Rat lungs as affected by an acute exposure to an increased level of carbon dioxide in the ambient air

Changes in lung characteristics of healthy adult male rats were studied following a 24-hr exposure to 15% CO₂ in air. The animals were weighed before and after the exposure period. Following the CO₂-exposure, the lungs of the rats were removed and their weights were determined. Continuous pressurevolume curves including inflation and deflation first with air and then with 0.9% saline were recorded from the excised lungs. The average gain in body weight of the control rats during the 24-hr period was 9 g while the CO₂-exposed rats lost 24 g. The mean values for wet and dry lung weights and trapped gas volume in the lung were essentially the same in the two groups of rats. Similarly the lung tissue compliance both during inflation and deflation was not significantly different between the two groups of animals. One characteristic feature of the total lung compliance for 69% of the CO₂-exposed rats was a progressive decrease in compliance on successive runs associated with a decrease in the area described by the compliance curves. These would suggest instability of lung alveoli in these rats with a significant alteration of their surfactant activity.

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Zusammenfassung In gesunden, erwachsenen männlichen Ratten wurden die Lungeneigenschaften nach 24-Stunden Haltung in 15% CO₂ haltiger Luft untersucht. Die Tiere wurden vor und nach der Belastung gewogen. Anschliessend wurden die Lungen entfernt, gewogen und fortlaufende Druck-Volumen Kurven mit Aufblasen und Ablassen zuerst von Luft dann von 0.9% Kochsalzlösung aufgenommen. Die Kontrolltiere nahmen in Mittel 9 g zu, während die CO₂-belasteten Tiere 24 g abnahmen. Die Gewichte der feuchten und trockenen Lungen und der eingeschlossenen Luftmenge waren in beiden Gruppen gleich. Die Nachgiebigkeit der Lungen beim Aufblasen und Ausblasen war nicht signifikant verschieden. Die Lungen der CO₂-belasteten Tiere wiesen in 69% ein progressives Nachlassen der Nachgiebigkeit bei wiederholten Füllungen auf, die mit einer Verkleinerung der Fläche der Retraktions-Schleife verbunden war. Dies weist auf eine Schwäche der Alveolarauskleidung mit einer signifikanten Veränderung ihrer oberflächlichen Aktivität hin.

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Resume On a étudié les modifications survenues aux caractéristiques des poumons de rats mâles adultes placés durant 24 heures dans une atmosphère contenant 15% de CO₂. Les animaux furent pesés avant et après l'expérience. On a en outre extrait et pesé les poumons des animaux après qu'ils aient subi le traitement au CO₂. On a ensuite établi les courbes continues du rapport pression/volume (gonflement et vidange inclus) en utilisant d'abord de l'air, puis une solution de sel de cuisine à 0,9%. Le gain de poids des rats de contrôle a été de 9 g en 24 heures, alors que les animaux soumis au CO₂ perdaient 24 g en moyenne. Le poids des poumons humides ou secs ainsi que la quantité d'air qu'ils pouvaient contenir ont été égaux dans les 2 groupes. L'élasticité des poumons n'a pas présenté de différence significative lors de leur gonflement ou de leur vidange. Pourtant, un trait caractéristique des poumons de rats soumis au traitement par CO₂ a été, dans 69% des cas, une diminution progressive de l'élasticité après avoir été gonflés et dégonflés plusieurs fois. Cette diminution est en relation avec un rétrécissement de la surface de la boucle de rétractation. Ce résultat laisse à penser qu'on a affaire à une altération du revêtement alvéolaire accompagnée d'une modification significative de son activité superficielle.

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This study was supported by the Air Force Office of Scientific Research, Office of Aerospace Research, US Air Force (Contract F44620-68-C-0014).     

The role of compensatory mutations in the emergence of drug resistance

Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence.     

The role of compensatory neutral mutations in molecular evolution

A pair of mutations at different loci (or sites) which are singly deleterious but restore normal fitness in combination may be called compensatory neutral mutations. Population dynamics concerning evolutionary substitutions of such mutants was developed by making use of the diffusion equation method. Based on this theory and, also, by the help of Monte Carlo simulation experiments, a remarkable phenomenon was disclosed that the double mutants can easily become fixed in the population by random drift under continued mutation pressure if the loci arc tightly linked, even when the single mutants are definitely deleterious. More specifically, I consider two loci with allelesA andA’ in the first locus, and allelesB andB’in the second locus, and assign relative fitnesses 1, 1-s’, 1-s’ and 1 respectively to the four gene combinationsAB, A’B, AB’ andA’B’, wheres’ is the selection coefficient against the single mutants (s’ > 0). Letv be the mutation rate per locus per generation and assume that mutation occurs irreversibly fromA toA’ at the first locus, and fromB toB’ at the second locus, whereA andB are wild type genes, andA’ andB’ are their mutant alleles. In a diploid population of effective size N _e (or a haploid population of 2N _e breeding individuals), it was shown that the average time (T) until joint fixation of the double mutant (A’B’) starting from the state in which the population consists exclusively of the wild type genes (AB) is not excessively long even for large 4N _e s’ values. In fact, assuming2N _e v = 1 we have -T = 54Ne for 4Nes’ = 400, and -T = 128Ne for 4N _e s’ = 1000. These values are not unrealistically long as compared with -T~ 5N _e obtained for 4N _e s’ = 0. The approximate analytical treatment has also been extended to estimate the effect of low rate crossing over in retarding fixation. The bearing of these findings on molecular evolution is discussed with special reference to coupled substitutions at interacting amino acid (or nucleotide) sites within a folded protein (orrna) molecule. It is concluded that compensatory neutral mutants may play an important role in molecular evolution.     

Modeling of unstable heat-mass air exchange in the lungs

A mathematical model of the unsteady-state heat and mass exchange of expired air in the bronchial tree is suggested. The model includes heat and mass exchange between air and bronchial walls, and heat exchange between blood circulation and bronchial tree. A problem has been numerically solved as a unidimensional one in the quasi-steady-state formulation. It is shown that air conditioning occurs through the whole length of a respiratory tract. During inspiration bronchial walls are cooled, that in its turn induces a decrease of air temperature and water vapour content in time. That process depends on the intensity of lung blood circulation and character of air velocity changes during inspiration.     

Morphogenesis of the respiratory bronchiole in rhesus monkey lungs

The epithelium of the respiratory bronchiole in the adult rhesus monkey consists of two populations: a pseudostratified epithelium with basal, mucous goblet, and ciliated cells located near the pulmonary artery (PA); and a simple cuboidal epithelium composed only of nonciliated bronchiolar epithelial (or Clara) cells in areas away from the PA. This study describes the pattern of differentiation of these two epithelial populations, and their relationship to the PA and to the time of appearance of alveoli in the respiratory bronchiole of the rhesus monkey during the period of 90-125 days gestational age (DGA). These events were related to changes in the adjacent parenchyma. Dissected airways of infusion-fixed, critical-point-dried lungs were evaluated by scanning microscopy followed by light microscopy of the same airways. At 54% of gestation (90 DGA), the distal airway was lined by a mixture of ciliated and nonciliated cells. By 67% of gestation (110 DGA), the ciliated cells were confined to the epithelium over the PA. The underlying connective tissue initially was cellular containing few fibers but was fibrous by 76% of gestation (125 DGA). Alveolarization began near the most distal cartilage at 57% of gestation (95 DGA), the same period at which secondary septation occurred in the distal acinus. Thus, alveolarization occurred simultaneously in two centers: 1) the proximal centriacinar region in the vicinity of the most distal cartilage and 2) the distal lung parenchyma. The duration of centriacinar alveolarization was short, approximately 5 days.     

The role of endogenous regulators in the compensatory process after salivary gland resection

The ways of penetration of submandibular salivary degeneration products into the blood after partial gland resection have been studied on 97 rats. Using isoenzyme LDH spectrum of the blood, as well as of gland and regional lymph node tissue, the acid-base balance values and morphological data, it has been shown that degeneration products of salivary glands penetrate into the general blood flow through regional lymph nodes, where they are partly modified. The true changes in LDH spectrum can be already registered half an hour after the injury of the gland. The influence of the degeneration products of gland tissue on the initiation of the compensation processes in cellular hyperplasia is discussed.     

The fate of light air ions in the respiratory pathways

From an analysis of the fate of the light air ions it was concluded that the most effective mechanism of deposition is the diffusion depriving the inhaled air of light ions at the level of intrasegmental bronchi and bronchioles. A natural electrostatic filter exists in the isthmus faucium.This filter influences the retention of light air ions during mouth-breathing. The electrostatic filter acts on electrically charged particles such as microbes as shown by an investigation of the density of microflora. An increase of the ion retention rate,although quite high in comparison with the same condition in the absence of an electric field,does not radically change the whole deposition pattern. However, a permanent supply of the opposite charge to the electrodes of the natural electrostatic filter may be of some importance to mouth-breathers.

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Zusammenfassung Es wurde das Schicksal der leichten Luftionen mit dem Ergebnis analysiert, dass der wirksamste Mechanismus der Ablagerung die Diffusion ist, durch die sich die inhalierte Luft mit leichten Ionen in der Höhe der Bronchien und Bronchiolen absetzt. Ein natürliches elektrostatisches Filter existiert in Form des isthmus faucium. Dieses Filter beeinflusst das Zurückhalten leichter Luftionen während der Mundatmung. Das elektrostatische Filter wirkt auf die elektrisch geladenen Teilchen wie Mikroben, wie man sie bei einer Untersuchung über die Dichte der Mikroflora beobachtet hat. Eine verstärkte Zurückhaltung der Ionen,obwohl sie im Vergleich zu denselben Bedingungen ohne elektrisches Feld recht hoch ist, ändert den ganzen Ablagerungsmechanismus nicht. Jedoch mag eine dauernde Zufuhr der den Elektoden des natürlichen elektrostatischen Filters entgegengesetzten Ladung von einiger Bedeutung für die Mundatmung sein.

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Resume On a analysé la destinée des ions légers de l'air.Il en découle que le mécanisme le plus efficace de déposition réside dans la diffusion qui prive l'air de ses ions légers au niveau des bronches et des bronchioles.Un filtre électrostatique naturel se trouve dans l'isthmus faucium. Ce filtre influence la rétention des ions légers de l'air durant la respiration par la bouche. Ce filtre électrostatique agit sur les particules chargées électriquement telles que les microbes,comme il découle de recherches effectuées sur la densité de la micro-flore. Un accroissement du taux de retenue des ions, même s il reste élevé en comparaison de ce qui se passe dans des conditions analogues mais en l'absence d'un champ électrique,ne modifie pas radicalement le mécanisme de sédimentation. Pourtant, un apport permanent de charges opposées aux électrodes du filtre électrostatique naturel peut avoir une certaine importance pour les individus respirant par la bouche.