Biomedical subjects

Sheila G Haworth

Publications and source records attributed to Sheila G Haworth.

At least 19 recordsLinked to original sources

PubMed2006

Epoprostenol treatment in children with severe pulmonary hypertension.

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.

Antihypertensive Agents↗

PubMed2006

Porcine pulmonary artery and bronchial responses to endothelin-1 and norepinephrine on recovery from hypoxic pulmonary hypertension.

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.

Animals↗

PubMed2006

Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension.

Hypoxia is a common cause of persistent pulmonary hypertension in the newborn (PPHN), a condition associated with endothelial dysfunction and abnormal pulmonary vascular remodeling. The GTPase RhoA has been implicated in the pathogenesis of PPHN, but its contribution to endothelial remodeling and function is not known. We studied pulmonary artery endothelial cells (PAECs) taken from piglets with chronic hypoxia-induced pulmonary hypertension and from healthy animals and analyzed the roles of Rho GTPases in the regulation of the endothelial phenotype and function under basal normoxic conditions, acute hypoxia, and reoxygenation. The activities of RhoA, Rac1, and Cdc42 were correlated with changes in the endothelial cytoskeleton, adherens junctions, permeability, ROS production, VEGF levels, and activities of transcription factors hypoxia-inducible factor (HIF)-1alpha and NF-kappaB. Adenoviral gene transfer was used to express dominant-negative GTPases, kinase-dead p21-activated kinase (PAK)-1, and constitutively activated Rac1 in cells. PAECs from pulmonary hypertensive piglets had a stable abnormal phenotype with a sustained reduction in Rac1 activity and an increase in RhoA activity, which correlated with an increase in actin stress fiber formation, increased permeability, and a decrease in VEGF and ROS production. Cells from pulmonary hypertensive animals were still able to respond to acute hypoxia. They also showed high activities of HIF-1alpha and NF-kappaB, likely to result from changes in the activities of Rho GTPases. Activation of Rac1 and its effector PAK-1 as well as inhibition of RhoA restored the abnormal phenotype and permeability of hypertensive PAECs to normal.

Animals↗

PubMed2006

Intravenous sildenafil as an effective treatment of pulmonary hypertensive crises during acute intestinal malabsorption.

Oral sildenafil has been demonstrated to be an effective treatment for pulmonary hypertension, and is increasingly used in children. We report an infant with pulmonary hypertension, stable on regular treatment with oral sildenafil, who presented in acute respiratory failure after aspiration, requiring ventilation and intensive care. The course of the stay in intensive care was difficult, with recurrent pulmonary hypertensive crises despite use of oral sildenafil, use of 100% oxygen, high frequency oscillatory ventilation, and inhaled nitric oxide. In view of his instability, and the presumed inability to absorb the sildenafil orally due to gastrointestinal malabsorption, sildenafil was administered as a continuous intravenous infusion. With this therapy, it proved possible to wean from oxygen, nitric oxide, and ventilatory support. Intravenous sildenafil, therefore, might be an effective alternative for children with pulmonary hypertension during episodes of acute deterioration and malabsorption, preventing life-threatening pulmonary hypertensive crises. Its pharmacokinetics, efficacy, and safety, nonetheless, need to be validated in randomized controlled trials.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Perinatal changes in pulmonary vascular endothelial function.

The pulmonary endothelium plays a crucial role in lung development and function during the perinatal period. Its 2 most important functions at this time are to help reduce pulmonary vascular resistance (PVR) in order to permit the entire cardiac output to pass through the lungs for the first time and to facilitate the clearance of lung fluid. In response to changes in environmental factors such as oxygen tension, blood flow, circulating cytokines, and growth factors, the endothelium synthesizes and/or extracts many vasoactive mediators such as endothelin-1 (ET-1), norepinephrine, angiotensin 1, thromboxane, prostacyclin (PGI(2)), and the endothelial-derived relaxing factor nitric oxide (NO). The endothelium acts as a transducer conveying information about environmental changes to the underlying smooth muscle cells (SMCs), which helps regulate their reactivity and pulmonary vascular tone. The endothelial layer also acts as a barrier, regulating the exchange of fluids and nutrients between blood components and the surrounding tissues. The purpose of this review is to demonstrate the importance of structural and functional changes in the pulmonary endothelium during the perinatal period and explain their role in the regulation of the pulmonary circulation in health and disease. We also highlight signalling pathways of some of the most important endothelium-derived factors and indicate potential targets for pharmacological intervention.

Animals↗

PubMed2005

Deletion of the eNOS gene has a greater impact on the pulmonary circulation of male than female mice.

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.

Actins↗

PubMed2005

Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. METHODS AND RESULTS: We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. CONCLUSIONS: The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.

Activin Receptors, Type I↗

PubMed2005

Cytoplasmic YY1 is associated with increased smooth muscle-specific gene expression: implications for neonatal pulmonary hypertension.

Immediately after birth the adluminal vascular SMCs of the pulmonary elastic arteries undergo transient actin cytoskeletal remodeling as well as cellular de-differentiation and proliferation. Vascular smooth muscle phenotype is regulated by serum response factor, which is itself regulated in part by the negative regulator YY1. We therefore studied the subcellular localization of YY1 in arteries of normal newborn piglets and piglets affected by neonatal pulmonary hypertension. We found that YY1 localization changed during development and that expression of gamma-smooth muscle actin correlated with expression of cytoplasmic rather than nuclear YY1. Analysis of the regulation of YY1 localization in vitro demonstrated that polymerized gamma-actin sequestered EGFP-YY1 in the cytoplasm and that YY1 activation of c-myc promoter activity was inhibited by LIM kinase, which increases actin polymerization. Consistent with these data siRNA-mediated down-regulation of YY1 in C2C12 cells increased SM22-alpha expression and inhibited cell proliferation. Thus, actin polymerization controls subcellular YY1 localization, which contributes to vascular SMC proliferation and differentiation in normal pulmonary artery development. In the absence of actin depolymerization, YY1 does not relocate to the nucleus, and this lack of relocation may contribute to the pathobiology of pulmonary hypertension.

Actins↗

PubMed2005

Relationship between structural remodeling and reactivity in pulmonary resistance arteries from hypertensive piglets.

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.

Animals↗

PubMed2004

Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells.

Hypoxia/reoxygenation-induced changes in endothelial permeability are accompanied by endothelial actin cytoskeletal and adherens junction remodeling, but the mechanisms involved are uncertain. We therefore measured the activities of the Rho GTPases Rac1, RhoA, and Cdc42 during hypoxia/reoxygenation and correlated them with changes in endothelial permeability, remodeling of the actin cytoskeleton and adherens junctions, and production of ROS. Dominant negative forms of Rho GTPases were introduced into cells by adenoviral gene transfer and transfection, and inhibitors of NADPH oxidase, PI3 kinase, and Rho kinase were used to characterize the signaling pathways involved. In some experiments constitutively activated forms of RhoA and Rac1 were also used. We show for the first time that hypoxia/reoxygenation-induced changes in endothelial permeability result from coordinated actions of the Rho GTPases Rac1 and RhoA. Rac1 and RhoA rapidly respond to changes in oxygen tension, and their activity depends on NADPH oxidase- and PI3 kinase-dependent production of ROS. Rac1 acts upstream of RhoA, and its transient inhibition by acute hypoxia leads to activation of RhoA followed by stress fiber formation, dispersion of adherens junctions, and increased endothelial permeability. Reoxygenation strongly activates Rac1 and restores cortical localization of F-actin and VE-cadherin. This effect is a result of Rac1-mediated inhibition of RhoA and can be prevented by activators of RhoA, L63RhoA, and lysophosphatidic acid. Cdc42 activation follows the RhoA pattern of activation but has no effect on actin remodeling, junctional integrity, or endothelial permeability. Our results show that Rho GTPases act as mediators coupling cellular redox state to endothelial function.

Actins↗

PubMed2004

End points and clinical trial designs in pulmonary arterial hypertension: clinical and regulatory perspectives.

To date, randomized controlled clinical trials performed in pulmonary arterial hypertension (PAH) have been relatively short-term studies involving mainly patients with advanced disease. The primary end points in these trials have addressed exercise capacity, usually by using the 6-min walk test. Although this approach is still warranted in future trials assessing new treatments, it is likely that the focus will shift toward trials of longer duration, involving patients with less advanced disease, and that different drugs and drug-combination regimens will be compared. In such trials, it is possible that a composite of markers indicating clinical deterioration (e.g., hospitalization for right heart failure, the requirement for the introduction of an alternative treatment, and predefined indicators of worsening exercise tolerance) may be more useful as primary end points. Quality of life will become a very important issue; however, appropriate quality-of-life questionnaires for PAH have yet to be developed. In addition, hemodynamics will likely remain valuable as secondary end points, but future clinical trials should include hemodynamics obtained both during exercise and at rest. Finally, cardiopulmonary exercise testing, echocardiographic studies, and biochemical parameters, such as brain natriuretic peptide or troponin T, may also prove useful as secondary end points in the future.

Clinical Trials as Topic↗

PubMed2004

Postnatal changes in response to norepinephrine in the normal and pulmonary hypertensive lung.

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.

Adrenergic alpha-Agonists↗

PubMed2004

RhoA activation by hypoxia in pulmonary arterial smooth muscle cells is age and site specific.

Hypoxia induces vasoconstriction of pulmonary arteries through contraction of smooth muscle cells (SMCs). The GTPase RhoA regulates smooth muscle contractility and actin cytoskeletal remodeling through the Rho-associated kinase (ROCK). We previously found that the postnatal fall in pulmonary vascular resistance was associated with actin cytoskeletal remodeling in porcine pulmonary arterial SMCs (PASMCs) in vivo. Here, we investigated the effects of acute and chronic hypoxia on the morphology and RhoA activity of PASMCs from fetal and neonatal piglets. Acute hypoxia enhanced actin stress fiber formation and RhoA activity in both inner and outer medial PASMCs from the fetus but only in the inner medial PASMCs from normal 3-day-old piglets. The increased stress fiber formation was dependent on Rho and ROCK. In outer medial PASMCs from 14-day-old animals, acute hypoxia decreased RhoA activity. Interestingly, outer medial PASMCs from animals exposed to chronic hypoxia had fewer stress fibers associated with a lower basal RhoA activity. Treatment of PASMCs from normal 3-day-old piglets with Rho or ROCK inhibitors for 24 hours induced a similar morphology. Rac activity was not altered by either acute or chronic hypoxia. These data show that acute hypoxia induces RhoA activation only in PASMCs from young animals, whereas chronic hypoxia selectively downregulates RhoA activity in outer medial PASMCs leading to an altered phenotype.

Actin Cytoskeleton↗

PubMed2004

Remodelling of the pulmonary arteries during recovery from pulmonary hypertension induced by neonatal hypoxia.

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.

Actins↗

PubMed2003

Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role.

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.

Blotting, Western↗

PubMed2003

Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia.

BACKGROUND: Nitric oxide (NO) plays an important part in lowering pulmonary vascular resistance after birth, and in persistent pulmonary hypertension of the newborn (PPHN), NO-mediated dilation is dysfunctional. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) circulates in plasma, and its concentrations are elevated in certain cardiovascular diseases, including pulmonary hypertension. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the activity of which regulates ADMA concentrations and provides a mechanism for modulating NO synthase in vivo. We investigated the changes in expression and activity of the 2 isoforms of DDAH in lungs from newborn piglets both during normal development and in PPHN. METHODS AND RESULTS: Using Western blotting, we showed that DDAHI expression did not change in the normal developing lung; however, DDAHII increased after birth and reached a peak at 1 day. This was reflected in an increase in total DDAH activity according to an L-citrulline assay. With pulmonary hypertension, no changes in DDAHI expression were observed, but DDAHII expression was markedly decreased compared with age-matched controls. Total DDAH activity was similarly reduced. CONCLUSIONS: These results indicate that each DDAH isoform is differentially regulated during both lung development and PPHN. Suppression of DDAHII isoform expression may be a mechanism underlying PPHN.

Amidohydrolases↗

PubMed2003

Paxillin-associated focal adhesion involvement in perinatal pulmonary arterial remodelling.

Birth is followed by remodelling of the actin cytoskeleton of pulmonary arterial smooth muscle cells, then by extracellular matrix deposition. Hypothesising that the cell/matrix adhesions would also be remodelled, we investigated the expression, localisation and biochemical characteristics of the focal adhesion protein paxillin in vivo, in vessels from normal and pulmonary hypertensive neonatal piglets. Initially we showed that in intact porcine pulmonary arteries exposed to cytochalasin D there was a reduction filamentous actin accompanied by a reduction in paxillin-associated focal adhesions, similar to that seen in cultured pulmonary arterial smooth muscle cells. Vessels from normal and hypoxic animals were found to have two isoforms of paxillin, of 60 and 66 kDa with pI values of 6.7-4.2. Transient changes occurred during the first 14 days of life. Between birth and 6 days there was a reduction in the amount of both paxillin isoforms, a shift to more acidic pI values and an increase in paxillin phosphorylation. Simultaneously, immunostaining showed a transient reduction in paxillin expression, a change temporally and spatially associated with a previously demonstrated reduction in actin. Findings are consistent with an immediate postnatal spatial reorganisation of paxillin-associated focal adhesions. Paxillin content and remodelling was abnormal in pulmonary hypertensive arteries, the response varying according to postnatal age.

Actins↗

PubMed2003

Lung development-the effects of chronic hypoxia.

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.

Chronic Disease↗