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1.
Thorax ; 66(4): 280-5, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21233480

RESUMO

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.


Assuntos
Brônquios/crescimento & desenvolvimento , Mucosa Respiratória/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Membrana Basal/anatomia & histologia , Membrana Basal/crescimento & desenvolvimento , Estatura/fisiologia , Peso Corporal/fisiologia , Brônquios/anatomia & histologia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Pessoa de Meia-Idade , Mucosa Respiratória/anatomia & histologia , Caracteres Sexuais , Adulto Jovem
2.
Lab Invest ; 89(1): 15-25, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19015642

RESUMO

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.


Assuntos
Receptores de Ativinas Tipo I/deficiência , Malformações Arteriovenosas/etiologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Pulmão/irrigação sanguínea , Telangiectasia Hemorrágica Hereditária/complicações , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Animais , Capilares/metabolismo , Endoglina , Hipertensão Pulmonar/genética , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Mutação , Artéria Pulmonar/metabolismo , Veias Pulmonares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Eur J Pharmacol ; 567(3): 240-4, 2007 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-17540365

RESUMO

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.


Assuntos
Animais Recém-Nascidos/fisiologia , Endotélio Vascular/fisiologia , Circulação Pulmonar/fisiologia , Vasodilatação/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Acetilcolina/farmacologia , Envelhecimento/fisiologia , Animais , Processamento de Imagem Assistida por Computador , Técnicas In Vitro , Camundongos , Músculo Liso Vascular/fisiologia , Nitroprussiato/farmacologia , Artéria Pulmonar/citologia , Artéria Pulmonar/fisiologia , Veias Pulmonares/citologia , Veias Pulmonares/fisiologia , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
4.
Br J Pharmacol ; 144(4): 467-76, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15655535

RESUMO

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.


Assuntos
Adaptação Fisiológica/fisiologia , Heme Oxigenase (Desciclizante)/biossíntese , Pulmão/fisiologia , Contração Muscular/fisiologia , Artéria Pulmonar/fisiologia , Fenômenos Fisiológicos Respiratórios , Animais , Animais Recém-Nascidos , Western Blotting , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1 , Pulmão/irrigação sanguínea , Pulmão/enzimologia , Pulmão/crescimento & desenvolvimento , Proteínas de Membrana , Camundongos , Camundongos Knockout , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/fisiologia , Artéria Pulmonar/crescimento & desenvolvimento , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos
5.
Br J Pharmacol ; 135(6): 1415-24, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11906954

RESUMO

1. beta-adrenoceptor activation leads to pulmonary vasodilatation. The increase in circulating catecholamines at birth may assist the postnatal fall in vascular resistance by their activation. To study beta(1)- and beta(2)-adrenoceptors during postnatal adaptation, we used [(125)I]-iodocyanopindolol (ICYP) binding to lung membranes and sections to quantify and locate the binding sites in piglets from birth to 14 days of age and compared them with those in adult pigs. In addition, pulmonary hypertension was induced in newborn piglets by hypobaric hypoxia. 2. In lung membranes the equilibrium dissociation constant (K(d)) did not change with age for total beta-adrenoceptors or for beta(2)-adrenoceptors, but there was a significant increase in maximum binding sites (B(max)) between birth and 3 days of age. On tissue sections, B(max) increased between 3 days and adulthood with no change in K(d). 3. Binding sites of beta(1)- and beta(2)-adrenoceptors were localized to the bronchial epithelium, to endothelium of extra- and intra-pulmonary arteries and to lung parenchyma. Total beta-adrenoceptor density increased with age at all locations (P<0.05 - 0.01). At birth intrapulmonary arteries showed no binding, beta(2)-adrenoceptors appeared on day 1 and increased up to 14 days of age. beta(1)-adrenoceptors appeared by 3 days of age and increased with age. 4. Hypobaric hypoxia from birth led to attenuation in the normal postnatal increase in receptor number, but hypoxia from 3 - 6 days did not decrease receptor density. 5. The normal postnatal increase in beta-adrenoceptors suggests a potential for catecholamine induced dilatation in the lung during adaptation which is attenuated in pulmonary hypertension.


Assuntos
Animais Recém-Nascidos/fisiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Pulmão/metabolismo , Receptores Adrenérgicos beta/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Sítios de Ligação/fisiologia , Feminino , Pulmão/crescimento & desenvolvimento , Gravidez , Suínos
6.
Eur J Pharmacol ; 473(2-3): 135-41, 2003 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12892830

RESUMO

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.


Assuntos
Monóxido de Carbono/fisiologia , Heme Oxigenase (Desciclizante)/biossíntese , Músculo Liso Vascular/enzimologia , Artéria Pulmonar/enzimologia , Western Blotting , Monóxido de Carbono/metabolismo , Divisão Celular , Sobrevivência Celular , Células Cultivadas , Heme Oxigenase-1 , Humanos , Proteínas de Membrana , Músculo Liso Vascular/ultraestrutura , Artéria Pulmonar/ultraestrutura
7.
Int J Cardiol ; 142(2): 159-65, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-19176261

RESUMO

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.


Assuntos
Frequência Cardíaca/fisiologia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Transplante de Coração/mortalidade , Transplante de Coração/tendências , Humanos , Hipertensão Pulmonar/mortalidade , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
8.
Int J Cardiol ; 135(1): 21-6, 2009 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18599134

RESUMO

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.


Assuntos
Biomarcadores/sangue , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/mortalidade , Peptídeo Natriurético Encefálico/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão Pulmonar/cirurgia , Lactente , Estimativa de Kaplan-Meier , Transplante de Pulmão , Masculino , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Sensibilidade e Especificidade
9.
High Alt Med Biol ; 10(4): 365-72, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20043379

RESUMO

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.


Assuntos
Altitude , Receptores ErbB/metabolismo , Hipóxia Fetal/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Artéria Pulmonar/fisiopatologia , Actinas/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Receptores ErbB/antagonistas & inibidores , Feminino , Hipóxia Fetal/etiologia , Hipóxia Fetal/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Quinazolinas , Carneiro Doméstico , Tirfostinas/farmacologia
10.
Am J Physiol Lung Cell Mol Physiol ; 292(5): L1273-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17259291

RESUMO

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.


Assuntos
Envelhecimento/fisiologia , Endotelina-1/farmacologia , Hipóxia/fisiopatologia , Veias Pulmonares/efeitos dos fármacos , Veias Pulmonares/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feto , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/fisiologia , Músculo Liso Vascular/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/crescimento & desenvolvimento , Artéria Pulmonar/fisiologia , Artéria Pulmonar/fisiopatologia , Veias Pulmonares/patologia , Veias Pulmonares/fisiopatologia , Suínos
11.
Heart ; 93(6): 739-43, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17065181

RESUMO

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.


Assuntos
Anti-Hipertensivos/uso terapêutico , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Criança , Pré-Escolar , Tolerância ao Exercício , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Lactente , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino
12.
Am J Physiol Lung Cell Mol Physiol ; 293(6): L1475-82, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17951313

RESUMO

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.


Assuntos
Doença da Altitude/fisiopatologia , Feto/fisiopatologia , Hipóxia/fisiopatologia , Fator de Ativação de Plaquetas/metabolismo , Artéria Pulmonar/fisiopatologia , Animais , Peso ao Nascer/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Feminino , Feto/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Fator de Ativação de Plaquetas/biossíntese , Fator de Ativação de Plaquetas/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Gravidez , Artéria Pulmonar/patologia , Receptores Acoplados a Proteínas G/metabolismo , Carneiro Doméstico
13.
Pediatr Res ; 60(1): 71-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16690956

RESUMO

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.


Assuntos
Brônquios/fisiologia , Endotelina-1/fisiologia , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Norepinefrina/fisiologia , Artéria Pulmonar/fisiologia , Animais , Animais Recém-Nascidos/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Brônquios/irrigação sanguínea , Brônquios/efeitos dos fármacos , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Suínos , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
14.
Pediatr Res ; 60(3): 252-7, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16857762

RESUMO

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.


Assuntos
Endotelina-1/metabolismo , Síndrome da Persistência do Padrão de Circulação Fetal/metabolismo , Canais de Potássio/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Ventrículos do Coração/anormalidades , Humanos , Recém-Nascido , Ovinos
15.
Am J Physiol Lung Cell Mol Physiol ; 289(2): L299-306, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15821017

RESUMO

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.


Assuntos
Deleção de Genes , Hipertensão Pulmonar/patologia , Músculo Liso Vascular/patologia , Óxido Nítrico Sintase/genética , Circulação Pulmonar , Actinas/metabolismo , Animais , Feminino , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/enzimologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Artéria Pulmonar/patologia , Fatores Sexuais
16.
Pediatr Res ; 58(3): 525-30, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16148068

RESUMO

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.


Assuntos
Hipertensão Pulmonar/patologia , Artéria Pulmonar/anatomia & histologia , Resistência Vascular , Animais , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Músculo Liso/citologia , Músculo Liso/ultraestrutura , Artéria Pulmonar/patologia , Suínos
17.
J Anat ; 201(4): 325-34, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12430957

RESUMO

In the adult lung the pulmonary arteries run alongside the airways and the pulmonary veins show a similar branching pattern to the arteries, though separated from them. During early fetal development the airways act as a template for pulmonary blood vessel development in that the vessels form by vasculogenesis around the branching airways. In later lung development the capillary bed is essential for alveolar formation. This paper reviews evidence for the interaction of the airways and blood vessels in both normal and abnormal lung development.


Assuntos
Pulmão/embriologia , Mamíferos/embriologia , Artéria Pulmonar/embriologia , Veias Pulmonares/embriologia , Animais , Artérias Brônquicas/embriologia , Displasia Broncopulmonar/embriologia , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/anormalidades , Organogênese/fisiologia
18.
Semin Neonatol ; 8(1): 1-8, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12667825

RESUMO

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.


Assuntos
Hipóxia/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/crescimento & desenvolvimento , Doença Crônica , Feminino , Hipóxia Fetal/etiologia , Hipóxia Fetal/fisiopatologia , Humanos , Hipóxia/complicações , Hipóxia/etiologia , Lactente , Recém-Nascido , Pulmão/embriologia , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Gravidez , Fumar/efeitos adversos
19.
Am J Respir Crit Care Med ; 170(6): 641-6, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15184201

RESUMO

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.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/irrigação sanguínea , Norepinefrina/farmacologia , Circulação Pulmonar/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Artéria Femoral/efeitos dos fármacos , Humanos , Hipóxia/fisiopatologia , Técnicas In Vitro , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Modelos Animais , Artéria Pulmonar/efeitos dos fármacos , Veias Pulmonares/efeitos dos fármacos , Suínos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
Am J Respir Cell Mol Biol ; 26(3): 333-40, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11867341

RESUMO

Recent studies on human embryonic and fetal lungs show that the pulmonary arteries form by vasculogenesis. Little is known of the early development of the pulmonary veins. Using immunohistochemical techniques and serial reconstruction, we studied 18 fetal and neonatal lungs. Sections were stained with antibodies specific for endothelium (CD31, von Willebrand factor) and smooth muscle (alpha and gamma smooth muscle actin, smooth muscle myosin, calponin, caldesmon, and desmin) and antibodies specific for the matrix glycoprotein tenascin, the receptor protein tyrosine kinase EphB4, and its ligand ephrinB2. Kiel University-raised antibody number 67 (Ki67) expression allowed qualitative assessment of cell replication. By 34 d gestation, there was continuity between the aortic sac, pulmonary arteries, capillaries, pulmonary veins, and atrium. The pulmonary veins formed by vasculogenesis in the mesenchyme surrounding the terminal buds during the pseudoglandular period and probably by angiogenesis in the canalicular and alveolar stages. EphB4 and ephrinB2 did not distinguish between presumptive venous and arterial endothelium as they do in mouse. All venous smooth muscle cells derived directly from the mesenchyme, gradually acquiring smooth muscle specific proteins from 56 d gestation. Thus, both pulmonary arteries and veins arise by vasculogenesis, but the origins of their smooth muscle cells and their cytoskeletal protein content are different.


Assuntos
Pulmão/irrigação sanguínea , Veias Pulmonares/citologia , Veias Pulmonares/embriologia , Animais , Diferenciação Celular , Endotélio Vascular/citologia , Endotélio Vascular/embriologia , Feminino , Humanos , Pulmão/embriologia , Camundongos , Morfogênese , Músculo Liso Vascular/citologia , Músculo Liso Vascular/embriologia , Gravidez
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