Biomedical subjects

S G Haworth

Publications and source records attributed to S G Haworth.

At least 19 recordsLinked to original sources

PubMed1992

Onset and evolution of pulmonary vascular disease in young children: abnormal postnatal remodelling studied in lung biopsies.

Pulmonary arterial structure was examined in lung biopsies from 26 children with severe pulmonary hypertensive congenital heart disease, aged 2 months-18 years, in whom the mean pulmonary arterial pressure was 55 (range 35-105) mmHg, using light, transmission, and scanning electron microscopy. Qualitative and quantitative techniques were applied and findings compared with those in age-matched controls. At 2 months, the smooth muscle cells showed hyperplasia, hypertrophy (mean cell diameter increased, P less than 0.001), and accelerated differentiation. In all pulmonary hypertensive cases aged less than 6 months, the contractile myofilament concentration was similar to the normal concentration at 6 months. Medial connective tissue was excessive for age. Smooth muscle cells within the intima (intimal proliferation) were first seen at 7 months, lying beneath a new internal elastic lamina. They showed a reduction in myofilament concentration in the more fibrotic lesions. In all cases, endothelial cells were abnormally thick (P less than 0.001) and elongated. Cytoskeletal remodelling was indicated by an increase in micro- and intermediate filament volume density (P less than 0.05 for both). The severity of endothelial damage was related to vessel size and position in the arterial pathway. These findings indicate that pulmonary vascular disease begins at or soon after birth with abnormal pulmonary vascular remodelling which leads to obliterative pulmonary vascular disease.

Adolescent↗

PubMed1992

Developmental changes in endothelium-dependent pulmonary vasodilatation in pigs.

1. We compared in vitro endothelium-dependent vasorelaxant responses to acetylcholine (ACh) and the endothelium-independent vasodilator response to sodium nitroprusside (SNP) in prostaglandin F2 alpha (PGF2 alpha)-precontracted muscular pulmonary arteries (PA) from pigs aged 5 min to 2 h (neonatal), 3-10 days, 3-8 weeks and adults. 2. In the pulmonary artery (PA) rings from neonatal animals, the vasodilator response to ACh was negligible. However, responses to ACh were present in all PA rings from older animals, being greatest at 3-10 days and then decreasing with age (P less than 0.001, ANOVA). ACh (30 microM) induced a 1 +/- 1%, 92 +/- 9%, 62 +/- 5% and 51 +/- 6% reduction of the PGF2 alpha-generated tension in neonatal, 3-10 days, 3-8 weeks and adult groups, respectively. 3. The relaxant response to SNP was present in the PA rings from all age groups and increased with age (P less than 0.001, ANOVA). SNP (1 microM)-induced relaxation was 55 +/- 9%, 73 +/- 7%, 97 +/- 5% and 93 +/- 6% in neonatal, 3-10 days, 3-8 week and adult groups, respectively. 4. Removal of the vascular endothelium abolished the relaxant response to ACh but had no effect on the response to SNP in any groups. 5. NG-monomethyl-L-arginine (30 microM), a nitric oxide synthesis inhibitor, inhibited the response to ACh but not to SNP. The lipoxygenase inhibitor, nordihydroguaiaretic acid, had no significant effect on responses to ACh or SNP in any group.6. These findings suggest that the nitric oxide pathway may not play a part in dilating the pig pulmonary arteries at birth, but may be important during the transitional period of establishing a stable post-natal pulmonary circulation. The increase in response to SNP with age parallels the increase in smooth muscle cell myofilaments to which it may be related.

Acetylcholine↗

PubMed1992

Transient ultrastructural injury and repair of pulmonary capillaries in transplanted rat lung: effect of preservation and reperfusion.

A donor lung is injured during preservation and is generally thought to be further injured by reperfusion on transplantation. Donor lungs from 15 adult male Lewis rats preserved by flush perfusion with cold Marshall's solution at 4 degrees C were examined by scanning and by quantitative transmission electron microscopy after 2, 4, or 7 h of storage at 4 degrees C and after transplantation (syngeneic) at 4 or 12 h (six animals per time interval). During preservation of the donor lung, capillary morphology changed rapidly. Both endothelial cells and type I pneumonocytes thinned (surface/volume ratio increased by 2 h in both; P less than 0.001). Pericapillary edema developed involving the blood-gas barrier. Basement membrane thickness increased significantly (P less than 0.001). Occasional breakage of the endothelial cell sheet occurred after 4 h of preservation, but even after 7 h of preservation there was no evidence of irreversible cell damage. The lamellar bodies of type II pneumocytes aggregated. Changes increased in severity with increase in preservation time. After transplantation, type I and type II pneumonocytes recovered after 12 h, but it took longer for the endothelial cell morphology to recover. Edema decreased rapidly during the first 4 h, despite the number of adherent neutrophils increasing 3-fold. The pulmonary capillaries of the transplanted lung showed no structural evidence of additional reperfusion injury, indicating a satisfactory method of preservation.

Animals↗

PubMed1992

Pathophysiological and metabolic manifestations of pulmonary vascular disease in children.

In children with congenital heart disease pulmonary vascular disease can be fatal for a variety of reasons. Even before the classical changes of advanced pulmonary vascular obstructive disease have developed, a marked increase in pulmonary vascular smooth muscle can be fatal due to pulmonary hypertensive crises. After the Fontan procedure, a modest increase in muscularity can jeopardise the outcome since there is no subpulmonary ventricle to support the pulmonary circulation. Following heart transplantation, a slight increase in muscularity can cause failure of the donor right ventricle unless that heart is already hypertrophied as in the domino procedure. In all children with pulmonary hypertension, either persistent pulmonary hypertension of the newborn or secondary to congenital heart disease the pulmonary vasculature fails to remodel normally after birth. Newborn vessels are characterized by the immaturity of the smooth muscle cells and the paucity of connective tissue. In the hypertensive lung smooth muscle differentiation and connective tissue deposition is accelerated. In children with congenital heart disease intimal changes follow. In these children the potential reversibility of disease following intracardiac repair is determined by the type of pathological change present at the time of repair. However, pulmonary hypertensive crises can occur in young children with potentially reversible disease. Operability is not synonymous with the potential reversibility of pathological lesions. Correlations between structural findings at lung biopsy and haemodynamic findings at cardiac catheterization have improved the accuracy with which the natural and unnatural history of pulmonary vascular disease can be predicted, but is still inadequate because we do not understand the functional implications of the changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Severe pulmonary vascular occlusive disease following bone marrow transplantation in Omenn syndrome.

A 5-month-old infant presented with severe combined immunodeficiency disease, reticuloendotheliosis, and hypereosinophilia (Omenn syndrome) resulting in recurrent infections and endomyocardial disease. Bone marrow transplantation from an HLA-identical donor after chemotherapeutic conditioning led to both immunological and clinical recovery. Bone marrow transplantation, however, was followed by severe pulmonary occlusive disease. The patient gradually recovered while on increased inspiratory oxygen and the calcium channel blocker nifedipine.

Arterial Occlusive Diseases↗

PubMed1991

Surgical factors affecting growth potential of the immature rat lung.

The transplanted immature rat lung has been shown capable of fulfilling its growth potential after left lung transplantation (LLTx) and concomitant right cardiac lobe resection (RCLR). However, unexpected findings in these studies included an abnormal rise in lung volume in the contralateral lung due to alveolar multiplication, and significant dilatation of the bronchi in the transplanted left lung. In the present study, the influence of surgical factors that could have contributed to these changes, i.e. RCLR, denervation, and anastomotic stenosis, were studied individually. Immature Lewis rats aged 4 and 6 weeks were used and (a) RCLR, (b) RCLR and right hilar stripping, and (c) RCLR and left pulmonary artery (PA) banding were performed in groups 1 (n = 12), 2 (n = 5) and 3 (n = 6), respectively. Animals were killed after 6 months and the lungs studied using quantitative morphometric techniques. In groups 1 and 2, right lungs did not show any significant increase in volume. Alveolar number and airway diameter in both lungs in all groups were not significantly different from controls. In group 3 both right and left lungs presented an increase in alveolar size (p less than 0.02 on the right and p less than 0.01 on the left). Changes seen after LLTx in the rat, such as alveolar multiplication, cannot be explained by compensatory growth (RCLR), denervation (RCLR and hilar stripping), or arterial stenosis at the anastomotic site (RCLR and left PA banding), but must be regarded as a consequence of transplantation per se. A role for neuropeptides in lung growth following transplantation is suggested.

Animals↗

PubMed1991

Pulmonary hypertensive crises following surgery for congenital heart defects in young children.

In this clinical study, 20 high risk infants and neonates were monitored to identify and characterize pulmonary hypertensive crises following surgery for congenital cardiac defects. Monitoring included right ventricular or pulmonary artery pressure catheters and transcutaneous oximetry. Eleven patients also had continuous analog recording of hemodynamic data so that antecedents of crises and the sequence of events following treatment could be reconstructed. Eleven of the 20 patients had one or more crises. Six of these ultimately died whereas 5 patients survived with aggressive vasodilator therapy. Four patients without crises but with episodic pulmonary hypertension benefitted from pulmonary vasodilator therapy to ease weaning from ventilatory support. Typically, each crisis was associated with a stress event. Crises were difficult to ablate if not rapidly treated and multiple crises would often cluster following an initial event. High dose narcotic (fentanyl) analgesia was found to be important in the postoperative management. Tolazoline and oxygen were the most consistently useful vasodilators, but isoproterenol and nitrates also played a role. Five of the children who died were examined post mortem: histologically, there was increased pulmonary arterial muscularization in 2, in none were there changes of fixed pulmonary vascular disease. The postoperative management must be individualized on the basis of monitored responses of pulmonary circulation.

Biopsy↗

PubMed1991

Fatal persistent pulmonary hypertension presenting late in the neonatal period.

Two cases of fatal idiopathic persistent pulmonary hypertension presented late in the neonatal period. Lungs were examined histologically by light and electron microscopy, and immunocytochemical studies were used to identify nerves. There was extension of medial smooth muscle distally along the arterial pathway so that most precapillary arteries had completely muscular walls, which in some cases completely obliterated the vessel lumen. Enlarged endothelial cells also contributed to the reduction in the size of the lumen. Nerve fibres accompanying muscular arteries were found in the alveolar region, more distal than is normal. The predominant neuropeptide was the vasoconstrictor tyrosine. Possible aetiological factors in persistent pulmonary hypertension of the newborn are increased muscularity of the peripheral pulmonary arteries antenatally, an increase in the number of vasoconstrictor nerves, or an imbalance in the production of leukotrienes and prostacyclins in the perinatal period.

Humans↗

PubMed1991

Greater permeability of the neonatal lung. Postnatal changes in surface charge and biochemistry of porcine pulmonary capillary endothelium.

Capillary permeability is partly determined by the distribution of anionic charge on the endothelial cell membrane and organelles and on the biochemical composition of these structures. Therefore the pulmonary capillaries of 18 Large White pigs aged less than 10 minutes, 1 week, and 6 months (six animals at each age) were perfused with cationized ferritin and the peroxidase conjugated lectins Dolichos bifloris, concanavalin A, Triticum vulgaris, and Ricinus communis type 2. Lectins bind to the carbohydrate cell surface antigen for which each shows monosaccharide specificity. The ultrastructural localization of each substance on the capillary endothelial cell was studied, and the length of labeled cell membrane was measured. The proportion of intracellular vesicles containing cationized ferritin was also determined. Binding of cationized ferritin to cell membrane and the number of cationized ferritin-labeled vesicles decreased between birth and 1 week (p less than 0.01 for both). Binding of lectins Triticum vulgaris and Dolichos bifloris decreased between birth and 1 week (p less than 0.01 for both) and between 1 week and adulthood (p less than 0.01 for Dolichos bifloris). Binding of concanavalin A and Ricinus communis type 2 showed a nonsignificant increase with age. Thus the area of pulmonary endothelial cell membrane and the proportion of vesicles with a negative charge decreased after birth, and the distribution of cell surface glycoconjugates also changed. Because these microdomains form differentiated pathways that help control transcellular movement of water and solutes, the findings help explain the greater permeability of the newborn lung.

Animals↗

PubMed1990

Pulmonary vascular damage and the development of cor pulmonale following hyaline membrane disease.

Light microscopic morphometric techniques have been used to study the lungs in 17 infants and young children aged 2 weeks to 3.5 years who were born prematurely, developed hyaline membrane disease (HMD), and died with chronic lung disease. They were divided into three groups. In group 1 the babies died without recovering from their initial illness at age 2-13 weeks. In group 2 they died, aged 4-15 months, having recovered from the neonatal illness. Neither group showed clinical or pathological evidence of cor pulmonale (CP). In group 3 children died aged 6 months to 3.5 years with CP. None of the 17 patients had classical fibrotic bronchopulmonary dysplasia (BPD) but all had a reduced alveolar number and an increase in bronchial smooth muscle in small airways. All three groups showed an increase in pulmonary arterial medial thickness (P less than 0.001). In group 1 the appearance of the arteries suggested persistance of the fetal state. In group 2 and 3 the vessels had a more mature structure; in group 3 a marked secondary increase in muscularity was found, approaching the thickness seen in fetal life. In groups 2 and 3 muscle extended into smaller arteries than normal. Vein wall thickness was increased. The alveolar to arterial ratio was normal, the alveolar number was reduced, therefore the total number of arteries was reduced in all three groups. Thus, babies who recover from HMD may have significant vascular abnormalities in the absence of CP; conversely, CP if present, does not mean advanced obliterative pulmonary vascular disease. Thus, pulmonary vascular morphology does not correlate with the presence or absence of CP.

Bronchopulmonary Dysplasia↗

PubMed1990

Kawasaki disease: echocardiographic features in 91 cases presenting in the United Kingdom.

Ninety-one patients with Kawasaki disease were examined by cross sectional echocardiography between 1980 and 1988. In the 75 patients evaluated during the acute phase of the illness (the first month), the first echocardiographic examination was carried out at a mean time of 16 days (range 5-30) and coronary arterial lesions were seen in 21 (28%). Two patients with medium sized aneurysms had myocardial infarctions, and one died. Coronary arterial lesions persisted in 17 (23%) patients, most often in younger children. The remaining 16 patients were examined from one month to four years after their acute illnesses, and this group did not have coronary arterial abnormalities. Seven patients with coronary artery lesions have reached school age and require regular echocardiographic examination and exercise electrocardiography. Selective coronary arteriography may be indicated in some patients to identify coronary artery stenosis, which the Japanese experience has shown may progress for several years after the acute illness.

Acute Disease↗

PubMed1990

Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia.

Blood Pressure↗

PubMed1990

Immunohistochemical localization of peptide-containing nerves in human airways: age-related changes.

Bronchial reactivity changes during childhood, indicating possible changes in neural control. Nerves supplying the intrapulmonary airways were therefore studied in autopsy tissue from 14 normal infants (0 to 3.5 yr), 3 children (8.3 to 10.75 yr), and 4 adults (17 to 24 yr). An indirect immunofluorescence technique was used to study the distribution and relative number of nerve fibers containing the general neuronal markers protein gene product 9.5 and synaptophysin. Nerve subpopulations were identified using antisera to neuropeptide tyrosine, vasoactive intestine polypeptide, somatostatin, substance P, calcitonin gene-related peptide, and the enzyme tyrosine hydroxylase. Between birth and 3 yr, the distribution and relative number of immunoreactive nerves shown by both the general neuronal markers and specific antisera did not change. Neuropeptide tyrosine-immunoreactive nerves were the most common peptide-containing nerve subpopulation identified in the human lung, supplying bronchial smooth muscle, submucosal glands, cartilage, and submucosa. Other peptide-containing nerves exhibited distinct distribution patterns. Two differences in the airway innervation were identified between cases aged 0 to 3.5 yr and the older age groups. Relatively fewer peptide-containing nerves occurred in the adult bronchioli and respiratory unit, but the relative number of vasoactive intestinal polypeptide-containing nerves supplying the bronchial and bronchiolar smooth muscle was greater in the two older age groups. Given these apparent age-related differences in the number of peptide-containing nerves supplying the human airway, studies on the development of peptide receptors are indicated.

Adolescent↗

PubMed1990

Growth potential of the immature transplanted lung. An experimental study.

Syngeneic (Lewis to Lewis) and allogeneic (Brown Norway to Lewis) unilateral left lung transplants were performed on immature rats at 6 weeks of age at a time when alveoli are still multiplying after birth. Left lung denervation without transplantation was performed in a further group of rats (Lewis) by stripping the hilum, at 4 and 6 weeks of age. Animals were killed at either 2 weeks or 6 months after operation. Right and left lungs were analyzed separately by light microscopic quantitative techniques and findings were compared with findings from control animals matched for age and strain. The transplanted left lung in both syngeneic and allogeneic animals continued to grow to a normal size by formation of new alveoli, despite the presence of low-grade rejection activity in the immunosuppressed allogeneic group. The airways showed an increase in diameter for age at the hilum and periphery (p less than 0.01 and less than 0.001, respectively). The volume of the contralateral right lung was greater than normal because of an increase in number (p less than 0.01) and size of alveoli for age. Denervation alone was associated with normal growth of both lungs. Thus it appears that, in rats, the transplanted immature lung can fulfill its growth potential.

Animals↗

PubMed1989

Cytoskeletal features of immature pulmonary vascular smooth muscle cells: the influence of pulmonary hypertension on normal development.

Using an immunohistochemical technique, the development of the cytoskeletal proteins desmin, vimentin, and actin (using alpha isotype and non-isotype specific antibodies) was assessed using a semi-quantitative grading system in the pulmonary vascular smooth muscle of nine normal pigs and 19 normal humans at different ages, and in 13 children with pulmonary hypertensive congenital heart disease. In the normal of both species, immunostaining for vimentin decreased after birth and then increased gradually while immunostaining for desmin and alpha actin increased steadily with age. In pulmonary hypertension, immunostaining for alpha actin and vimentin showed an accelerated increase at between 2 and 8 months. Also, the media showed regional differences in immunostaining which preceded the development of intimal proliferation. The inner media showed less immunoreactivity for all cytoskeletal proteins studied than did the outer media. Within areas of intimal proliferation many cells were immunonegative. These results suggest that the cytoskeletal features of medial smooth muscle cells are remodelled in the normal infant; that this process is altered from at least 2 months in the pulmonary hypertensive infant; and that the smooth muscle cells immediately beneath the internal elastic lamina are remodelled before migrating to form intimal proliferation. Changes in cytoskeletal composition can be related to the previously described postnatal maturation of pulmonary vascular smooth muscle cells.

Actins↗

PubMed1989

Multiple pulmonary arteriovenous fistulas in childhood.

Three cases of multiple pulmonary arteriovenous fistulas are described in children who presented at five months, two and nine years of age. Mass spectrometry was used to measure pulmonary blood flow and, in two cases, the intrapulmonary right-to-left shunt. The shunt fractions were 51% and 35%, with no significant change on breathing 100% oxygen. In one case, effective pulmonary blood flow was measured during cardiac catheterisation by the argon-freon rebreathing method and agreed closely with that found from the Fick, principle with measured oxygen consumption. Treatment consisted of surgical ligation of a lower lobe pulmonary artery in the youngest child, balloon embolisation in the second, and initial surgical oversewing of a single large fistula followed twenty months later by steel coil embolisation in the third. The last and oldest child is well and no longer cyanosed. The first two children died seven months after treatment with evidence of progression of their pulmonary arteriovenous fistulas. The first of these, who also had an atrial septal defect and discordant thoraco-abdominal arrangement, died of heart failure. Autopsies on both children confirmed extensive involvement of both lungs by arteriovenous fistulas. In one case who had a diffuse, telangiectatic form of pulmonary arteriovenous fistulas, microscopic serial reconstructions of lung tissue revealed that anastomoses occurred between arteries accompanying terminal bronchioles and intra-acinar arteries and adjacent veins. Occlusion of the pulmonary arteries supplying the fistulas led to extensive fibrosis within them, and was associated with enlargement of the corresponding bronchial arterial circulation.

Arteriovenous Fistula↗

PubMed1989

A study of nerves containing peptides in the pulmonary vasculature of healthy infants and children and of those with pulmonary hypertension.

Nerves containing peptides that supply the human intrapulmonary vasculature were studied in 21 controls aged one month to 24 years and in 13 patients with pulmonary hypertension aged 11 days to eight years. An indirect immunofluorescence technique was used to study the distribution and relative density of nerve fibres containing the general neuronal marker, protein gene product 9.5; tyrosine hydroxylase; synaptophysin; neuropeptide tyrosine; vasoactive intestinal polypeptide; substance P, somatostatin; and calcitonin gene related peptide. At all ages in normal and hypertensive lungs neuropeptide tyrosine was the predominant neuropeptide associated with the pulmonary vascular nerves. In normal lungs the relative density of nerve fibres increased during childhood only in the arteries of the respiratory unit. Pulmonary hypertension was associated with the premature innervation of these arteries during the first year of life. Innervation of small, abnormally thick-walled pre-capillary vessels by predominantly vasoconstrictor nerves may help to explain the susceptibility of infants to pulmonary hypertensive crises.

Age Factors↗

PubMed1989

Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation.

Light microscopic morphometric techniques were used to study the inflated airways of 17 normal infants from 22 wk of gestation to 8 months postnatal age, plus three young adults. In addition, the lungs of four premature and seven mechanically ventilated infants were studied. A computer-assisted digitizer was used to measure airway diameter and to determine the area of cartilage, gland, and muscle in each type of airway. Epithelial height was also measured, and goblet cell number was counted. Using histochemical stains, types of glycoprotein were identified in goblet cells and submucosal glands. Between 22 wk of gestation and 8 months of age, the normal infant showed a linear increase with age in airway diameter. With age the area of muscle and submucosal gland increased in total amount and showed a significant linear increase when related to the size of the airways, except the submucosal gland in hilar airways. By contrast, the increase in cartilage was only commensurate with the increase in size of intrapulmonary airways, but showed a linear size-related increase in the main bronchus. Epithelial height and goblet cell number increased with age in the bronchi, but not more peripherally. Premature infants had for their postconceptional age normal-sized airways with an increase in amount of bronchial smooth muscle and an increase in number of goblet cells. Ventilated infants had a greater increase in smooth muscle (p less than 0.05 to p less than 0.002) and goblet cells (p less than 0.05) and an increase in submucosal gland area (p less than 0.04) whether or not the infant had had hyaline membrane disease.

Bronchi↗