.M., Manes, A., Simonneau, G.
(2004). Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J
24: 353-359
[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]
Ricciardolo, F. L. M., Sterk, P. J., Gaston, B., Folkerts, G.
(2004). Nitric Oxide in Health and Disease of the Respiratory System. Physiol. Rev.
84: 731-765
[Abstract][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]
Fike, C. D., Aschner, J. L., Zhang, Y., Kaplowitz, M. R.
(2004). Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn piglets. Am. J. Physiol. Lung Cell. Mol. Physiol.
286: L1244-L1254
[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]
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]
Fantozzi, I., Zhang, S., Platoshyn, O., Remillard, C. V., Cowling, R. T., Yuan, J. X.-J.
(2003). Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
285: L1233-L1245
[Abstract][Full Text]
Blanpain, C., Le Poul, E., Parma, J., Knoop, C., Detheux, M., Parmentier, M., Vassart, G., Abramowicz, M. J
(2003). Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res
60: 518-528
[Abstract][Full Text]
Saiki, Y., Nitta, Y., Tsuru, Y., Tabayashi, K.
(2003). Successful weaning from inhaled nitric oxide using dipyridamole. Eur. J. Cardiothorac. Surg.
24: 837-839
[Abstract][Full Text]
Sauzeau, V., Rolli-Derkinderen, M., Lehoux, S., Loirand, G., Pacaud, P.
(2003). Sildenafil Prevents Change in RhoA Expression Induced by Chronic Hypoxia in Rat Pulmonary Artery. Circ. Res.
93: 630-637
[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]
Cooke, J. P.
(2003). A Novel Mechanism for Pulmonary Arterial Hypertension?. Circulation
108: 1420-1421
[Full Text]
Schulze-Neick, I., Hartenstein, P., Li, J., Stiller, B., Nagdyman, N., Hubler, M., Butrous, G., Petros, A., Lange, P., Redington, A. N.
(2003). Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease. Circulation
108: II-167-173
[Abstract][Full Text]
Lowson, S. M.
(2003). Nitric Oxide Signaling and Clinical Alternatives to Nitric Oxide. SEMIN CARDIOTHORAC VASC ANESTH
7: 239-252
[Abstract]
Kao, P. N., Faul, J. L.
(2003). Emerging therapies for pulmonary hypertension: Striving for efficacy and safety. J Am Coll Cardiol
41: 2126-2129
[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]
Mehta, S.
(2003). Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required. Chest
123: 989-992
[Full Text]
Rondelet, B., Kerbaul, F., Motte, S., van Beneden, R., Remmelink, M., Brimioulle, S., McEntee, K., Wauthy, P., Salmon, I., Ketelslegers, J.-M., Naeije, R.
(2003). Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension. Circulation
107: 1329-1335
[Abstract][Full Text]
Castro, O., Hoque, M., Brown, B. D.
(2003). Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood
101: 1257-1261
[Abstract][Full Text]
Blumberg, F. C., Wolf, K., Arzt, M., Lorenz, C., Riegger, G. A. J., Pfeifer, M.
(2003). Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs. J. Appl. Physiol.
94: 446-452
[Abstract][Full Text]
Ricciardolo, F L M
(2003). Multiple roles of nitric oxide in the airways. Thorax
58: 175-182
[Abstract][Full Text]
Ovadia, B., Reinhartz, O., Fitzgerald, R., Bekker, J. M., Johengen, M. J., Azakie, A., Thelitz, S., Black, S. M., Fineman, J. R.
(2003). Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow. Am. J. Physiol. Heart Circ. Physiol.
284: H480-H490
[Abstract][Full Text]
Hubloue, I., Biarent, D., Kafi, S. A., Bejjani, G., Kerbaul, F., Naeije, R., Leeman, M.
(2003). Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction. Eur Respir J
21: 19-24
[Abstract][Full Text]
Previous
500 µm in diameter) and large (300 to 500 µm), medium-sized (>100 to <300 µm), and small (
100 µm) muscular pulmonary arteries. The level of immunostaining was significantly higher in the control group (group 3) than in the patients with pulmonary hypertension (P<0.001 for all artery types). When group 2 was compared with group 1, P = 0.014 for medium-sized pulmonary arteries and P = 0.009 for small pulmonary arteries. Immunohistochemical grades were determined semiquantitatively, as described elsewhere.