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1.  Development of the bronchial epithelial reticular basement membrane: relationship to epithelial height and age 
Thorax  2011;66(4):280-285.
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.
doi:10.1136/thx.2010.149799
PMCID: PMC3471130  PMID: 21233480
2.  Role of Epidermal Growth Factor Receptor in Ovine Fetal Pulmonary Vascular Remodeling Following Exposure to High Altitude Long-Term Hypoxia 
High Altitude Medicine & Biology  2009;10(4):365-372.
Abstract
Sheng, Lavonne, Weilin Zhou, Alison A. Hislop, Basil O. Ibe, Lawrence D. Longo, and J. Usha Raj. Role of epidermal growth factor receptor in ovine fetal pulmonary vascular remodeling following exposure to high altitude long-term hypoxia. High Alt. Med. Biol. 10:365–372, 2009.—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.
doi:10.1089/ham.2008.1034
PMCID: PMC3140299  PMID: 20043379
EGFR; fetal pulmonary vasculature; smooth muscle; proliferation
3.  Epoprostenol treatment in children with severe pulmonary hypertension 
Heart  2006;93(6):739-743.
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×m2. 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.
doi:10.1136/hrt.2006.096412
PMCID: PMC1955199  PMID: 17065181
4.  Pulmonary arterial development during childhood: branching pattern and structure 
Thorax  1973;28(2):129-135.
In lungs from 18 children aged between birth and 11 years the development of the branching pattern and structure of the pulmonary arteries, particularly the intralobular and intra-acinar, has been quantitatively analysed after injection with a radio-opaque medium. Up to 18 months of age as new alveolar ducts appear conventional arterial branches develop within the acinus: supernumerary arteries increase in number up to 8 years as new alveoli form. Both types increase in size with age.
After birth there is an immediate drop in wall thickness of the vessels below 200 μm diameter while the larger vessels take up to 4 months to fall to adult thickness, suggesting two types of response—one dilatation, the other a growth rate change of the muscle cells. During childhood muscle cell formation in the intra-acinar arteries lags behind increase in artery size so that during childhood few muscular arteries are found within the acinus. The functional significance of these changes is discussed.
PMCID: PMC470003  PMID: 4731102
5.  Development of the acinus in the human lung 
Thorax  1974;29(1):90-94.
Hislop, Alison, and Reid, Lynne (1974).Thorax, 29, 90-94. Development of the acinus in the human lung. Development and remodelling of the acinus (those structures distal to the terminal bronchiolus) occurs during fetal life and childhood. Multiplication of the acinar air spaces and the structural changes they undergo have been described and represented schematically by summarizing previous studies, particularly those of the last two decades.
Most acinar airways are present before birth. Future respiratory bronchioli are represented by the 19th intrauterine week; alveolar ducts are present as saccules by the 28th week. Alveolar sacs and alveoli, as properly described, do not appear until after birth: alveoli increase in number, particularly in the first seven or so years of life, and in size with thoracic growth.
PMCID: PMC470408  PMID: 4825556
6.  Unilateral congenital dysplasia of lung associated with vascular anomalies 
Thorax  1973;28(4):435-441.
Hislop, A., Sanderson, M., and Reid, L. (1973).Thorax, 28, 435-441. Unilateral congenital dysplasia of lung associated with vascular anomalies. In three cases of unilateral lung dysplasia the structural changes have been analysed quantitatively to throw light on the nature of the anomaly and stage of its appearance. In one case the pulmonary artery was hypoplastic and the systemic supply normal but increased, suggesting onset in late intrauterine life or early childhood: in the other two cases the blood supply was only systemic, from both normal and abnormal arteries, suggesting onset in the early weeks of intrauterine development. Airway development was consistent with this interpretation. All cases had additional signs of maldevelopment of mesodermal tissue. The origin of the various types of systemic artery is discussed.
Images
PMCID: PMC470055  PMID: 4741444
7.  Fetal and childhood development of the intrapulmonary veins in man—branching pattern and structure 
Thorax  1973;28(3):313-319.
The drainage pattern and the structure of the pulmonary veins have been described quantitatively in a series of fetal and child lungs after injection of the veins with a radio-opaque medium. The drainage pattern of the pre-acinar region is complete by half-way through gestation and corresponds with the growth of the pulmonary arteries. There is new growth of veins within the acinus during childhood. Four types of veins arising from five peripheral sites have been described. The change in dimensions with age have also been measured. A measurable muscle layer could not be found in the walls of the veins before birth though some muscle cells were present from 28 weeks of gestation. The thickness of the muscle coat in any vein was similar at birth and in a 3- and 10-year-old child and in all cases was less than in a pulmonary artery of the same size. The muscle cells were of smaller diameter in the veins than in the arteries. Along any venous pathway between a non-muscular and muscular structure was a region where part of the wall was muscular: these veins were termed partially muscular. Their distribution by size was similar at all ages.
Images
PMCID: PMC470035  PMID: 4724499
8.  Weight of the left and right ventricle of the heart during fetal life 
Journal of Clinical Pathology  1972;25(6):534-536.
The hearts from 31 fetuses aged from 12 to 40 weeks' gestation were dissected after fixation. The right ventricle and the left ventricle plus septum were weighed separately and a ratio was established. The total and separate ventricular weights increase steadily with age and at a similar rate. Throughout fetal life the left ventricle plus septum is larger than the right ventricle, but the right ventricle forms a greater proportion of the total ventricular weight than it does in the child or the adult.
For the first time, a table of normal fetal heart weights and ratios obtained using the method of Fulton, Hutchinson, and Jones (1952) is presented.
PMCID: PMC477374  PMID: 5043378
9.  Postnatal growth and function of the pre-acinar airways 
Thorax  1972;27(3):265-274.
The postnatal growth of the pre-acinar or conducting airways of the lung was examined by measuring the dimensions of selected axial pathways in lungs at different stages of development. The material included both formalin-fixed specimens and bronchograms. A method of comparing the relative sizes of each part of the pathways was developed which allowed for differences between the number of branches or generations measured in each specimen. The results indicate that the pre-acinar airways of the infant may be regarded as a miniature version of those in the adult and that this relationship persists during postnatal growth. Each individual branch grows in a symmetrical fashion both in length and in diameter and bears a constant relation to the whole. The physiological function of the conducting airways during growth was investigated using published data on the breathing pattern of infants. Particular attention was given to the conditions of airflow, to the warming and humidification of inhaled air, and to the filtration of airborne dust.
PMCID: PMC472584  PMID: 5039441
10.  New pathological findings in emphysema of childhood: 3. Unilateral congenital emphysema with hypoplasia—and compensatory emphysema of contralateral lung 
Thorax  1971;26(2):195-205.
A quantitative study is here reported on the lungs of a child of 9 months with unilateral emphysema associated with hypoplasia, and with compensatory emphysema in the contralateral lung. The left lung was judged to show congenital hypoplasia because of the reduced number of bronchi and arteries, its small volume, and a total alveolar number less than that normally found at birth. This last was due mainly to reduction in the number of acini, the intra-acinar number seeming little affected. As the alveoli were eight times the normal volume, the case was considered to be one of congenital hypoplastic emphysema.
The right lung was evidently normal at birth, since it had a normal number of bronchi, arteries, and alveoli. The lung was increased in volume due to an increase in alveolar volume—an example of compensatory emphysema.
This case is discussed with relation to two previously reported cases of lobar emphysema and other cases in the literature. It is emphasized that a quantitative analysis of the state of bronchi, alveoli, and blood vessels is important to establish the nature of the pathological change. A preliminary classification based on the anatomical features is offered.
Images
PMCID: PMC1019127  PMID: 5576537
11.  New pathological findings in emphysema of childhood: 2. Overinflation of a normal lobe 
Thorax  1971;26(2):190-194.
A quantitative study of the structure of the affected lobe from a patient with childhood lobar emphysema is here reported. The left upper lobe was removed from a child aged 2½ months who was suffering from acute respiratory distress and showing on his radiograph hypertransradiancy of the left lung.
At operation the lobe was found to be increased in volume and rotated through 180° on its pedicle. After laboratory injection of some of the pulmonary artery branches and distension of the lobe, the stage of development of the various lung structures was studied quantitatively. The arteries and bronchi were normal in number and structure: the alveolar number was normal for the age of the child but the volume of an alveolus was increased four to five times, as was total lung volume.
The antenatal development of this lobe was normal and it seems that the emphysema could have followed the rotation of the lobar hilum, although no cause for this rotation was found.
Images
PMCID: PMC1019126  PMID: 5089799
12.  New pathological findings in emphysema of childhood: 1. Polyalveolar lobe with emphysema 
Thorax  1970;25(6):682-690.
A new pathological entity is here described—a polyalveolar lobe with or without emphysema—giving rise to the clinical features of childhood lobar emphysema.
A detailed and quantitative study of the airways, alveoli and arteries was carried out on the left upper lobe removed because of shortness of breath, thought to be due to `childhood lobar emphysema'. The child was 17 days old and the radiograph showed hypertransradiancy of the left lung. The alveolar number was increased five-fold. Alveolar size was normal, so it was found that emphysema, accepted today as a structural diagnosis, was not present. The increase in alveolar number seemed confined to the apical, posterior, and anterior segments, the lingula being unaffected. By contrast, the airways and arteries were normal for age in number, size and structure, suggesting that the condition was a `giantism' of the alveolar region. The blood flow was probably too low for the lobar volume; certainly the excessive alveolar number could not be due to increase in blood flow.
In two further specimens, previously dissected, a similar polyalveolar condition was found, associated with emphysema. The patients were older at the time of surgical resection and the emphysema may have developed post-natally. In all three cases the radiographic features had suggested emphysema. It is suggested that the condition be called `polyalveolar lobe', `with emphysema' or `without emphysema' being added as a separate item to the description.
Images
PMCID: PMC472210  PMID: 5494677

Results 1-12 (12)