SUMMARY1. In the chronically catheterized fetal lamb, intravenous infusion of adrenaline at 0 5 jug/min produced slowing of the secretion of lung liquid or its absorption, an effect which increased exponentially with advancing gestation. Between 120 and 130 days, the characteristic response was slowing of secretion, whereas after 130 days it was absorption.2. Stimulus-response curves, relating secretion or absorption rate to plasma adrenaline concentration, were obtained by infusing adrenaline into the fetus intravenously at rates between 0-1 and 1.0 #sg/min (0-55-5 5 nmol/min). These curves allowed estimation of the minimum concentration of adrenaline required to inhibit secretion ([Ai]) and this was found to decrease from 0-43 ng/ml. (2-35 nM) at 132-4 days' gestation to 0-029 ng/ml. (0 16 nM) at gestations above 140 days.3. During spontaneous labour there was a slowing of lung liquid secretion in the early stages followed by absorption during the last 50-150 min. The mean concentration of adrenaline in plasma increased from 0-087 ng/ml. (048 nM) in early labour to 6-86 ng/ml. (37 5 nM) in the last 50 min and to 7-17 ng/ml. (39-2 nM) in the early post-natal period. Mean noradrenaline levels at the same times were 1-71 ng/ml.(10-1 nM), 12-14 ng/ml. (71'8 nM) and 9-10 ng/ml. (53 9 nM). The relationship between the plasma adrenaline concentration and the rate of absorption during labour was similar to that found when adrenaline was infused at various rates into the non-labouring fetus of comparable gestational age.4. The upper airway of the fetus was shown to be capable of acting as a one-way valve allowing outflow but not inflow of liquid. Thus withdrawal of liquid at 5-20 ml./hr from the fetal trachea below the larynx caused closure of the upper airway and this result was obtained both when the recurrent laryngeal nerves were intact and when they were divided.

SummaryWe have examined the effect on lung liquid secretion of catecholamines ipfused in chronically catheterized fetal lambs in utero. Isoproterenol and epinephrine inhibited secretion, an effect which increased with gestation and, in fetuses near delivery, caused absorption of lung liquid. In 7 out of 8 experiments nor-epinephrine had no effect on secretion. This pattern of response and the fact that the inhibitory effect could

2. The permeability sequence of the pulmonary epithelium for alkali metals was, Na+ > K+ > Rb+ > Li+ > Cs+ and that for halides I-Br-> C1-. Permeabilities to alkaline earths were lower than for the other ions, no definite sequence being established.3. There was an electrical potential difference of -1 to -10 mV (mean -4.3 mV) between lung liquid and plasma (lung liquid negative). Plasma/lung liquid chemical activity ratios were less than unity for the halides (Cl-, Br-, I-), and for K+ and Rb+, whereas the ratio of oneway fluxes (plasma --lung liquid)/(lung liquid -+ plasma) was in each case greater than unity. From the difference between the measured flux ratios and those predicted from the forces determining passive flux, it was concluded that the halides, K+ and Rb+ were actively transported from plasma to lung liquid, Cl-being quantitatively the most important. Na+ and Ca2+ appeared to move passively down a gradient of electrochemical potential.R. E. OLVER AND L. B. STRANG 4. When alveolar liquid [HCO ] was artificially raised, a net flux of HCO-from lung liquid against a gradient of electrochemical activity was observed, suggesting active transport of that ion out of lung liquid.5. The addition of KCN to lung liquid stopped the secretion of liquid and absorption took place.

SUMMARY1. Adrenaline was infused intravenously at rates of 0 1-10 tg/min into chronically catheterized fetal lambs (125-141 days gestation) to induce slowing of secretion or reabsorption of lung liquid.2. There was an electrical potential difference (p.d.) of -0 3 to -9-5 mV (mean -3.4 mV) between lung liquid and plasma (lung liquid negative) during control lung liquid secretion. In response to adrenaline infusion, the p.d. increased (lung lumen more negative) and this change was greatest (1-8+0±3 mV) in experiments in which reabsorption occurred.3. Measurements were made of bidirectional fluxes of Na+ and Cl-across the pulmonary epithelium during control lung liquid secretion and during adrenaline infusion. Adrenaline-induced reabsorption of lung liquid was associated with an increase in Na+ flux from lung lumen to plasma. Similar but smaller changes occurred when the adrenaline response was slowing of secretion.

The developing distal lung epithelium displays an evolving liquid transport phenotype, reflecting a changing and dynamic balance between Cl- ion secretion and Na+ ion absorption, which in turn reflects changing functional requirements. Thus in the fetus, Cl--driven liquid secretion predominates throughout gestation and generates a distending pressure to stretch the lung and stimulate growth. Increasing Na+ absorptive capacity develops toward term, anticipating the switch to an absorptive phenotype at birth and beyond. There is some empirical evidence of ligand-gated regulation of Cl- transport and of regulation via changes in the driving force for Cl- secretion. Epinephrine, O2, glucocorticoid, and thyroid hormones interact to stimulate Na+ absorption by increasing Na+ pump activity and apical Na+ conductance (GNa+) to bring about the switch from net secretion to net absorption as lung liquid is cleared from the lung at birth. Postnatally, the lung lumen contains a small Cl--based liquid secretion that generates a surface liquid layer, but the lung retains a large absorptive capacity to prevent alveolar flooding and clear edema fluid. This review explores the mechanisms underlying the functional development of the lung epithelium and draws upon evidence from classic integrative physiological studies combined with molecular physiology approaches.