The rate of transfer of a hydrophilic solute from the alveoli to pulmonary blood following inhalation as an aerosol depends on the molecular size of the solute and the permeability of the alveolar epithelium. The value of this measurement for assessing damage to the epithelium in lung disease is compromised by cigarette smoking, which accelerates clearance by unknown mechanisms. The rates of clearance of 99m Tc-labelled diethylenetriaminepenta-acetic acid (DTPA) (molecular mass 492 Da) and 113m In-labelled biotinylated DTPA (B-DTPA) (molecular mass 1215 Da) were monitored simultaneously by dynamic γ-radiation camera imaging following simultaneous inhalation, and compared between eight normal non-smoking subjects and nine habitual cigarette smokers. The clearance rates of DTPA were 0.95 (S.D. 0.39)%/min in non-smokers and 4.13 (1.06) %/min in smokers. These were about twice the clearance rates of B-DTPA, which in the corresponding groups were 0.41 (0.26) and 2.12 (0.72)%/min respectively. The ratio of the B-DTPA/DTPA clearance rates was, in all subjects, less than the ratio (0.74) of the cube roots of the molecular masses of the solutes, assumed to correspond to the ratio of their free diffusion coefficients in water, and was not significantly different between smokers and non-smokers. As alveolar permeability increased, the ratio of clearance rates in the entire population showed a significant trend to increase in a non-linear fashion towards the value corresponding to the ratio of the free diffusion coefficients. We conclude that the diffusion of at least the larger of these two solutes through the pulmonary alveolar epithelium is restricted (i.e. associated with a reflection coefficient greater than zero). Cigarette smoking, however, does not appear to cause a loss of this restriction, and may increase solute clearance by other mechanisms, such as reducing fluid volume within the alveolus, thereby raising the local radiotracer concentration, or increasing the number of pores available for solute exchange without affecting pore size. Conversely, if restriction was lost in lung disease, the ratio of the clearance rates of two solutes of dissimilar sizes could be used to detect disease in smokers as well as non-smokers.

The aim of the study was to measure the peripheral blood levels of soluble E-selectin in patients with systemic inflammation and compare them with in vivo granulocyte activation, pulmonary intravascular granulocyte pooling, pulmonary extravascular granulocyte migration and 99m Tc-diethylenetriaminepenta-acetic acid (DTPA) aerosol clearance, an index of lung injury. The level of soluble E-selectin was measured by capture ELISA. Granulocytes were labelled with 111 In and 99m Tc for quantification of pulmonary granulocyte kinetics. The pulmonary vascular granulocyte pool (PGP) was expressed as a fraction of the total blood granulocyte pool. Pulmonary granulocyte migration was quantified on 24-h images using the 111 In signal. Granulocyte activation was quantified as the percentage of circulating cells showing shape change (‘primed’). Lung injury was assessed from the clearance rate of inhaled 99m Tc-DTPA aerosol. Eighteen patients with systemic inflammation were studied: five with inflammatory bowel disease, eight with systemic vasculitis, four with graft versus host disease and one with a recent renal transplant. The peripheral blood levels of soluble E-selectin were significantly elevated in patients with systemic inflammation. The level of soluble E-selectin showed a significant association with granulocyte migration (Spearman rank correlation coefficient, R s = 0.53; P < 0.05) but not with PGP or with the percentage of cells showing shape change ( P > 0.05 for both). Granulocyte migration was bimodal: patients were therefore subdivided into ‘migrators’ and ‘non-migrators’. Soluble E-selectin level, 99m Tc-DTPA clearance and PGP, but not the percentage of cells showing shape change, were significantly higher in migrators than in non-migrators. We conclude that pulmonary intravascular granulocyte pooling is increased in the presence of increased numbers of circulating primed granulocytes but increased pooling does not by itself promote granulocyte migration into the lung interstitium. Insofar as an elevated level of E-selectin in peripheral blood reflects vascular endothelial activation, the data are consistent with the notion that pulmonary endothelial activation is required, in addition to granulocyte activation and an expanded PGP, for granulocyte migration into lung parenchyma and, therefore, for lung injury to occur.

1. The aim of the study was to examine the relationship between granulocyte activation, pulmonary intravascular granulocyte transit, pulmonary extravascular granulocyte migration and lung injury in patients with systemic conditions (bone marrow transplant recipients, inflammatory bowel disease and systemic vasculitis) in which abnormalities of pulmonary granulocyte traffic have previously been reported. 2. A double 111 In- 99m Tc granulocyte labelling technique was used for quantification of granulocyte kinetics in 23 patients, of whom five were control patients. The pulmonary vascular granulocyte pool was measured from dynamic data centred on the 99m Tc signal and expressed as a percentage of the total blood granulocyte pool. Granulocyte migration was quantified on 24 h images using the 111 In signal. Granulocyte activation was measured as the percentage of cells showing a change in shape. The clearance rate of an inhaled aerosol of 99m Tc-diethylenetriaminepenta-acetic acid (DTPA) was used as a marker of lung injury. 3. Pulmonary granulocyte pool, migration, activation and aerosol clearance, although highly variable in the patient groups, were, in general, elevated compared with the controls. 4. Granulocyte activation correlated with pulmonary granulocyte pool ( Rs = 0.72, n = 22, P <0.01), while the t 1/2 of DTPA clearance correlated with migration ( Rs = −0.84, n = 17, P < 0.01). Fifteen patients had an expanded pulmonary granulocyte pool, of whom six with no evidence of migration, had a normal DTPA clearance, while nine, who had an abnormal migration signal, had an accelerated DTPA clearance. The pulmonary granulocyte pool in these nine was significantly higher than in the six without a migration signal. 5. Activation of granulocytes results in delayed transit through the lung vasculature. With increasing margination, granulocytes migrate into the lung interstitium and injure the lung. An increased intravascular pool does not by itself lead to lung injury.

1. The effects of the continuous infusion of atrial natriuretic peptide on the development of pulmonary hypertension were studied in rats exposed to chronic hypoxia. 2. Continuous intravenous infusion of two doses of synthetic rat atrial natriuretic peptide, 300 ng/h per rat (0.10 pmol/h per rat) and 800 ng/h per rat (0.28 pmol/h per rat), attenuated the development of pulmonary hypertension in rats exposed to chronic hypoxia (fractional concentration of oxygen in inspired air = 10%) for 7 days: (i) the pulmonary artery pressure (mean ± sd ) in the vehicle-treated hypoxic group was 45 ± 6 mmHg compared with 28 ± 6 mmHg in the vehicle-treated normotoxic group ( n = 8, P < 0.001); (ii) treatment with atrial natriuretic peptide in normoxia did not alter the pulmonary artery pressure, systemic blood pressure or heart rate; (iii) treatment with atrial natriuretic peptide in hypoxia resulted in a lower pulmonary artery pressure in the group treated with 800 ng of atrial natriuretic peptide/h per rat (38 ± 8 mmHg, P < 0.05 compared with the vehicle-treated hypoxic group) without affecting the systemic blood pressure or heart rate. 3. Chronic hypoxia resulted in an extension of vascular smooth muscle towards the periphery of the lung with the development of muscle in normally non-muscularized vessels (remodelling). Quantitative assessment of the small pulmonary vessels (external diameter 25–55 μm) showed that atrial natriuretic peptide treatment reduced pulmonary vascular remodelling in hypoxia (the percentage of thick-walled vessels in the peripheral lung hypoxic vehicle-treated group was 25 ± 6 compared with 19 ± 4 in the group given 300 ng of atrial natriuretic peptide/h per rat and 17 ± 7 in the group given 800 ng of atrial natriuretic peptide/h per rat, means ± sd , both P < 0.01 compared with the vehicle-treated normoxic group). 4. These data show that infusion of synthetic atrial natriuretic peptide attenuated the pulmonary vascular remodelling and associated pulmonary hypertension produced by chronic hypoxia.

1. In seven normal subjects the ventilatory responses to progressive isocapnic hypoxia and hyperoxic hypercapnia were measured during rebreathing. 2. During an infusion of somatostatin (10 nmol/mm) the mean hypoxic response decreased by 66% (control: − 1.6 sd 1.2 litres min −1 % −1 S ao 2 : somatostatin: − 0.6 sd 0.7) but the mean hypercapnic response was unchanged (control: 2.0 sd 0.8 litre min −1 mmHg −1 ; somatostatin: 2.3 sd 1.2). There was no change in resting V ˙ O 2 or V ˙ CO 2 during somatostatin infusion. 3. The opiate antagonist, naloxone (0.1 mg/kg, intravenously), caused little change in either response (mean hypoxic response: − 1.7 sd 1.0 litre min −1 % −1 S ao 2 ; mean hypercapnic response: 2.4 sd 0.9 litre min −1 mmHg −1 ). 4. In five of the subjects the dopamine antagonist, prochlorperazine (10 mg, intravenously), increased the mean hypoxic response by 134% (control: − 1.9 sd 1.4 litres min −1 % −1 S ao 2 ; after prochlorperazine: − 3.8 sd 1.6; P < 0.05). The mean hypercapnic response after this drug was also increased (control: 2.1 sd 1.0 litre min −1 mmHg −1 ; after prochlorperazine: 3.1 sd 1.0) but this change did not achieve significance. 5. The selective effect of somatostatin on the hypoxic response, suggestive of an action on the carotid body, was not inhibited by prior injection of either naloxone or prochlorperazine, and its mode of action remains to be found.

1. Almitrine bismesylate (5–10 μg/kg) was given as an intravenous bolus to anaesthetized, paralysed dogs (a) with closed-chest ( n = 5) and (b) with open-chest ( n = 7) in whom the retrocardiac lobe was separately ventilated. Pulmonary, lobar and systemic haemodynamics were measured under hypoxic, normoxic and hyperoxic conditions. Total pulmonary blood flow was measured by thermodilution and lobar flow by electromagnetic flow meter. 2. In the closed-chest preparations, almitrine caused an increase in pulmonary vascular resistance (PVR) at all levels of inspired oxygen, the increments being 82% (30% O 2 ), 91% (air) and 9% (13% O 2 ). The control PVR varied inversely with arterial P o 2 but there was no significant interaction between the almitrine and hypoxia induced vasoconstriction with multiple linear regression analysis. 3. In the open-chest preparations, PVR and lobar vascular resistance (LVR) increased after almitrine by 48% and 41% respectively when both lung and lobe inspired 30% O 2 . When the lobe was switched to 12.5% O 2 or nitrogen (lung inspiring 30%) PVR again increased (+ 52%) after almitrine but LVR decreased in five of seven lobes (lobar flow increasing despite constant cardiac output), the overall change being − 4%. Analysis of covariance showed that the lobar response to almitrine was significantly different under hypoxic conditions compared with hyperoxic ( P < 0.05). 4. With ventilation maintained constant, there was no significant change in arterial P o 2 after almitrine in any experimental condition. 5. In conclusion, almitrine is generally a pulmonary vasoconstrictor but can dilate vessels when they are constricted by local hypoxia. Almitrine does not enhance local hypoxic vasoconstriction in the dog.

1. Almitrine at a low dose of 100 mg orally significantly raises P ao 2 and lowers P aco 2 in patients with chronic obstructive pulmonary disease, compared with placebo, when they were breathing air or 28% oxygen. 2. The estimated ideal alveolar — arterial P o 2 difference was less after almitrine compared with placebo, when patients were breathing either air or 28% oxygen. 3. After almitrine overall ventilation breathing air increased by 10% but this did not reach statistical significance. During 28% oxygen breathing almitrine hardly altered overall ventilation but the inspiratory duty cycle (T i /T tot. ) decreased and mean inspiratory flow rate ( V T /T i ) increased compared with placebo. These changes were significant on a paired t -test ( P <0.05). 4. Changes in both volume and pattern of breathing may explain the improved gas exchange in the lung after almitrine.

1. Serial estimations of the diffusing capacity for carbon monoxide, with a standard single-breath technique, were used to assist the monitoring of disease activity in patients at risk from intrapulmonary haemorrhage. 2. A reversible rise in diffusing capacity for carbon monoxide per unit alveolar volume ( D L co/ V A ) of 50% or more above baseline values was detected on 61 occasions and in the diffusing capacity for carbon monoxide ( D L co) alone on 45 occasions in 39 patients. 3. Concurrent with these rises in D L co /V A or D L co, two or more traditional indicators of intrapulmonary haemorrhage (haemoptysis, abrupt fall in haemoglobin concentration, chest X-ray opacities) were found on 47 occasions. 4. In the appropriate clinical context, acute reversible rises in D L co/ V A or D L co reflect active intrapulmonary haemorrhage.

1. The distribution of regional function in the lungs of six patients with bilateral diaphragmatic paralysis was investigated by continuous inhalation and infusion of the radioactive gases 81m Kr and 85m Kr during tidal breathing. 2. In the supine and right lateral decubitus postures the vertical distribution of ventilation per unit alveolar volume was less in the dependent zones, the reverse of that found in normal subjects. In the upright posture ventilation was slightly decreased at the lung base. Perfusion per unit alveolar volume was more uniformly distributed than normally in the upright posture, and decreased from superior to inferior in the supine posture. In the lateral decubitus posture, perfusion of the lower lung was greater than that of the upper. Ventilation/perfusion ratios were more uniformly distributed in the patients than in normal subjects, except in the right lateral decubitus posture. 3. Alterations in the distribution of ventilation may be explained in terms of the altered mechanical interaction of chest wall, mediastinal and abdominal contents, with selective use of intercostal and accessory muscles. The effects on the distribution of blood flow are probably related to the low end-expiratory lung volume.

1. Ten studies were performed on nine patients with haematological disorders but with normal lungs, who required intermittent blood transfusions. The transfer factor for carbon monoxide and uptake of carbon monoxide per unit lung volume ( K CO ) were measured with the single breath technique before and at various intervals after transfusion. 2. The mean haemoglobin concentration increased from 7·7 to 11·1 g/dl. 3. The T L CO increased according to a formula based on the Roughton & Forster (1957) diffusion equations, T L CO (standardized) = T L CO (observed). (10·2 + Hb)/1·7 Hb, where haemoglobin (Hb) is expressed as g/dl. 4. The correlation between measured and predicted values was slightly better if changes in alveolar volume were taken into account, by using the K CO value.

1. Sixteen patients with chronic bronchitis and airways obstruction were given radioactive nitrogen ( 13 N) by intravenous injection and by inhalation, while breathing air and after 10–20 min breathing 30% oxygen. The clearance of 13 N from four zones of each patient's whole lung field was monitored. 2. The 13 N clearance of each region in these patients with chronic bronchitis was much slower than in normal subjects. Oxygen breathing produced a significant delay in the clearance of intravenously administered 13 N in 23 zones in 10 patients but no systematic change in clearance after inhaled 13 N. 3. With inhalation of 30% oxygen there was no significant change in the mean minute ventilation, tidal volume or arterial P co 2 . 4. The results suggest that local hypoxic vasoconstriction is present in some patients on breathing air and that this is relieved by 30% oxygen, resulting in a diversion of local blood flow from well-ventilated to more poorly ventilated areas. The fall in V̇ A /Q̇ on 30% oxygen is insufficient to increase arterial P co 2 .

1. Seated subjects stopped ventilation briefly at end expiration while a 5 ml bolus of 133 Xe was injected close to the mouth. They then inspired air at different flow rates and the distribution of radioactivity in the lungs was measured with a scanning technique during a period of breath-holding at maximal inspiration. 2. In five normal subjects the dependent zones received a greater fraction of the 133 Xe bolus than the apex during slow inspirations, but apical distribution exceeded basal for fast inspirations. The volume history of the lungs before the bolus injection had no effect on the slow/fast difference in four out of five subjects. 3. In five patients with clinical bronchitis but normal forced expired volume, dependent zone ventilation was much reduced on a slow inspiration compared with normals, but at fast flow rates the distribution was normal. 4. Insofar as the bolus in the fast inspiration was distributed according to regional airway conductances, these results suggest that in normal subjects differences in airway resistance exist between the upper and lower zones of the upright lung. An early abnormality in bronchitis appears to be a reduction of compliance in the dependent zones, as judged from the decrease in basal ventilation on a slow inspiration.