Biomedical subjects

A A Hislop

Publications and source records attributed to A A Hislop.

At least 37 records · Page 2Linked to original sources

PubMed1997

Chronic hypoxia inhibits postnatal maturation of porcine intrapulmonary artery relaxation.

Neonatal pulmonary hypertension is associated with increased pulmonary vascular reactivity. We studied the responses of isolated porcine intrapulmonary arteries after exposure of piglets to chronic hypobaric hypoxia (CHH) from 0 to 2.5, 3 to 6, or 14 to 17 days of age. CHH inhibited the postnatal development of endothelium-dependent vasorelaxation to acetylcholine (ACh) and the calcium ionophore A-23187. Basal accumulation of guanosine 3', 5'-cyclic monophosphate (cGMP) was unaffected, but cGMP response to ACh was inhibited. Endothelium-independent relaxation to nitric oxide (NO) and zaprinast (a phosphodiesterase inhibitor) was also inhibited, but cGMP accumulation in response to these agonists was normal. The ability of sodium nitroprusside (SNP) to cause vasorelaxation and increase cGMP accumulation was unaffected. Contractile responses to potassium chloride and prostaglandin F2 alpha (PGF2 alpha) were similar to normal after exposure from birth and 3 days and were decreased in the older group, but the ability of NG-monomethyl-L-arginine acetate to increase PGF2 alpha-induced contractions decreased. Thus exposure of newborn piglets to CHH causes 1) no increase in contractile responses and 2) impairment of endothelium-dependent and -independent relaxation by impairing signal transduction mechanisms involved in the release of NO and the effectiveness of cGMP.

Acetylcholine↗

PubMed1995

Early abundance of nerves containing NO synthase in the airways of newborn pigs and subsequent decrease with age.

We have localized by immunocytochemistry, and quantified by intercept counting, NO-synthase-containing nerves in newborn pig intrapulmonary airways and maturational changes in their density in juvenile and adult lung. NO-synthase-containing nerves supplying airway smooth muscle and epithelium were evident at all ages (< 2 h, 1-2 days, 3-5 days, 6-10 days, 10 and 16 weeks). They were most abundant in neonates, and their density decreased with age (intercepts/mm2 +/- SEM: newborn, 94 +/- 3.3; 16 weeks, 7 +/- 0.3; P < 0.001), as did their percentage of the total nerves defined by the general neuronal marker PGP 9.5 (newborn, 38 +/- 2.7%; 16 weeks, 18 +/- 2.3%; P < 0.01). Neural-derived NO may be important in pulmonary adaptation to extra-uterine life.

Age Factors↗

PubMed1995

Abundance of endothelial nitric oxide synthase in newborn intrapulmonary arteries.

A monoclonal antibody to endothelial NOS (eNOS) was used to demonstrate the distribution and density of eNOS in the developing porcine lung. Lung tissue from large white pigs aged from less than 5 minutes to 3 months was immunostained and, using light microscopy, distribution of eNOS was assessed by a semiquantitative scoring system. At all ages eNOS was located on the endothelial cells of pulmonary and bronchial arteries and veins. Immunoreactivity for eNOS was greater in the larger, more proximal pulmonary arteries than at the periphery. In the lung of newborn pigs immunoreactivity for eNOS was present in arteries of all sizes but some showed no positive staining. At 2-3 days of age almost all arteries showed positive immunoreactivity. By 3 months of age the amount of eNOS had decreased and was less than that seen in the newborn. The highest level of eNOS was seen immediately after birth when the pulmonary arteries are dilating. eNOS may therefore play an important part in adaptation to extra-uterine life.

Animals↗

PubMed1995

Postnatal changes in endothelin-1 binding in porcine pulmonary vessels and airways.

As the lung adapts to extrauterine life, the structure of the intrapulmonary arteries changes rapidly, in a similar manner in humans and pigs. The response to exogenous endothelin also changes in the perinatal porcine lung. Therefore we investigated the distribution and type of endothelin binding sites in the airways and vasculature of six to eight pig lungs in each of five age groups, from birth to adulthood. Using an in vitro autoradiographic technique, the distribution and density of 125I ET-1 binding was determined and characterized. At all ages, dense ET-1 binding was localized over the pulmonary and bronchial arteries and veins, bronchial smooth muscle, and the parenchymal region. Muscular pulmonary arteries and pulmonary veins had a higher density of binding than elastic arteries (P < 0.01). Between birth and adulthood, binding density decreased in extrapulmonary arteries (P < 0.05) and bronchial arteries (P < 0.01). The elastic intrapulmonary arteries showed a transient increase in binding density at 2 to 3 days of age (P < 0.05) and the muscular intra-pulmonary arteries showed one at 10 days of age (P < 0.05). The ETA antagonist BQ-123 and the ETB agonist sarafatoxin 6c were used to identify the receptor subtypes. Both subtypes were found on the medial smooth muscle cells at all ages. The majority of binding sites in the pulmonary arteries were ETA (75 to 92%). At 2 to 3 days of age only, ETB receptors were seen on the endothelium of the elastic pulmonary arteries, increasing the proportion of ETB receptors present. Thus we have demonstrated changes in endothelin receptors at a time when pulmonary vascular resistance falls. Their physiologic role remains to be elucidated.

Age Factors↗

PubMed1993

Growth of immature lung transplanted into an adult recipient.

Syngeneic (Lewis-to-Lewis) and allogeneic (Brown Norway-to-Lewis) unilateral left lung transplants were performed between immature rats aged 6 wk (donors) and adult animals aged 4 mo (recipients). Transplanted animals were killed either 2 wk or 6 mo after operation. Right and left lungs were analyzed separately by quantitative light microscopic techniques, and findings were compared with control animals matched for age and strain. The immature transplanted left lung continued to grow to achieve its predicted adult number of alveoli. Six months after transplantation the alveoli and airways were larger than controls in allogeneic animals (P < 0.001) but were of normal size in syngeneic animals. After both syngeneic and allogeneic transplantation the recipient contralateral mature native right lung showed an increase in volume after 6 mo (P < 0.001), abnormal in a mature lung, due to an increase in size (P < 0.01 in allogeneic, P < 0.05 in syngeneic) and alveolar number (P < 0.02 in both). This study indicates that in rats, transplanted immature lungs can fulfill their growth potential even when transplanted into mature recipients.

Aging↗

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↗

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↗

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

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

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↗

PubMed1988

Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease.

Pulmonary vascular resistance was measured in air, oxygen, and after administration of vasodilators in 14 children with pulmonary hypertension and congenital heart disease. Lung morphology was examined by light microscopy and assessed quantitatively. In this selected group of patients (a) medial muscle thickness of greater than 20% in the intra-acinar arteries and Heath-Edwards changes of I or II were significantly associated with perioperative death from pulmonary complications after cardiac surgery; (b) children with lower percentage medial muscle thickness had a higher baseline resistance (r = -0.84) associated with Heath-Edwards grade III or higher changes (most of these patients were not offered corrective surgery); (c) when the lowest pulmonary vascular resistance was less than 3 units, Heath-Edwards grading was I or II (n = 4). When the pulmonary vascular resistance was greater than 6 units, however, there was no direct correlation with Heath-Edwards grading (n = 9). Four patients with a resistance of greater than 6 units had only grade I or II changes. Three had a medial muscle thickness above 20%, and were among those who died at or soon after operation. It is concluded that (a) patients with a lowest pulmonary vascular resistance of greater than 6 units have a bad prognosis whatever their lung morphology; and (b) some patients with Heath-Edwards grade I or II will have a high resistance (this group has a high medial muscle mass and a poor prognosis and would not be detected by Heath-Edwards grading alone).

Adult↗

PubMed1987

The effects of preterm delivery and mechanical ventilation on human lung growth.

The effects of preterm birth and mechanical ventilation on growth of the alveolar region of the lung were assessed by morphometric and/or quantitative biochemical methods in the lungs from 104 perinatal and infant autopsies. The lungs of 4 preterm infants who died at 4-16 weeks age without having received mechanical ventilation were large relative to body weight but showed normal alveolar number and alveolar surface area. Infants treated by mechanical ventilation for hyaline membrane disease (HMD) and who died at ages from 1 week up to 14 months showed impairment in alveolar development evidenced by low alveolar number and a low alveolar surface area. Lung volume and total lung DNA values were relatively normal. Dilated alveolar ducts were a feature at all ages with emphysematous changes apparent in the longest surviving infants. Biochemical features included a high concentration of hydroxyproline, reflecting collagen, and a high desmosine concentration, reflecting elastin, in infants dying at less than 60 weeks postconceptional age. Changes in the lungs of infants ventilated at low pressures for conditions other than HMD were of a similar nature but less severe than those seen in the HMD group. These findings indicate that preterm birth alone may have little adverse influence on lung development but that conditions necessitating mechanical ventilation may lead to permanent impairment in alveolar development. We postulate that the standard technique of applying positive pressure ventilation may itself lead to impaired alveolar growth, although the effect is enhanced by concomitant HMD and BPD.

Apnea↗

PubMed1987

Fetal lung growth in congenital laryngeal atresia.

Morphometric and biochemical indexes of lung growth were measured in 2 cases of uncomplicated laryngeal atresia at 27 and 30 weeks gestation and in 1 case of cryptophthalmos syndrome with anomalies including laryngeal atresia and renal agenesis. Findings were compared with those in normally formed fetuses and newborn infants. The cases of pure laryngeal atresia showed a marked increase in surface area and lung volume for age, associated with an increase in alveolar number and apparent advance in elastin maturation, but little increase in cell population as measured by lung DNA content. Alveolar walls were thin but there was no increase in disaturated phosphatidylcholine (DSPC) content. Similar features were observed in the case of cryptophthalmos in marked contrast to the lung hypoplasia expected to result from renal agenesis. The results give further support to the importance of lung liquid retention for normal fetal lung growth. Overdistention with lung liquid appears to promote alveolar development by redistribution of cells rather than increase in cell population.

Female↗

PubMed1986

Alveolar development in the human fetus and infant.

The lungs from 29 infants aged from 29 weeks of gestation to 18 weeks postnatal age were studied using morphometric analysis; total DNA was estimated in 12 of these. Alveoli could first be counted and measured at 29 weeks gestation; with increasing age they became more mature in appearance as the walls elongated and thinned, and they gradually increased in diameter. Lung volume increased 4-fold between 29 weeks and term, and further doubled in the 4 months after birth. Lung volume, alveolar surface area and DNA all increased linearly with age and weight. Alveolar number showed a curvilinear increase with age and DNA, but a linear relationship to body weight. At birth the lungs had an average of 150 million alveoli, half of the expected adult number. There was a wide normal range. The surface area was between 3 and 5 m2 at birth, one twentieth of the adult value.

Body Weight↗

PubMed1983

Pulmonary vascular development: normal values of peripheral vascular structure.

Uninjected postmortem normal lung from 49 children aged 1 hour to 14 years was studied using quantitative morphometric techniques to assess arterial size, number and muscularity, particularly in the respiratory region of lung. Arterial size increased most rapidly during the first 2 months of life, but growth rate remained high during the first 4 years. At all ages, the range of values for the mean external diameter of arteries accompanying peripheral airways was considerable, but marked differences from the normal range were usually associated with a marked difference in stature. Arterial number increased rapidly in the first 2 months, but subsequently arteries multiplied at the same rate as alveoli, and the alveolar:arterial ratio was relatively constant. Mean percentage arterial medial thickness fell quickly during the first 10 days and continued to decrease during the first 3 months of life, after which there was little change. The intra-acinar arteries became more muscular during childhood as they increased in size. Vein muscle wall thickness was low throughout childhood. The normal values given in this paper provide a basis for the evaluation of lung biopsies in childhood.

Child↗

PubMed1983

Effect of tracheostomy on lung development in fetal lambs.

The effects of fetal tracheostomy on lung development in lambs have been investigated. Seven ewes, all with twin fetuses, were given a general anesthetic. One fetus in each set of twins was tracheostomized and the other fetus was sham operated (117-122 days gestation). The fetuses were delivered by cesarean section between 137 and 140 days gestation. Fetal tracheostomy decreased lung weight and volume, altered DNA concentration and the structural development of the acinus, and decreased lung distensibility. However, tissue and airway saturated phosphatidylcholine and lung stability during deflation were not significantly affected by fetal tracheostomy. It seems that tracheostomy in fetal lambs alters lung growth but does not affect the formation or release of surfactant. These data support the hypothesis that lung volume is actively maintained and lung growth promoted by the secretion of lung fluid against the resistance of the upper airway in fetal lambs.

Animals↗