J.S. Wigglesworth

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.

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.

Effects on lung growth of cervical cord section in the rabbit fetus

Experiments were performed to clarify the mechanism by which cervical cord transection retards lung growth in the fetal rabbit. In 10 sets of fetuses operated on at 24 1/2 days gestation and studied 3--4 days later, cord section at C1--C3 (high section) caused a significantly greater reduction in lung weight and lung DNA than cord section at C5--C8 (low section) as compared with control littermates. Comparison with the lungs of additional control fetuses removed at the time of operation showed that high section had reduced lung growth by 70% and low section had reduced growth by 40% relative to sham-operated controls. The hypoplastic lungs of the high-section group had poorly expanded, thick-walled terminal sacs, while those of the low section group more nearly resembled the controls. Fetal weights and weights of liver, kidneys, thymus and diaphragm did not differ significantly between the groups, but the hearts of the low-section group were unduly large. In a separate 6 sets of fetuses tracheal ligation at the time of high-cord section was found to result in large fluid-filled lungs with a normal DNA content. The results indicate that preservation of an upper motor neurone supply to the phrenic nucleus is of critical importance for fetal lung growth, and confirm the growth-promoting effects of liquid distension of the fetal lungs. We conclude that normal fetal lung growth depends on development and maintenance of a sophisticated form of function involving integration of respiratory movements and lung lipid secretion. This functional control of fetal lung growth has important implications for perinatal medicine.

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.

An integrated model for haemorrhagic and ischaemic lesions in the newborn brain

The vascular anatomy of the developing brain changes from a predominantly basal ganglia orientated pattern at 24 wk to a cortically orientated pattern by 34 wk. This information, combined with other known data on cerebral vascular anatomy and physiology, allows us to develop a model for haemorrhagic and ischaemic lesions in the newborn brain based on two main series of reactions. One series involves the effects of hypoxia and hypercapnia in leading to breakdown of the blood--brain barrier with resultant oedema or haemorrhage. The other links a fall in perfusion pressure and factors causing vasoconstriction with the development of ischaemic lesions. Application of the model involves additional consideration of the state of development of the cerebral vessels at the gestational age concerned. The model helps to explain the observed findings in germinal layer haemorrhage/intraventricular haemorrhage, periventricular leukomalacia and venous infarction, in the preterm brain. Its use also suggests that there are three patterns of vulnerability in the term infant brain. The model carries several implications for the neonatal management of preterm infants. Routine continuous monitoring of blood pressure is of critical importance as cerebral blood flow may vary with blood pressure in the ill newborn. It is important to avoid head compression which may lead to impaired cerebral perfusion. Finally, control of the acid--base status is essential for maintenance of the blood--brain barrier. Correction of abnormal values must be carried out without provoking rapid swings in either the serum osmolarity or the blood pressure.

Ultrasound evolution and later outcome of infants with periventricular densities

The evolution of ultrasound findings in 59 infants with transient periventricular densities is described and the neurodevelopmental outcome of 53 of these infants was compared with 92 of 107 infants with normal ultrasound scans, born during the same 24-month period. Four of the 53 infants with transient periventricular densities developed spastic diplegia and 24 developed transient dystonia, whereas only 8 of the 92 children with normal ultrasound scans demonstrated this finding (P less than 0.001). Persistence of the densities for more than 10 days and the presence of densities in the trigone were especially related with subsequent problems. Postmortem findings in two infants and MRI studies in six infants also suggested that transient periventricular densities represent the milder end of the spectrum of periventricular leukomalacia.

Assessment of elastin maturation by radioimmunoassay of desmosine in the developing human lung

Desmosine has been quantitated in the normally grown fetal and early infant lung by radioimmunoassay. Desmosine could first be detected at 22 weeks gestation: the concentration of desmosine expressed per milligram lung DNA increased in approximately linear form up to about 55 weeks postconceptional age. The concentration in peripheral lung was approximately half that in whole lung homogenates. Lungs of infants dying with acute HMD and lungs of growth retarded infants showed no significant differences from the normals, although there was a tendency for higher desmosine concentrations in prematurely born growth retarded infants.

Quantitative aspects of perinatal lung growth

Weight, DNA, protein, hydroxyproline and disaturated phosphatidylcholine (DSPC) content were investigated in lungs of 97 normally formed infants over an age range from 22 to 75 postconceptional weeks, including 25 cases of hyaline membrane disease (HMD) and 13 small-for-dates infants (SFD). Lung weight and lung DNA relative to body weight were markedly lower in infants who died at 37-41 weeks than in those who died at shorter gestations or in early infancy. Total lung DSPC and DSPC concentration had a narrow peak at 36-41 weeks. The DSPC concentration per milligram of lung DNA in the first few months of infant life was similar to that in infants at 24 weeks gestation. Lung protein concentrations increased steadily but were variable at all ages. SFD infants had significantly higher concentrations of hydroxyproline and showed a peak DSPC concentration at an earlier gestation than the normals. Lungs of HMD infants showed some increase in hydroxyproline concentration but little other quantitative evidence of difference from the normals. We suggest that the relatively small lung size in many infants who die near term may result from recurrent intrauterine stress. Lung changes in small for dates infants are compatible with an advance in lung maturation, while the increased hydroxyproline concentration in the lungs of cases of HMD implies an early proliferative response to lung injury.

Biochemical and Morphometric Analyses in Hypoplastic Lungs

We report the results of biochemical and morphometric studies on lungs of infants with bilateral lung hypoplasia either with or without oligohydramnios (OH or NOH) in comparison with findings in normally grown lungs. The OH and NOH lungs were equally hypoplastic in terms of DNA content but OH lungs had a significantly lower disaturated phosphatidylcholine (DSPC) concentration than NOH or normal lungs, apart from a subgroup with gastrointestinal or airway obstruction. Hydroxyproline concentration in OH lungs was higher than that in NOH or normal lungs. Desmosine concentrations did not differ significantly between groups despite the obvious lack of elastin in the septal crests of the OH group on histology. Morphometry revealed low lung volume, low radial alveolar counts, low alveolar numbers, and low alveolar surface area in both OH and NOH groups. Alveoli and alveolar ducts constituted a higher proportion of lung volume in NOH than in OH lungs. The similarity of most morphometric indices in the two groups implies that maturation does not depend on quantitative elaboration of airways and alveoli. The finding of impaired epithelial maturation despite the high hydroxyproline concentration in the OH lungs suggests an abnormality in epithelial-mesenchymal interaction that is not present in the equally small lungs of the NOH group.

EPITHELIAL CELL MORPHOLOGY AND AIRSPACE SIZE IN HYPOPLASTIC HUMAN FETAL LUNGS ASSOCIATED WITH OLIGOHYDRAMNIOS

The relative frequency of different types of respiratory epithelial cells in normal fetal lungs (control, CON) and hypoplastic lungs associated with oligohydramnios (OH) was determined at the electron microscopic level and airspace size was measured. At 24+ weeks CON lungs had 82.4 +/- 1.2% undifferentiated cells, 15.9 +/- 1.2% type II cells, and 1.7 +/- 0.4% type I cells (n = 3), whereas OH lungs had 94.6 +/- 2.1% undifferentiated cells, 5.4 +/- 2.1% type II cells, and no type I cells (n = 3). At 36+ weeks CON lungs had 7.8 +/- 3.4% undifferentiated cells, 46.1 +/- 3.1% type II cells, and 46.1 +/- 1.4% type I cells (n = 3), whereas OH lungs had 37.7 +/- 1.2% undifferentiated cells, 42.5 +/- 1.7% type II cells, and 19.8 +/- 0.8% type I cells (n = 3). Differences between CON and OH lungs in the proportions of undifferentiated and type I cells at 36+ weeks were highly significant (p less than .001), whereas type II cell proportions did not differ significantly in either age group. The proportion of lung occupied by airspaces increased from 38.3% at 24+ weeks to 68.7% at 36+ weeks in CON lungs but only from 26.7% to 35.7% in OH lungs. The differences between the groups were significant at both 24+ weeks (p less than .01) and 36+ weeks (p less than .001). Mean airspace size in CON lungs varied from 2.8 x 10(-6) mm2 at 24+ weeks to 4.4 x 10(-6) mm2 at 36+ weeks and in OH lungs from 1.7 x 10(-6) mm2 at 24+ weeks to 2.7 x 10(-6) mm2 at 36+ weeks. These results give quantitative expression to the severity of impaired morphologic maturation in OH lungs.