The Clara cell

Smith, P., Heath, D., and Moosavi, H. (1974).Thorax, 29, 147-163. The Clara cell. The ultrastructure of the bronchiolar Clara cell was examined in normal adult and neonatal rats, in similar animals which had been acutely exposed to hypoxia, and in adult rats following repeated doses of the anorexigen chlorphentermine. The Clara cell has all the features of a secretory cell, the product of secretion accumulating within smooth cisternae at the apex of the cell. The apical region is then extruded into the bronchiolar lumen in a process of apocrine secretion. Acute hypoxia accelerates this secretion in adult rats but has little effect upon neonatal rats. Administration of chlorphentermine induces a hyperplasia of Clara cells which is associated with large quantities of phospholipid free within the alveolar spaces and in macrophages. The Clara cells also contain accumulations of what appear to be phospholipid. This suggests that the Clara cell secretes the phospholipid pulmonary surfactant.     

Quantitative characteristics of the Feyrter (APUD) cells of the neonatal rabbit lung in normoxia and chronic hypoxia.

Our studies show that the apparent number of Feyrter cells in the lung declines during the neonatal period in normoxic rabbits, and that in hypoxic animals a uniformly and significantly lower number of cells occurs as compared with the normoxic rabbits. There is some indication of degranulation of cells in the hypoxic groups. It is suggested that environmental and/or physiological factors associated with the start of extrauterine life, or lung development, may affect the apparent number and probable level of activity of these cells. These changes seem to be enhanced by hypoxia. Mast cells are scarce, and Feyrter cells are relatively more numerous along the airways. These cell types could possibly represent storage sites for 5-hydroxytryptamine, as suggested also by other investigators. Intraepithelial nerve fibres in bronchi and bronchioles were found but they were not limited to innervations of Feyrter cells or related cell bodies.     

Bronchial and extrabronchial factors in chronic airflow obstruction

Leaver, D. G., Tattersfield, A. E., and Pride, N. B. (1974).Thorax, 29, 394-400. Bronchial and extrabronchial factors in chronic airflow obstruction. Chronic airflow obstruction may be due either to disease of the airway wall and lumen or to loss of airway-distending forces acting on the outer wall of the bronchus. In 17 patients with chronic airflow obstruction the relative importance of bronchial and extrabronchial factors was assessed by analysing the relation between airways conductance and static transpulmonary pressure over a range of lung volumes. Using previously established clinical, radiological, and functional criteria (which did not include measurements of the mechanical properties of the lungs), six of these patients had evidence of widespread emphysema and six patients had predominant `bronchial' disease. In four of the six `emphysematous' patients there was no functional evidence of disease of the bronchial wall or lumen during quiet breathing, and airway narrowing could be explained by loss of airway-distending forces. The six patients with characteristic `bronchial' features showed functional evidence of disease of the bronchial wall or lumen.     

Ultrastructure of high altitude pulmonary oedema

Heath, D., Moosavi, H., and Smith, P. (1973).Thorax, 28, 694-700. Ultrastructure of high altitude pulmonary oedema. When rats are exposed for 12 hours to simulated high altitude corresponding to the summit of Mount Everest, they develop ultrastructural changes in the lungs. These consist of the formation and protrusion of multiple endothelial vesicles into the pulmonary capillaries. It seems likely that they are associated with the development of high altitude pulmonary oedema.     

Radiographic appearance of bronchial carcinoid

Altman, R. L., Miller, W. E., Carr, D. T., Payne, W. S., and Woolner, L. B. (1973).Thorax, 28, 433-434. Radiographic appearance of bronchial carcinoid. The chest radiographs of 67 patients with bronchial carcinoid were reviewed. Seven had negative radiographs. Fifty-five had single abnormalities, the common manifestations being collapse or pneumonitis (21 patients), a small peripheral mass (20 patients), and a hilar or perihilar mass (11 patients). Five patients had multiple abnormalities, the most common combination being a mass with evidence of bronchial obstruction such as collapse of the related segment or lobe. Comparison with other reports revealed a significant difference in the frequency of the various abnormalities, a difference probably due to chance variations in the locations and to the age of the tumours at the time of diagnosis.     

Primary haemangiopericytoma of lung

Meade, J. B., Whitwell, F., Bickford, B. J., and Waddington, J. K. B. (1974).Thorax,29, 1-15. Primary haemangiopericytoma of lung. Haemangiopericytoma is a rare neoplasm which may occur at any age and arise in almost any part of the body. At least 247 examples have been reported in the world literature, but only 24 appear to have arisen primarily in the lung. A summary of the features of these cases, collected from the literature, is presented, and four additional cases are described. The tumour may be innocent [ill] malignant, but there are no characteristic clinical or radiological features to distinguish it from other neoplasms of the lung. Because of uncertainty as to diagnosis and prognosis, surgical excision appears to be the treatment of choice. In the whole series of 28 cases, rather more than half (16) were female, and they tended to be older than the male patients. The mortality from recurrence was higher in males than in females (50% compared with 32%). The prognosis in general seems to be best with small, asymptomatic tumours, especially in female patients. A brief account is given of the nature and function of the pericyte. It was originally thought to be a cell of muscular type, but recent research suggests that it is a multipotent cell capable of development into other cell types and having phagocytic properties. It lies in the basement membrane of capillary blood vessels and may have some connection with antibody formation, but its exact function has not yet been elucidated.     

Immunoglobulin and complement inclusions in peripheral blood polymorphonuclear leucocytes of patients with bronchial carcinoma

Jansen, H. M., The, T. H., de Gast, G. C., Huiges, H. A., Esselink, M. T., Van der Wal, A. M., and Orie, N. G. M.Thorax, 32, 706-710. Immunoglobulin and complement inclusions in peripheral blood polymorphonuclear leucocytes of patients with bronchial carcinoma. Inclusions in peripheral blood polymorphonuclear leucocytes (PMN) of 23 patients with bronchial carcinoma, of 11 individuals with chronic obstructive lung disease (COLD), and of 11 healthy controls were studied by the indirect immunofluorescence technique for IgG and complement. The relationships of these inclusions to the clinical stage and histology of the malignant disease as well as the influence of subsequent therapy were studied.     

Effects of chlorphentermine on the rat lung

Heath, D., Smith, P., and Hasleton, P. S. (1973).Thorax, 28, 551-558. Effects of chlorphentermine on the rat lung. Chlorphentermine hydrochloride (`Lucofen') is a sympathomimetic agent which is used in the treatment of obesity at a dosage of 25 mg thrice daily. When this drug, which is available on the British market, was administered intraperitoneally to rats in a dosage of 50 mg per kg body weight for 50 days, they all developed striking pathological changes in the lungs. Numerous large cells with foamy cytoplasm appeared in the alveolar spaces. Groups of them clumped together and disintegrated to pack the alveoli with granular eosinophilic material. The identification of these cells proved to be difficult even by electron microscopy, and this ultrastructural study is described separately in the following paper. During our acute experiments the rats did not develop right ventricular hypertrophy or hypertensive pulmonary vascular disease.     

Pulmonary function in bronchial carcinoma

Legge, J. S., and Palmer, K. N. V. (1973).Thorax, 28, 588-591. Pulmonary function in bronchial carcinoma. Pulmonary function was measured preoperatively in 330 patients with bronchial carcinoma. Obstructive bronchitis was present in 62%. Of 225 patients considered fit for thoracotomy and lung resection, 13 developed postoperative ventilatory failure and six died of this. Those who developed ventilatory failure had more marked airway obstruction, lung hyperinflation, and higher arterial carbon dioxide tensions, and also increased respiratory frequencies and physiological dead space/tidal volume ratios on exercise.     

Serum zinc, bronchiectasis, and bronchial carcinoma

Beeley, J. M., Darke, C. S., Owen, G., and Cooper, R. D. (1974).Thorax, 29, 21-25. Serum zinc, bronchiectasis, and bronchial carcinoma. Serum zinc levels were measured by atomic absorption spectrophotometry in 65 patients with proven bronchiectasis; the mean level was 93 μg/100 ml, while the levels in two groups of healthy control subjects were 88·6 and 92·7 μg/100 ml respectively. The range of individual values was similar in all groups and the differences between the mean serum zinc levels of the two groups of control subjects and the mean level of the group of patients with bronchiectasis were small and did not attain significance at the conventional 0·05 level. In contrast, the mean level in bronchial carcinoma patients (75·9 μg/100 ml) was significantly less than in each of the other groups of subjects.     

Interaction between isoprenaline and aminophylline in asthma

Campbell, I. A., Middleton, W. G., McHardy, G. J. R., Shotter, Margaret V., McKenzie, R., and Kay, A. B. (1977).Thorax, 32, 424-428. Interaction between isoprenaline and aminophylline in asthma. Using a factorially designed study, 38 patients with bronchial asthma received a single dose of either isoprenaline by inhalation (9), aminophylline intravenously (10), isoprenaline and aminophylline (11), or placebo (8). The maximum expiratory flow (V max), the maximum expiratory flow at 50% of vital capacity (V max₅₀), and the concentrations of plasma cyclic AMP were measured at time intervals up to two hours. The combination of isoprenaline and aminophylline acted synergistically in terms of the percent increase in V max₅₀. However, this was statistically significant only at 20 minutes. Plasma cyclic AMP concentration rose with a similar time course of response to the changes in small airways. The elevations in plasma cyclic AMP observed with the drug combination were higher than those for the individual drugs at 10, 20, 30, and 60 minutes but these differences were not statistically significant. These observations support the concept that changes in bronchial smooth muscle tone are mediated by concentrations of cyclic nucleotides and that combinations of isoprenaline and aminophylline, rather than the administration of each drug separately, may have therapeutic advantages in the treatment of bronchial asthma.     

Carbon monoxide paradoxically protects against hypoxia

Background: Tissue hypoxia is fundamental to the development of cellular injury caused by multiple processes, including hemorrhagic shock. Others and we have previously demonstrated that endogenous production of carbon monoxide (CO) by heme oxygenase or exogenous administration of CO can protect against organ injury induced by hemorrhage. The purpose of these experiments was to test the hypotheses that CO abrogates the development of tissue hypoxia in vivo and diminishes effects of hypoxia in vitro.Methods: Male C57/BL6 mice were hemorrhaged to a mean arterial pressure of 25 mmHg. Control animals underwent the same procedure but were not hemorrhaged (sham). Inhalational CO exposure (250 ppm) was initiated concurrently with hemorrhage Mice were administered EF5 (10 μl/g; ip), which is an agent that irreversibly binds to intracellular proteins under hypoxic conditions and can then be detected by immunohistochemistry. Mice were sacrificed after 75 minutes of shock and livers were harvested. For in vitro experiments, primary mouse hepatocytes were exposed to normoxia (21% O₂) or hypoxia 1% O₂) with and without CO (250 ppm). Cells were harvested and assayed for viability, ATP content, or VEGF production. Results: Untreated hemorrhaged mice had a 17-fold increase in EF5 staining compared to shams. Hepatic hypoxia was most pronounced around the central veins. CO-treated hemorrhaged mice had a 79±13% reduction in EF5 staining compared to untreated hemorrhaged mice (P < 0.05). Additionally, CO-treated sham mice demonstrated no significant liver hypoxia. In vitro, CO significantly protected against hypoxia-induced cell death (P < 0.05). Hepatocytes exposed to hypoxia demonstrated a 54 ± 4% reduction in intracellular ATP levels after 6 hours, whereas CO treatment of hypoxic cells resulted in only a 9 ± 3% reduction in ATP (P < 0.01). Likewise, CO significantly inhibited VEGF elaboration by hypoxic hepatocytes. Conclusions: Inhaled low dose CO can paradoxically abrogate liver hypoxia during hemorrhage. Additionally, CO diminishes the consequences of hypoxia in vitro. CO may exert these effects by decreasing cellular metabolic activity and oxygen requirements, though further investigation is required. CO may prove to be a useful clinical adjunct in the treatment of hemorrhagic shock.     

Loss of ciliated cells and altered airway epithelial integrity in cystic fibrosis

BackgroundIn cystic fibrosis, the respiratory epithelium is the target tissue of both the genetic abnormality of the disease and of external aggressions, notably by pathogens (Pseudomonas aeruginosa). A detailed characterisation of the cystic fibrosis bronchial epithelium is however lacking, as most previous studies focused on the nasal epithelium or on cell lines. This study aimed to characterise the abnormal phenotype and epithelial-to-mesenchymal transition in cystic fibrosis bronchial epithelium and to evaluate in cell cultures whether abnormalities persist ex vivo.MethodsExplant lung tissues (n = 44) were assessed for bronchial epithelial cell phenotyping by immunostaining. Human bronchial epithelial cells were derived from basal cells isolated from cystic fibrosis patients or control donors and cultured in air-liquid interface for 2, 4 or 6 weeks.ResultsEnhanced mucin 5AC and decreased β-tubulin expression were observed in cystic fibrosis airways reflecting a decreased ciliated/goblet cell ratio, associated with increased number of vimentin-positive cells, indicating epithelial-to-mesenchymal transition process. These features were recapitulated in vitro, in cystic fibrosis-derived reconstituted epithelium. However, they were not induced by CFTR inhibition or Pseudomonas infection, and most abnormalities tended to disappear in long-term culture (6 weeks) except for increased fibronectin release, an epithelial-to-mesenchymal transition marker.ConclusionsThis study provides new insights into airway epithelial changes in cystic fibrosis, which are imprinted through an acquired mechanism that we could not relate to CFTR function.     

Exercise-induced airway obstruction in relation to chronic obstructive lung disease

Gimeno, F., Berg, W. Chr., Steenhuis, E. J., de Vries, K., Peset, R., and Sluiter, H. J. (1974).Thorax,29, 16-20. Exercise-induced airway obstruction in relation to chronic obstructive lung disease. Forty-two patients with chronic obstructive lung disease and clinically suspected exercise-induced airway obstruction were studied to ascertain whether those with proven exercise-induced airway obstruction had specific distinguishing features. Exercise-induced airway obstruction (defined as a fall of FEV₁ of at least 10% of the pre-exercise values) was detected in 20 of the 42 patients. These 20 were found to have a lower elastic recoil but were otherwise identical with the remainder as regards clinical and physiological abnormality. It is postulated that exercise-induced airway obstruction can be a manifestation of chronic obstructive lung disease.     

An experimental evaluation of continuous normothermic, intermittent hypothermic, and intermittent normothermic coronary perfusion

Hedley Brown, A., Braimbridge, M. V., Darracott, Sally, Chayen, J., and Kasap, H. (1974).Thorax, 29, 38-50. An experimental evaluation of continuous normothermic, intermittent hypothermic, and intermittent normothermic coronary perfusion. Coronary perfusion and hypothermia both have disadvantages, and excellent clinical results are obtained without them, though short operations, spontaneous cooling of unperfused hearts, hyperglycaemia, heparinization, and young and cyanotic subjects may allow more tolerance of ischaemia. Functional, macroscopic, histological, ultrastructural, chemical, and metabolic evidence of the inadvisability of ischaemia, especially of hypertrophied hearts, abounds, though statistical support and histochemical proof are lacking.     

Pulmonary endocrine cells immunoreactive for calcitonin in the lungs of fetal and neonatal rats.

Previous studies have shown that the size of the population of bronchopulmonary endocrine (Feyrter) cells appears to be greatest in fetal and neonatal life. This has led to the logical assumption that these cells are important during this period and undergo a subsequent decline in number thereafter. In this study endocrine cells containing calcitonin or a closely related cross reacting peptide have been demonstrated in the lungs of fetal and neonatal rats by immunoenzyme histochemistry. They appear first about three days before birth and their number, expressed as immunoreactive cells per cm2 of histological section, remains relatively constant for up to three weeks after birth. It has been shown previously in this department that endocrine cells immunoreactive for calcitonin are present in the lungs of the normal adult rat. Their number in these adult animals is closely similar to the numbers of cells in the lungs of the developing animals of the present study. It is suggested that, at least in the rat, bronchopulmonary endocrine cells immunoreactive for calcitonin have a role that is not confined merely to the period of transition from fetal to neonatal life.     

Metabolic aspects of neonatal rat islet hypoxia tolerance

Sensitivity of pancreatic islets to hypoxia is one of the most important of the obstacles responsible for their failure to survive within the recipients. The aim of this study was to compare the in vitro hypoxia tolerance of neonatal and adult rat islet cells and to study the glucose metabolism in these cells after exposure to hypoxia. Islet cells from both age categories were cultured in different hypoxic levels for 24 h and insulin secretion and some metabolites of glucose metabolism were analysed. Glucose‐stimulated insulin secretion decreased dramatically in both cell preparations in response to the decrease in oxygen level. The reduction of insulin secretion was more detectable in adult cells and started at 5% O₂, while a significant reduction was obtained at 1% O₂ in neonatal cells. Moreover, basal insulin release of neonatal cells showed an adaptation to hypoxia after a 4‐day culture in hypoxia. Intracellular pyruvate was higher in neonatal cells than in adult ones, while no difference in lactate level was observed between them. Similar results to that of pyruvate were observed for adenosine triphosphate (ATP) and the second messenger cyclic adenosine monophosphate (cAMP). The study reveals that neonatal rat islet cells are more hypoxia‐tolerant than the adult ones. The most obvious metabolic observation was that both pyruvate and lactate were actively produced in neonatal cells, while adult cells depended mainly on lactate production as an end‐product of glycolysis, indicating a more enhanced metabolic flexibility of neonatal cells to utilize the available oxygen and, at the same time, maintain metabolism anaerobically.     

An antibiotic policy for bacterial infections after thoracic and other injuries

Atherton, S. T., Wright, D. M., White, D. J., and Jones, E. S. (1977).Thorax,32, 596-600. An antibiotic policy for bacterial infections after thoracic and other injuries. Twenty-four patients suffering from thoracic and other injuries were admitted to an intensive care unit over a three-year period. The first four patients died from infection by Gram-negative bacilli with associated features of bacterial toxaemia although it was anticipated that most, if not all, of the patients would have recovered with intensive care. Antibiotics had been started when a patient showed signs of bacterial toxaemia but were ineffective. Retrospective analysis showed that, in each patient, a rapid rise in rectal temperature, white cell count, and blood sugar preceded the clinical features of bacterial toxaemia by one or two days. These observations were incorporated into an antibiotic policy for patients with similar injuries.     

Distribution and ultrastructural characteristics of Feyrter cells in the rat and hamster airway epithelium.

Feyrter cells were found both singly and in groups at all levels of the respiratory tract studied in both rats and Syrian golden hamsters. Particularly large and prominent groups of Feyrter cells were present at bronchiolar bifurcations and bronchiolar-alveolar junctions. Single Feyrter cells were also found throughout the respiratory tract, but their distribution appeared entirely random. In all cases examined the groups of Feyrter cells were overlaid by intermediate and serous secretory epithelial cells. Occasionally small areas of the Feyrter cells were exposed to the airway lumen. Small canaliculi-like intercellular spaces were present between adjacent Feyrter cells. Single unmyelinated axons which contained neurotubules, mitochondria, and vesicles were occasionally seen in close association with Feyrter cells.     

Plasma cortisol and the use of hydrocortisone in the treatment of status asthmaticus

Cayton, R. M., and Howard, P. (1973).Thorax, 28, 567-573. Plasma cortisol and the use of hydrocortisone in the treatment of status asthmaticus. Plasma cortisol, intravenous synacthen tests of adrenal function, arterial blood gases, and spirometric tests of respiratory function were measured in patients with bronchial asthma during clinically stable periods and during status asthmaticus. Intravenous hydrocortisone was given in a predetermined manner in an attempt to measure the effective dose for treatment. The presence of adrenal suppression did not influence the severity of the attack nor the amount of hydrocortisone required for treatment. Clinical signs, arterial oxygen tension, forced expiratory volume, forced vital capacity, pulse rate, and blood pressure gave no indication as to which patients would respond to a single injection of aminophylline or require repeated hydrocortisone for days or weeks. The results are discussed in relation to the mechanism of bronchial asthma.