RESUMEN
BACKGROUND: The bronchial epithelium and underlying reticular basement membrane (RBM) have a close spatial and functional inter-relationship and are considered an epithelial-mesenchymal trophic unit (EMTU). An understanding of RBM development is critical to understanding the extent and time of appearance of its abnormal thickening that is characteristic of asthma. METHODS: RBM thickness and epithelial height were determined in histological sections of cartilaginous bronchi obtained postmortem from 47 preterm babies and infants (median age 40 weeks gestation (22 weeks gestation-8 months)), 40 children (2 years (1 month-17 years)) and 23 adults (44 (17-90) years) who had died from non-respiratory causes, and had no history of asthma. RESULTS: The RBM was visible by light microscopy at 30 weeks gestation. RBM thickness increased in successive age groups in childhood; in infants (r=0.63, p<0.001) and in children between 1 month and 17 years (r=0.82, p<0.001). After 18 years, RBM thickness decreased with increasing age (r=-0.42, p<0.05). Epithelial height showed a similar relationship with age, a positive relationship from preterm to 17 years (r=0.50, p<0.001) and a negative relationship in adulthood (r=-0.84, p<0.0001). There was a direct relationship between epithelial height and RBM thickness (r=0.6, p<0.001). CONCLUSIONS: The RBM in these subjects was microscopically identifiable by 30 weeks gestation. It thickened during childhood and adolescence. In adults, there was either no relationship with age, or a slow reduction in thickness in older age. Developmental changes of RBM thickness were accompanied by similar changes in epithelial height, supporting the close relationship between RBM and epithelium within the EMTU.
Asunto(s)
Bronquios/crecimiento & desarrollo , Mucosa Respiratoria/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Membrana Basal/anatomía & histología , Membrana Basal/crecimiento & desarrollo , Estatura/fisiología , Peso Corporal/fisiología , Bronquios/anatomía & histología , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Persona de Mediana Edad , Mucosa Respiratoria/anatomía & histología , Caracteres Sexuales , Adulto JovenRESUMEN
INTRODUCTION: Objective risk stratifiers are required to assess need for escalation of medical therapy or listing for transplantation in children with pulmonary arterial hypertension (PAH). We aimed to assess whether heart rate variability (HRV) predicts outcome in children with severe PAH. PATIENTS AND METHODS: Parameters of HRV [SDNN = standard deviation of normal-to-normal intervals, SDANN = standard deviation of mean values for normal-to-normal intervals over 5 min, and RMSSD = square root of the mean square differences of successive RR intervals] were determined from Holter electrocardiograms of 47 patients (27 male; mean age 11.4+/-5.5 years) with PAH (idiopathic PAH n=21; associated PAH n=26). HRV was assessed in relation to WHO Functional Class, six-minute-walk-test, echocardiographic and haemodynamic data, and as a predictor of death or lung transplantation. RESULTS: The mean follow-up period was 19+/-11.5 months (1.8-49.1 months). Ten patients died and 7 underwent transplantation and these children had significantly lower values of HRV [SDANN (70.7+/-30.9 vs. 119.2+/-57.2), SDNN (79.5+/-30.5 vs. 129.9+/-63.6), and RMSSD (22.+/-11.7 vs. 47.7+/-34.5); p<0.001 for all]. On univariate Cox-proportional-hazards analysis all parameters of HRV predicted death or transplantation (p<0.05). SDANN and SDNN were also predictive of mortality alone (p<0.05). On bivariate analysis SDANN and SDNN predicted outcome independently of functional status, syncope, right ventricular function, and haemodynamic parameters. CONCLUSIONS: HRV is a useful, non-invasive means of predicting a poor outcome and hence need to escalate therapy in children with PAH.
Asunto(s)
Frecuencia Cardíaca/fisiología , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Trasplante de Corazón/mortalidad , Trasplante de Corazón/tendencias , Humanos , Hipertensión Pulmonar/mortalidad , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del TratamientoRESUMEN
High altitude long-term hypoxia (LTH) in the fetus may result in pulmonary vascular smooth muscle cell (PVSMC) proliferation and pulmonary vascular remodeling. Our objective was to determine if epidermal growth factor receptor (EGFR) is involved in hypoxia induced PVSMC proliferation or in pulmonary vascular remodeling in ovine fetuses exposed to high altitude LTH. Fetuses of pregnant ewes that were held at 3820-m altitude from *30 to 140 days (LTH) gestation and sea level control pregnant ewes were delivered near term. Morphometric analyses and immunohistochemistry were done on fetal lung sections. Pulmonary arteries of LTH fetuses exhibited medial wall thickening and distal muscularization. Western blot analyses done on protein isolated from pulmonary arteries demonstrated an upregulation of EGFR. This upregulation was attributed in part to PVSMC in the medial wall by immunohistochemistry.Proliferation of fetal ovine PVSMC after 24 h of hypoxia (2% O2) was attenuated by inhibition of EGFR with 250 nmol tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), a specific EGFR protein tyrosine kinase inhibitor, when measured by [3H]-thymidine incorporation. Our data indicate that EGFR plays a role in fetal ovine pulmonary vascular remodeling following long-term fetal hypoxia and that inhibition of EGFR signaling may ameliorate hypoxia-induced pulmonary vascular remodeling.
Asunto(s)
Altitud , Receptores ErbB/metabolismo , Hipoxia Fetal/fisiopatología , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/fisiopatología , Actinas/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Receptores ErbB/antagonistas & inhibidores , Femenino , Hipoxia Fetal/etiología , Hipoxia Fetal/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Embarazo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Quinazolinas , Oveja Doméstica , Tirfostinos/farmacologíaRESUMEN
BACKGROUND: We aimed to assess whether levels of B-type natriuretic peptide (BNP)--an established marker of ventricular dysfunction--relate to functional status and outcome in children with idiopathic and associated pulmonary hypertension (PH). METHODS AND RESULTS: BNP was measured in 50 children with PHT aged 8.4 +/- 5.1 years, all receiving PH specific therapies. Twenty-seven patients were diagnosed with idiopathic PH (IPAH), while 23 patients had associated PH [congenital heart disease (n = 17), lung disease (n = 4), other (n = 2)]. Functional status, six-minute walk test, echocardiographic and haemodynamic data were assessed. Mean BNP value was 143.5 +/- 236.2 pg/ml (range <5-1250). BNP correlated with Functional Class II, III, and IV (50.8 +/- 61.3, 196.9 +/- 291.2 and 280.0 +/- 276.5 respectively; p = 0.01), with echocardiographic assessment of right ventricular function (p < 0.01), hypertrophy (p < 0.01) and dilatation (p < 0.01). In IPAH BNP correlated with pulmonary arterial pressure and, on inhaled nitric oxide also with vascular resistance. During a mean follow-up of 14.0 +/- 7.5 months seven patients died, five underwent transplantation and two were listed for transplantation. Using ROC analysis, a BNP value >130 pg/ml predicted death or need for transplantation (p < 0.04). However, six children who died or were transplanted had a BNP value lower than this. CONCLUSION: BNP correlated positively with functional status in children with pulmonary hypertension, but had limited sensitivity (57%) for predicting death or need for transplantation.
Asunto(s)
Biomarcadores/sangre , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/mortalidad , Péptido Natriurético Encefálico/sangre , Adolescente , Niño , Preescolar , Femenino , Humanos , Hipertensión Pulmonar/cirugía , Lactante , Estimación de Kaplan-Meier , Trasplante de Pulmón , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Sensibilidad y EspecificidadRESUMEN
Arteriovenous malformations (AVMs) are direct connections between arteries and veins associated with loss of the intervening capillary bed. In the lungs, pulmonary AVMs can result in right to left shunts and severe cyanosis and dyspnoea. However, the cellular and molecular mechanisms underlying AVM formation are poorly understood. One important clue comes from the fact that pulmonary AVMs frequently occur in the familial disease hereditary haemorrhagic telangiectasia (HHT), which is associated with mutations in one of two receptors involved in transforming growth factor-beta family signalling, either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). To elucidate the potential link between ENG or ACVRL1 deficiency and AVM formation in HHT, we performed a comprehensive study of Acvrl1 and Eng expression in wild-type and Eng-deficient (Eng+/-) mouse lungs using a combination of immunohistochemistry and RT-PCR from laser-microdissected arteries, veins and capillaries. We found that Eng and Acvrl1 have distinct expression profiles in the pulmonary vasculature and are only co-expressed in the distal (pre-capillary) arteries, distal veins and capillaries, consistent with the tendency for pulmonary AVMs to form in the distal pulmonary vessels in HHT. Downstream pSmad1/5/8 activity was found in the distal arteries and was specifically reduced in Eng+/- mice, consistent with previous in vitro data showing that Eng promotes Acvrl1-mediated Smad1/5/8 phosphorylation. Eng was more widely expressed than Acvrl1 in the lungs, as Eng alone was found in pulmonary veins, potentially explaining the increased frequency of AVMs in HHT1 patients. Furthermore, the association of ACVRL1 mutations with a second vascular disease, familial pulmonary artery hypertension, underlines the importance of ACVRL1 expression in the distal arteries that are affected in this disorder.
Asunto(s)
Receptores de Activinas Tipo I/deficiencia , Malformaciones Arteriovenosas/etiología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Pulmón/irrigación sanguínea , Telangiectasia Hemorrágica Hereditaria/complicaciones , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Animales , Capilares/metabolismo , Endoglina , Hipertensión Pulmonar/genética , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones , Ratones Mutantes , Mutación , Arteria Pulmonar/metabolismo , Venas Pulmonares/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Platelet-activating factor (PAF) is implicated in pathogenesis of chronic hypoxia-induced pulmonary hypertension in some animal models and in neonates. Effects of chronic hypoxia on PAF receptor (PAF-R) system in fetal pulmonary vasculature are unknown. We investigated the effect of chronic high altitude hypoxia (HAH) in fetal lambs [pregnant ewes were kept at 3,801 m (12,470 ft) altitude from approximately 35 to 145 days gestation] on PAF-R-mediated effects in the pulmonary vasculature. Age-matched controls were kept at sea level. Intrapulmonary arteries were isolated, and smooth muscle cells (SMC-PA) were cultured from HAH and control fetuses. To determine presence of pulmonary vascular remodeling, lung tissue sections were subjected to morphometric analysis. Percentage medial wall thickness was significantly increased (P < 0.05) in arteries at all levels in the HAH lambs. PAF-R protein expression studied by immunocytochemistry and Western blot analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (femtomoles per 10(6) cells) in HAH SMC-PA was 90.3 +/- 4.08 and 66% greater than 54.3 +/- 4.9 in control SMC-PA. Pulmonary arteries from HAH fetuses synthesized >3-fold PAF than vessels from controls. Compared with controls SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10 nM PAF, respectively. Our data demonstrate that exposure of ovine fetuses to HAH will result in significant upregulation of PAF synthesis, PAF-R expression, and PAF-R-mediated effects in pulmonary arteries. These findings suggest that increased PAF-R protein expression and increased PAF binding contribute to pulmonary vascular remodeling in these animals and may predispose them to persistent pulmonary hypertension after birth.
Asunto(s)
Mal de Altura/fisiopatología , Feto/fisiopatología , Hipoxia/fisiopatología , Factor de Activación Plaquetaria/metabolismo , Arteria Pulmonar/fisiopatología , Animales , Peso al Nacer/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Femenino , Feto/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Factor de Activación Plaquetaria/biosíntesis , Factor de Activación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria/metabolismo , Embarazo , Arteria Pulmonar/patología , Receptores Acoplados a Proteínas G/metabolismo , Oveja DomésticaRESUMEN
At birth, with the first breath, pulmonary vessels undergo profound adaptive processes. A failure in the ability of pulmonary vessels to adapt at birth results in persistent pulmonary hypertension of the new born. The mechanisms regulating pulmonary adaptation at birth are still unclear. Progress in this area is slow, not least because genetically modified mice have not yet been used to address questions in this area of research, principally because pulmonary vessels in new born mice are very small making the study of dilator response in vitro difficult. In the current study we have used precision cut lung slices to characterise the functional vasomotor changes in lung vessels of new born mice (1-4 days old), 8-15 day old mice or adult mice. The internal luminal area of pulmonary artery and airways was measured digitally. Vasoconstriction and vasodilatation were expressed as the percentage change in internal luminal area compared with the control area. The thromboxane A(2) mimetic U-46619 (3x10(-7) M) caused a significant vasoconstriction in vessels of all groups. However, acetylcholine (3x10(-5) M) induced arterial dilation only in the 8-15 days, and adult groups. By contrast, sodium nitroprusside, which acts independently of the endothelium, was an effective vasodilator in lung vessels from neonates. These data are the first to characterise the development of endothelium dependent vasodilatation in lung after birth in mice. This approach can be used with genetically modified mice, which is important to further our understanding of the physiology in this area.
Asunto(s)
Animales Recién Nacidos/fisiología , Endotelio Vascular/fisiología , Circulación Pulmonar/fisiología , Vasodilatación/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Acetilcolina/farmacología , Envejecimiento/fisiología , Animales , Procesamiento de Imagen Asistido por Computador , Técnicas In Vitro , Ratones , Músculo Liso Vascular/fisiología , Nitroprusiato/farmacología , Arteria Pulmonar/citología , Arteria Pulmonar/fisiología , Venas Pulmonares/citología , Venas Pulmonares/fisiología , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
The response of pulmonary arteries to endothelin-1 (ET-1) changes with age in normal pigs and is abnormal in pulmonary hypertension. The purpose of this study was to determine if the same is true of the pulmonary veins. We studied the wall structure and functional response to ET-1 in pulmonary veins from normal pigs from fetal life to adulthood and from pigs subjected to chronic hypobaric hypoxia either from birth for 3 days or from 3 to 6 days of age. In isolated normal veins, the contractile response decreased by 40% between late fetal life and 14 days of age with a concomitant twofold increase in endothelium-dependent relaxant response. The ET(A) antagonist BQ-123 reduced the contractile response significantly more in newborn than older animals, whereas the ET-B antagonist BQ-788 had no effect in fetal animals and maximally increased contraction at 14 days of age. Hypoxic exposure significantly increased pulmonary vein smooth muscle area and contractile response to ET-1. The relaxation response was impaired following hypoxic exposure from birth but not from 3 to 6 days of age. The ET(A) antagonist BQ-123 decreased contractile and increased dilator responses significantly more than in age-matched controls. Thus pulmonary veins show age-related changes similar to those seen in the pulmonary arteries with a decrease in ET(A)-mediated contractile and increase in ET-B-mediated relaxant response with age. Contractile response was also increased in hypoxia as in the arteries. This study suggests that pulmonary veins are involved in postnatal adaptation and the pathogenesis of pulmonary hypertension.
Asunto(s)
Envejecimiento/fisiología , Endotelina-1/farmacología , Hipoxia/fisiopatología , Venas Pulmonares/efectos de los fármacos , Venas Pulmonares/fisiología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Feto , Músculo Liso Vascular/crecimiento & desarrollo , Músculo Liso Vascular/fisiología , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/crecimiento & desarrollo , Arteria Pulmonar/fisiología , Arteria Pulmonar/fisiopatología , Venas Pulmonares/patología , Venas Pulmonares/fisiopatología , PorcinosRESUMEN
INTRODUCTION: Severe, sustained pulmonary arterial hypertension leads to a progressive reduction in exercise capacity, right heart failure and death. Use of intravenous epoprostenol has improved survival in adults, but data are limited in children. PATIENTS AND METHODS: This study included all 39 children treated with continuous intravenous epoprostenol since November 1997 at Great Ormond Street Hospital for Children (London, UK). Patients were aged 4 months to 17 years (median 5.4 years) at the onset of therapy. The male:female ratio was 1:1.3. 25 patients had idiopathic pulmonary arterial hypertension and 14 had pulmonary arterial hypertension associated with congenital heart disease, connective tissue disease, chronic lung disease or HIV. All were in WHO functional class III and IV. Mean pulmonary arterial pressure (SD) was 59 (17) mmHg and mean pulmonary vascular resistance was 23.3 (11.6) units x m(2). Patients were assessed regularly (2-3 monthly intervals) by physical examination, electrocardiography, transthoracic echocardiography and a 6-min walk test, when practicable. RESULTS: The mean duration of follow-up was 27 (21) months. 7 patients died and 8 underwent transplantation. Cumulative survival at 1, 2 and 3 years was 94, 90 and 84%. The 6-min walking distance improved by a mean of 77 m (p<0.003). WHO functional class improved during the first year (p<0.001) and improvement was maintained for up to 3 years. Weight improved significantly from a baseline z score of -1.55 (1.74) to -1.16 (1.8) (p<0.03). 28 children had additional oral specific therapy. Hickman line changes were 0.33/patient year. CONCLUSIONS: Epoprostenol therapy improved survival, WHO functional class, exercise tolerance and ability to thrive in children with severe pulmonary arterial hypertension. Epoprostenol represents an effective and feasible therapy even in young children.
Asunto(s)
Antihipertensivos/uso terapéutico , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Niño , Preescolar , Tolerancia al Ejercicio , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Lactante , Infusiones Intravenosas , Estimación de Kaplan-Meier , MasculinoRESUMEN
Persistent pulmonary hypertension of the newborn is a life-threatening condition in which half of infants fail to respond to inhaled nitric oxide. Development of new therapeutic pathways is crucial. The adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)) may be important in this condition. Concentration-response curves to the K(ATP) channel opener (SR47063) were performed in isolated pulmonary arterial rings from normal newborn lambs (n = 8) and pulmonary hypertensive lambs (n = 7) induced by intrauterine ductus arteriosus ligation. The effect of endothelin (ET) receptor antagonists was analyzed. Expression in the lung of the subunit Kir 6.1 of the K(ATP) channel and of ET were analyzed using Western blot and immunohistochemistry. Relaxation to SR47063 was increased in ligated animals compared with the control group. Endothelium removal enhanced this response in ligated animals (p < 0.01). The inhibitory effect of the endothelium was reversed by the Endothelin-A receptor (ET-A) antagonist BQ 123 (p < 0.01). Kir 6.1 expression was not different between groups and that of endothelin-1 (ET-1) was increased threefold in ligated animals (p = 0.007). In pulmonary hypertensive lambs, vasodilation to K(ATP) channel openers was enhanced compared with controls and further potentiated by ET-A blockade. These data might lead to new therapeutic strategies in infants with pulmonary hypertension.
Asunto(s)
Endotelina-1/metabolismo , Síndrome de Circulación Fetal Persistente/metabolismo , Canales de Potasio/metabolismo , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Ventrículos Cardíacos/anomalías , Humanos , Recién Nacido , OvinosRESUMEN
Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrine-induced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries.
Asunto(s)
Bronquios/fisiología , Endotelina-1/fisiología , Hipertensión Pulmonar/fisiopatología , Hipoxia/fisiopatología , Norepinefrina/fisiología , Arteria Pulmonar/fisiología , Animales , Animales Recién Nacidos/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Bronquios/irrigación sanguínea , Bronquios/efectos de los fármacos , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Arteria Pulmonar/efectos de los fármacos , Recuperación de la Función/fisiología , Porcinos , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
In neonatal pulmonary hypertension, the pulmonary arteries fail to adapt to extrauterine life and remain thick walled. In a previous study on normal neonatal resistance arteries, perfusion myography and confocal microscopy showed that responses to agonist stimulation were related to wall structure. We hypothesized that in hypertensive resistance pulmonary arteries, an enhanced response to contractile and relaxant agonist stimulation would be associated with an increased wall thickness and abnormal postnatal cytoskeletal remodeling of smooth muscle cells (SMC). Pulmonary arteries (110-140 microm external diameter) from normal piglets and those exposed to chronic hypobaric hypoxia from birth or from 3 d of age were mounted on a perfusion myograph. Lumen diameter and SMC nuclear positions were tracked after addition of KCl, the thromboxane mimetic U46619, and bradykinin. After fixation in situ, SMC dimensions were measured using confocal and electron microscopy. In all hypertensive animals, wall thickness and SMC density were increased and SMC length/width ratio decreased. After hypoxic exposure for 3 d, arteries from animals exposed from birth showed a greater and faster contractile response than controls, but arteries from piglets first exposed at 3 d of age did not, though both showed similar structural appearance. Increase of exposure to 11 d elicited an enhanced response and further cytoskeletal remodeling. All vessels relaxed fully to bradykinin. SMC remodeling and reactivity appear to be influenced by the age at onset and the duration of the hypoxic insult.
Asunto(s)
Hipertensión Pulmonar/patología , Arteria Pulmonar/anatomía & histología , Resistencia Vascular , Animales , Microscopía Confocal , Microscopía Electrónica de Transmisión , Músculo Liso/citología , Músculo Liso/ultraestructura , Arteria Pulmonar/patología , PorcinosRESUMEN
Nitric oxide is involved in development and postnatal adaptation of the pulmonary circulation. This study aimed to determine whether genetic deletion of nitric oxide synthase (NOS) would lead to maldevelopment of the pulmonary arteries in fetal life, compromise adaptation to extrauterine life, and be associated with a pulmonary hypertensive phenotype in adult life and if any abnormalities were detected, were they sex dependent. Morphometric analyses were made on lung tissue from male and female fetal, newborn, 14-day-old, and adult endothelial NOS-deficient (eNOS-/-) or inducible NOS-deficient (iNOS-/-) and wild-type mice. Hemodynamic studies were carried out on adult mice with deletion of either eNOS or iNOS genes. We found that in eNOS-/- mice, lung development was normal in fetal, newborn, and adult lungs. Pulmonary arterial muscularity was greater than normal in both male and female eNOS-/- during fetal life and at birth, but the abnormality persisted only in male mice. Right ventricular hypertrophy was present in 14-day-old and adult male eNOS-/- but not in female mice. Adult male eNOS-/- mice had higher mean right ventricular and systemic pressures than female eNOS-/- mice (P < 0.05). Thus deletion of the eNOS gene was associated with structural evidence of pulmonary hypertension in both sexes during fetal life, but pulmonary hypertension persisted only in the male. In neither sex did iNOS or neuronal NOS appear to compensate for the eNOS deletion. Adult iNOS-/- mice did not have structural or hemodynamic evidence of pulmonary hypertension. Possible compensatory mechanisms are discussed.
Asunto(s)
Eliminación de Gen , Hipertensión Pulmonar/patología , Músculo Liso Vascular/patología , Óxido Nítrico Sintasa/genética , Circulación Pulmonar , Actinas/metabolismo , Animales , Femenino , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Arteria Pulmonar/patología , Factores SexualesRESUMEN
1. In systemic vessels, haem-oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well-documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extra-uterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO-1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth. 2. We show, for the first time, that another isoform, HO-2, is present constitutively at birth and HO-1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO-1 mRNA declines after birth in the mouse lung. 3. Inhibitors of HO did not modify vasodilator responses in vessels from 14-day-old pigs. 4. Moreover, lungs from HO-1-deficient mice developed normally after birth. 5. HO-1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO-1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth.
Asunto(s)
Adaptación Fisiológica/fisiología , Hemo Oxigenasa (Desciclizante)/biosíntesis , Pulmón/fisiología , Contracción Muscular/fisiología , Arteria Pulmonar/fisiología , Fenómenos Fisiológicos Respiratorios , Animales , Animales Recién Nacidos , Western Blotting , Hemo Oxigenasa (Desciclizante)/genética , Hemo-Oxigenasa 1 , Pulmón/irrigación sanguínea , Pulmón/enzimología , Pulmón/crecimiento & desarrollo , Proteínas de la Membrana , Ratones , Ratones Noqueados , Músculo Liso Vascular/crecimiento & desarrollo , Músculo Liso Vascular/fisiología , Arteria Pulmonar/crecimiento & desarrollo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , PorcinosRESUMEN
The aim of this study was to assess pulmonary arterial blood flow changes induced by the creation of a systemic arteriovenous fistula (120 d gestation) in the fetal lamb using Doppler technique. Doppler echocardiographic assessment of the pulmonary artery blood flow performed 1, 6, and 14 d after surgery showed that mean pulmonary arterial blood flow in the left or right pulmonary artery was 224 +/- 58 mL/min at day 1 in the fistula group, significantly higher than in the control group (113 +/- 22 mL/min; p < 0.01, ANOVA test) whether no difference was found at days 6 and 14. The mean inner diameter of the left pulmonary artery measured on postmortem lung arteriograms compared favorably to the one measured on day 14 at the same level on ultrasound. The mean left pulmonary arterial blood flow, measured at birth on day 14 after surgery, using ultrasonic flow transducer, was not statistically different from the one measured by Doppler on day 14. Our data demonstrate that echocardiography allows accurate assessment of pulmonary arterial blood flow in utero, providing evidence suggesting transient high pulmonary blood flow that did not last >6 d after the creation of a systemic fistula.
Asunto(s)
Feto/fisiología , Hipertensión Pulmonar , Arteria Pulmonar , Flujo Sanguíneo Regional , Animales , Fístula Arteriovenosa , Presión Sanguínea/fisiología , Ecocardiografía Doppler , Femenino , Feto/anatomía & histología , Edad Gestacional , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Embarazo , Arteria Pulmonar/anatomía & histología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/cirugía , OvinosRESUMEN
The effect of norepinephrine administration on pulmonary blood flow during the neonatal period is unclear. Therefore, norepinephrine responses were studied in isolated pulmonary arteries, pulmonary veins, and femoral arteries taken from normal pigs from birth to adulthood and from pigs subjected to chronic hypoxia either from birth for 3 days or from 3 to 14 days of age. Normally, the contractile response of pulmonary arteries and veins to norepinephrine decreased after birth (p < 0.01), and alpha2-adrenoceptor-mediated relaxation increased in pulmonary arteries and veins and in femoral arteries. Hypoxic exposure from birth prevented the normal postnatal reduction in pulmonary arterial contractile response, nor was there a postnatal increase in pulmonary arterial adrenoceptor-mediated relaxation. When hypoxic exposure followed a period of normal adaptation, the pulmonary arterial contractile response was not enhanced, but relaxation was significantly impaired. The response of pulmonary veins and femoral arteries was not affected by hypoxic exposure. The contractile effect of norepinephrine was 15- to 60-fold greater in isolated systemic arteries than in pulmonary arteries taken from both normal and pulmonary hypertensive piglets at all ages. This suggests that use of norepinephrine to manage systemic hypotension in infants and children will not compromise the pulmonary vasculature.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Hipertensión Pulmonar/fisiopatología , Pulmón/irrigación sanguínea , Norepinefrina/farmacología , Circulación Pulmonar/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Arteria Femoral/efectos de los fármacos , Humanos , Hipoxia/fisiopatología , Técnicas In Vitro , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Modelos Animales , Arteria Pulmonar/efectos de los fármacos , Venas Pulmonares/efectos de los fármacos , Porcinos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Little is understood of the mechanisms involved in reducing pulmonary arterial wall thickness on recovery from pulmonary hypertension and the present study sought to clarify the events that occur. Piglets were exposed to hypobaric hypoxia for 3 days, either from birth or from 3 days of age, and others were exposed for 11 days starting at 3 days. All recovered in room air for up to 6 days. Using light and electron microscopy, the pulmonary artery wall thickness, the relative contribution of smooth muscle and matrix, smooth muscle cell replication, and apoptosis were assessed after hypoxic exposure and during recovery from hypoxic exposure. In elastic arteries, after 6 days' recovery in room air, a reduction in wall thickness to normal was associated with a similar reduction in proportional area of smooth muscle cells and matrix (p < 0.05), increased apoptosis (p < 0.05), and an abnormally low replication rate (p < 0.05). In peripheral muscular arteries, an increase in external diameter, and wall thinning on recovery, was achieved by smooth muscle cell remodelling and a reduction in cell replication (p < 0.05). Apoptosis did not contribute. Thus, different mechanisms are involved in recovery from hypoxia-induced pulmonary hypertension in elastic and muscular pulmonary arteries. Recovery is slower in animals exposed from birth rather than from 3 days of age.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Actinas/análisis , Animales , Animales Recién Nacidos , Arterias , División Celular/fisiología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipoxia/complicaciones , Hipoxia/fisiopatología , Metaloproteinasa 2 de la Matriz/análisis , Microscopía Electrónica/métodos , Músculo Liso/irrigación sanguínea , Músculo Liso/patología , Músculo Liso/fisiopatología , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Miocardio/patología , Necrosis , Tamaño de los Órganos , Arteria Pulmonar/patología , Porcinos , Tenascina/análisisRESUMEN
Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to carbon monoxide, bilirubin and free iron. Many cell types express heme oxygenase-2 constitutively while heme oxygenase-1 is induced at sites of inflammation and oxidative stress. In systemic blood vessels, carbon monoxide may have an important homeostatic role where, like its better-studied counterpart nitric oxide, it is emerging as a vasodilator and an inhibitor of proliferation. However, much less is known regarding the role of heme oxygenase and carbon monoxide in the pulmonary circulation where vascular responses are very different. Here, using primary cultures of human pulmonary artery smooth muscle cells, we present novel data showing that this cell type expresses heme oxygenase-2 constitutively and, in the presence of oxidants, can induce heme oxygenase-1. We also show that the carbon monoxide-releasing molecule, tricarbonyldichlororuthenium (II) dimer, potently and profoundly inhibits proliferation of human pulmonary artery smooth muscle cells. Pulmonary hypertension is a disease characterised by abnormal vascular smooth muscle cell growth and remodelling of the pulmonary vasculature. Our observations support the growing evidence that the heme oxygenase/carbon monoxide system may play a role in the pathology of pulmonary hypertension.
Asunto(s)
Monóxido de Carbono/fisiología , Hemo Oxigenasa (Desciclizante)/biosíntesis , Músculo Liso Vascular/enzimología , Arteria Pulmonar/enzimología , Western Blotting , Monóxido de Carbono/metabolismo , División Celular , Supervivencia Celular , Células Cultivadas , Hemo-Oxigenasa 1 , Humanos , Proteínas de la Membrana , Músculo Liso Vascular/ultraestructura , Arteria Pulmonar/ultraestructuraRESUMEN
Several cases of systemic arteriovenous fistula diagnosed in the human fetus have been associated with the postnatal development of persistent pulmonary hypertension. The aim of this study was to determine the effects of a prenatally created systemic arteriovenous fistula on the structure and reactivity of the pulmonary circulation in the fetal lamb. A fistula between the jugular vein and carotid artery was created in fetal lambs at 119-124 days of gestation. At delivery (134-139 days), left pulmonary artery (LPA) pressure was increased in the fistula group (n = 12) compared with controls (n = 11, P < 0.01). The pulmonary vascular resistance was significantly higher in the fistula group (P < 0.05), whereas mean LPA blood flow was not statistically different between the two groups. Morphometric analysis of the pulmonary vascular bed revealed an increase in the number of peripheral muscular arteries, together with an increase in pulmonary arterial medial thickness in the fistula group. There was no difference in the relative number or size of intraacinar arteries. In vitro organ bath studies on pulmonary arterial rings showed impaired endothelium-dependent relaxation in the fistula group compared with controls. However, endothelial nitric oxide synthase protein expression was similar in both groups, whereas endothelium-independent relaxation to sodium nitroprusside was greater in the fistula group compared with controls. A systemic arteriovenous fistula leads to both structural and functional alteration of the pulmonary vasculature, which might lead to the development of persistent pulmonary hypertension after birth.
Asunto(s)
Fístula Arteriovenosa/fisiopatología , Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/fisiología , Acetilcolina/farmacología , Animales , Fístula Arteriovenosa/patología , Western Blotting , Calcimicina/farmacología , Femenino , Hipertensión Pulmonar/patología , Ionóforos/farmacología , Contracción Isométrica/efectos de los fármacos , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa de Tipo III , Embarazo , Arteria Pulmonar/anomalías , Mucosa Respiratoria/enzimología , Mucosa Respiratoria/patología , Mucosa Respiratoria/fisiopatología , Ovinos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Chronic hypoxia compromises the development of both airways and pulmonary vasculature following exposure before or after birth. It also impairs adaptation to extrauterine life. The immediate morbidity and mortality is high, and long-term sequelae in terms of lung structure, and thus function, are common, particularly in premature infants. Chronic lung disease or bronchopulmonary dysplasia can develop with or without cor pulmonale. The extensive fibrotic disease of classical bronchopulmonary dysplasia has become uncommon with the development of improved treatment strategies, but the development of the lung periphery can still be compromised as more immature babies survive. This article highlights the landmarks of normal lung development together with the principal established and newly recognized features of exposure to chronic hypoxic in the young. In doing so, it indicates promising areas for research activity.