1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2a, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2a and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (± )-noradrenaline in the lung strip was isoprenaline > adrenaline > noradrenaline but in the trachea was isoprenaline > noradrenaline > adrenaline. 4 fl2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting P2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of /2-adrenoceptors in lung strip and 516-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyraminetreated lung strip and trachea was not due to prostaglandins E1, F2a or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.
Spontaneous contractions of the fetal airways are a well recognized but poorly characterized phenomenon. In the present study spontaneous narrowing of the airways was analyzed in freshly isolated lungs from early to late gestation in fetal pigs and rabbits and in cultured fetal mouse lungs. Propagating waves of contraction traveling proximal to distal were observed in fresh lungs throughout gestation which displaced the lung liquid along the lumen. In the pseudoglandular and canalicular stages (fetal pigs) the frequency ranged from 2.3 to 3.3 contractions/min with a 39 to 46% maximum reduction of lumen diameter. In the saccular stage (rabbit) the frequency was 10 to 12/min with a narrowing of ف 30%. In the organ cultures the waves of narrowing started at the trachea in whole lungs, or at the main bronchus in lobes (5.2 Ϯ 1.5 contractions/min, 22 Ϯ 8% reduction of lumen diameter), and as they proceeded distally along the epithelial tubes the luminal liquid was shifted toward the terminal tubules, which expanded the endbuds. Spontaneous narrowing and relaxation of the airways in the developing fetal lung has been described since the early part of the twentieth century. These spontaneous contractions are characteristic of phasic smooth muscle where regular bursts of action potentials give rise to rhythmic mechanical activity, typified by the smooth muscle of the viscera (1). Yet the contraction of mammalian airway smooth muscle in postnatal life is characterized by slow, graded contractions leading to airway narrowing and occurs without the generation of action potentials during membrane depolarization (2, 3). This is classified as tonic smooth muscle, in common with many blood vessels (1). Perhaps the rhythmic contractile activity of fetal airway smooth muscle is not so surprising since the intestine and the lung have a common embryological origin, with the lung developing as an outgrowth of the foregut in the late embryonic stage (4). Nevertheless, it indicates that airway smooth muscle would need to lose its capacity to generate spontaneous electrical activity sometime during fetal life or at birth and acquire the characteristics of tonic smooth muscle. If and when this occurs is unknown.The phenomenon of spontaneous narrowing of airways in the fetal lung was first observed in explants of lung in culture from embryos of chicken (5) and guinea pigs (6). More recently it was reported in explants of first-trimester human lung (7) and in gestation Day 11 mouse lung (8), where by 48 h in culture, spontaneous contractions began. However, much less information is available for intact fetal airways. McCray (7) noted spontaneous activity of epithelial tubules in small fragments of fresh lungs from first-trimester human fetuses and characterized their contractile responses to pharmacologic agents (discussed later). Sparrow and colleagues (9, 10) video-recorded sequences of strong spontaneous narrowing of individual airways in the isolated intact bronchial tree in the late first and early second trimesters of fetal pig l...
Neural tissue and smooth muscle appear early in the developing fetal lung, but little is known of their origin and subsequent distribution. To investigate the spatial and temporal distribution of nerves, ganglia, and airway smooth muscle during the early pseudoglandular stage, fetal mouse lungs at embryonic days (E) 11 to 14 were immunostained as whole-mounts and imaged by confocal microscopy. At E11, the primordial lung consisted of the future trachea and two budding epithelial tubules that were covered in smooth muscle to the base of the growing buds. The vagus and processes entering the lung were positive for the neural markers PGP 9.5 (protein gene product 9.5) and synapsin but no neurons were stained at this stage. An antibody to p75 NTR revealed neural crest cells on the future trachea as well as in the vagus and in processes extending from the vagus to the lung. This finding indicates that even though neuronal precursors are already present at this stage, they are still migrating into the lung. By E12, neural tissue was abundant in the proximal part of the lung and nerves followed the smooth muscle-covered tubules to the base of the growing buds. At E13 and E14, a neural network of interconnected ganglia, innervated by the vagus, covered the trachea. The postganglionic nerves mainly followed the smooth muscle-covered tubules, but some extended out into the mesenchyme beyond the epithelial buds. Furthermore, we show in a model of cultured lung explants that neural tissue and smooth muscle persist and continue to grow and differentiate in vitro. By using fluorescent markers and confocal microscopy, we present the developing lung as a dynamic structure with smooth muscle and neural tissue in a prime position to influence growth and development.
Measurements were made of the growth and of the changes in rates of protein turnover in the anterior latissimus dorsi muscle of the adult fowl in response to the attachment of a weight to one wing. Over 58 days there was a 140% increase in the protein content with similar increases in the RNA and DNA contents. The fractional rate of protein synthesis, measured by the continuous-infusion technique using [14C]proline, increased markedly during hypertrophy. This increase was mediated initially (after 1 day) by an increase in the RNA activity but at all other times reflected the higher RNA content. The rate of protein degradation, calculated from the difference between the synthesis and growth rates, appeared to increase and remain elevated for at least 4 weeks. At no time was there any suggestion of a fall in the rate of degradation. The following events are discussed as central to the changes that occur during skeletal-muscle hypertrophy. 1. Nuclear proliferation is necessary to maintain the characteristic synthesis rate because of the inability of existing nuclei to 'manage' increased protein synthesis for more than a limited period. 2. The increased protein breakdown during hypertrophy is consistent with the known over-production of a new muscle fibres and may indicate some 'wastage' during the growth. Such wastage may also be associated with myofibrillar proliferation. 3. Muscle stretch must be recognized as the major activator of growth and as such can be compared with the 'pleiotypic activators' that have been described for cells in culture.
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