Lysozyme and mucin cDNAs as tools for the study of serous and mucous cell differentiation.
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Animals↗
Biomedical subjects
B Jany
Publications and source records attributed to B Jany.
Mucin gene expression in rat airways following infection and irritation.
Airway mucus hypersecretion occurs in response to infection and irritation and poses an important and poorly understood clinical problem. In order to gain insight into its pathogenesis, we have focused on an mRNA encoding the major mucus glycoprotein, mucin. Northern blots showed that mucin mRNA was abundant in the intestine of specific pathogen free rats whereas it was undetectable in the airways of these rats until pathogen-free conditions were suspended and rats acquired Sendai (Parainfluenza I) virus infections. Airway mucin hybridization signals in rats that were both infected with Sendai virus and exposed to SO2 were more intense than those in rats with infection alone. These results suggest that pathogen-and irritant-induced hypersecretion may be partly controlled at the level of mucin mRNA.
Animals↗
Mucin in disease. Modification of mucin gene expression in airway disease.
Mucus hypersecretion is a characteristic feature of several human airway diseases, including chronic bronchitis, cystic fibrosis, and asthma. Although its pathogenesis is poorly understood, hypersecretion apparently results from the abnormally large number of mucous cells found in hypersecretory airways. The factors giving rise to these mucous cells are unknown, but experimental evidence supports possible roles for both mitosis (mucous cell hyperplasia) and differentiation (mucous cell metaplasia). On the basis of the hypothesis that differentiation would require activation of mucin mRNA transcription, we have used mucin cDNA to monitor mucin mRNA levels in an animal model of chronic bronchitis. We first showed that a mucin gene (SMUC or MUC-2) cloned from the human intestine is also expressed in the human airways and is the same or homologous to genes expressed in other human mucin-producing organs. We next showed that a homologue of the SMUC gene is expressed in several animal species, including the rat. Finally, we showed that the induction of experimental chronic bronchitis by SO2 in rats is accompanied by the induction (from near zero baseline) of airway mucin mRNA. The induction by irritants of high steady-state levels of mucin mRNA may represent one of the early events in mucous cell differentiation and hypersecretion.
Animals↗
Plasticity in the airway epithelium.
Normal cell turnover as well as the response to injury require cell proliferation and differentiation. The airway epithelium maintains these processes throughout adult life. Controlled homeostatically, cell proliferation and differentiation usually restore, as an end point, the pseudostratified architecture of the normal mucociliary epithelium. After injury, however, cell proliferation and differentiation sometimes establish, as an end point, regions of metaplastic cells. In this brief review, we have tried to summarize research findings that 1) describe the development of metaplastic lesions in morphological terms, 2) identify cells the proliferation of which forms the basis of these lesions, and 3) identify molecular changes within these cells that control development of the metaplastic phenotype.
Animals↗
Modification of mucin gene expression in the airways of rats exposed to sulfur dioxide.
The molecular mechanisms mediating mucous cell metaplasia and hypersecretion in the respiratory tract are unknown. Previous work suggests that mucous metaplasia requires the induction of mucin gene expression. We are investigating this possibility by monitoring steady state levels of mucin mRNA in a model of mucous cell metaplasia induced by SO2 exposure. Male Sprague Dawley rats were exposed to 400 ppm SO2 gas in air for 3 h per day, 5 days per week for 0,1,2, or 3 weeks. Sham controls were exposed to air under similar conditions. After 3 weeks, morphological changes were apparent in the epithelium of SO2 exposed rats at all levels from the trachea to the distal airways. The epithelial thickness increased, as well as the number and size of glands in the trachea. Epithelial mucous (goblet) cells increased from 0 to 4.5 per mm in the trachea, 0.2 to 6.2 per mm in the main stem bronchi, and 0.2 to 22.7 per mm in the distal airways (mean values obtained for 3-6 tissue blocks per airway level per condition). In parallel experiments, we used SMUC41, a 950 bp human intestinal cDNA to isolate a human airway cDNA, HAM-1 from a cDNA library constructed in bacteriophage from human bronchial poly A+RNA. HAM-1 is a 90 bp cDNA encoding a threonine- and proline-rich peptide with 96% homology to the human intestinal cDNA SMUC-41. Next we probed total and poly A+ airway RNA from rats in each exposure condition with SMUC-41 or HAM-1. Blots were then stripped and reprobed with cDNA encoding beta actin. Densitometry values normalized for the amount of RNA loaded per lane (as determined by actin hybridization intensity) showed that mucin mRNA increased 8-9 fold as a function of SO2 exposure. This is consistent with the possibility that mucin gene transcription is induced by SO2 exposure, and may represent a primary event in the development of mucous metaplasia and hypersecretion.
Animals↗
Neuron-specific enolase and thymidine kinase as an aid to the diagnosis and treatment monitoring of small cell lung cancer.
The serum levels of neuron specific enolase (s-NSE) and thymidine kinase (s-TK) were studied in detail in patients with small cell lung cancer (SCLC) to evaluate as to whether their combined use may aid to diagnosis and follow-up of this particular tumor. Only s-NSE could differentiate between SCLC and non-small cell lung cancer (NSCLC) or benign pulmonary diseases (BPD) to some extent, pathologic serum concentrations occurring in 81%, 17%, and 0%, respectively. The comparable figures for s-TK were 62%, 24%, and 28%, respectively. Serum NSE decreased and increased paralleling tumor regression and progression, respectively, except when brain metastases were present. Alterations of s-TK, in contrast, did not usually mirror the course of disease. During initial chemotherapy (CT) a transitory increase of serum levels was observed for both NSE and TK. Monitoring, based on daily blood samples, showed comparable peaks only for s-TK during the following CT cycles, whereas s-NSE was within the normal range even when tumor mass was still present. Those subsequent s-TK peaks under CT may be due to tumor cell lysis as a result of CT indicating the efficacy of treatment by this way. Rapidly proliferating tissues such as bone marrow or bowel mucosa, however, have also to be considered as possible sources of s-TK.
Aged↗
[In suspected bronchial cancer are the tumor markers neuron-specific enolase, carcinoembryonic antigen and squamous cell carcinoma antigen, of diagnostic help?].
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Antigens, Neoplasm↗
Differential effects of beta-adrenergic blockade on P0.1 and mean inspiratory flow.
To quantitatively examine and compare the effects of beta-adrenergic blockade on ventilation, we studied 20 healthy volunteers during inhalation of room air and at steady state CO2 (2.0, 4.4, 6.0%) following a single oral dose of bupranolol (vs. placebo). During room air breathing, minute ventilation (VE) and mean inspiratory flow (VT/TI) were significantly reduced after beta-blockade with a concomitant increase in blood PaCO2 (p less than 0.01). The timing factor TI/Ttot and mouth occlusion pressure P0.1 remained unchanged. These differences were, as shown from calculated effective alveolar ventilation, mainly attributed to a decrease in physiological dead space ventilation following beta-blockade. With a stepwise increase in FICO2, the difference in PaCO2 between placebo and bupranolol tended to approach zero, whereas VE and VT/TI remained significantly lower during beta-blockade (P less than 0.05). In contrast, no difference existed in P0.1 between bupranolol and placebo. We suggest that (1) respiratory drive assessed by P0.1 is unaffected by beta-blockade and (2) mean inspiratory flow depends also on CO2 elimination characteristics, which are influenced by beta-blockade.
Adult↗
[Effect of bupranolol on hypoxic respiratory stimulation in healthy probands].
To determine whether hypoxic ventilatory response results, in part, from concomitant systemic sympathoadrenal stimulation, we studied ventilation in 20 healthy subjects before and after administration of a beta-blocking agent. A single oral dose of 100 mg bupranolol (vs placebo) significantly lowered minute ventilation from 9.4 +/- 0.7 to 8.3 +/- 0.2 l/min (mean +/- SEM) during normoxia, and from 10.8 +/- 0.8 to 8.9 +/- 0.2 l/min, when 11% O2 was inhaled. In our study, there were marked oscillations of ventilation on changing from room air to hypoxic breathing and back. They were ascribed to the preceding sampling of specimens for blood gas analysis. However, bupranolol had no influence on these transients. Bupranolol also had only slight cardiocirculatory effects during normoxia and did not prevent significant T-wave flattening, increase in heart rate, and fall in diastolic blood pressure during hypoxia. However, it did block the hypoxic increase in systolic blood pressure. From our results we suggest that (1) in spontaneously breathing conscious subjects, hypoxia-induced hyperventilation is also due to hypoxic sympathoadrenal activity and individual mental state, and (2) these influences do not affect all aspects of the cardiocirculatory response.
Adult↗
[Efficacy of nasal O2 administration during mouth breathing].
27 subjects with healthy lungs received during conscious mouth breathing of room air simultaneously also nasally applied O2. The mean O2 concentration of the expiratory air at the mouth was a measure for the effective inspiratory oxygen concentration. Application through a nasal mask at 4 l/min O2 flow proved only slightly superior to the airtight nose frame (25.2 vs 23.6 per cent by volume O2), whereas the highest concentration was achieved by mask and reservoir (35.3 vol.%; 2P less than 0.001). The five habitual mouth breathers of the subject group did not show any O2 uptake through the nose in any of the experiments, the mean nasal share of the inspiration being calculated at 2.5% against 25% for the other subjects (2P less than 0.001). The interindividual differences proved independent of nose resistance and are ascribed to changing active positioning of the soft palate. This mechanism must be taken into consideration when assessing the arterial blood gases in oronasal respiration.
Adult↗
[Mechanisms of supralaryngeal airway obstruction in normal persons and habitual mouth breathers].
We examined oronasal flow partitioning in 27 volunteers with normal or slightly increased nasal resistance (mean +/- SD, 0.24 +/- 0.19 kPa/l/s). Mean percentage of inspiratory nasal flow contribution was measured during spontaneous oronasal breathing. The averaged nasal admixture of airflow differed considerably within and between all subjects (mean +/- SD, 20.9% +/- 16.5%; range 1%-70%), showing no correlation to nasal resistance. Five of 27 subjects with a history of habitual mouth breathing had a significantly lower nasal admixture as compared with controls (2.5% +/- 1.7% vs 25.1% +/- 15.4%; P less than 0.005), but with no statistical difference in nasal resistance. To evaluate the hypothesis that velopharyngeal narrowing is due to an increased tone of the soft palate, measurements were also performed under positive nasal pressure, inspiratory resistive loading at the mouth, and during breath-holding. There was no significant difference of airflow distribution between these modifications and unloaded breathing in either group. These data suggest, therefore, that oronasal flow distribution is due to active positioning of the soft palate, and that habitual mouth breathing without any nasal obstruction may be associated with closure of the velopharyngeal isthmus as a consequence of disturbed neural control mechanisms.
Adult↗
[Significance of neuron-specific enolase (NSE) in the diagnosis of bronchial carcinomas and neuroendocrine tumors].
The diagnostic significance of neuron-specific enolase in serum was examined in 54 patients with bronchial carcinoma and in 28 with neuroendocrine tumors. Control groups were 42 patients with epithelial and 39 with nonepithelial malignant neoplasms as well as 40 patients with benign pulmonary diseases. The sensitivity of neuron-specific enolase in small-cell bronchial carcinoma was 60% and increased to 87.5% in advanced stages ("extensive disease"). On the other hand, non-specific enolase showed an increase in only 13.8% of patients with other than small-cell bronchial carcinoma. The proportion of false-positive enolase values in non-malignant pulmonary diseases was 5%. Some endocrinal tumors (e.g. tumors of the APUD cell system) showed pathological serum concentrations in 7.1% of the cases only. 37.5% of epithelial malignant neoplasms had enhanced levels, but only 5.1% in nonepithelial neoplasms. Small-cell bronchial carcinoma is most probably present in patients with bronchial carcinoma and neuron-specific enolase serum concentrations above 25 micrograms/l.
Adenocarcinoma↗
[Expanding clinical diagnosis of lung function by hyperoxia respiration].
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Adult↗
Neuron-specific enolase in the diagnosis and therapy monitoring of lung cancer: a comparison with CEA, TPA, ferritin and calcitonin.
The significance of neuron-specific enolase (NSE) in the diagnosis and treatment monitoring of lung cancer was investigated in comparison with such established tumour markers as carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), ferritin and calcitonin. We determined the serum concentrations of these tumour markers in 25 patients with small cell lung cancer (SCLC), 30 patients with non small cell lung cancer (NSCLC), and 38 patients with benign pulmonary diseases (BPD). In 14 patients with lung cancer, it was possible to follow up the behaviour of the tumour markers under treatment for up to 16 months. Calcitonin proved to have a surprisingly low sensitivity for SCLC. The utility of TPA and of ferritin was restricted, although the sensitivity was comparably high, by the high rate of false positive results. For NSCLC, CEA proved to be the best tumour marker. At present, NSE appears to be the tumour marker with the greatest specificity and sensitivity for SCLC. Its determination in the diagnosis, treatment and follow-up of SCLC makes good sense.
Adult↗
Nasal admixture during mouth breathing in awake normal subjects.
We tested the flow-impeding properties of the nasopharynx in 27 healthy subjects with normal nasal resistance (mean +/- SD: 2.45 +/- 1.92 cmH20.l-1 X s). While the subjects inspired and expired deliberately through a rubber mouth-piece, a tight-fitting nose-mask was supplied with 100% O2 from a filled 30-1 rubber bag. Recording instantaneous FEO2 at the mouth was a sensitive indicator of whether nasal flow was present during the preceding inspiration. On a theoretical basis, we are describing a method of calculating the mean percentage of nasal admixture during inspiration. Fluctuations in FEO2 in relation to time revealed varying nasal flow in some individuals. The mean nasal admixture differed considerably between all subjects (mean +/- SD: 20.9 +/- 16.5%; range: 1-70%), showing no correlation to nasal resistance. Five of 27 subjects with a history of habitual mouth breathing had a significantly lower nasal admixture (2.5 +/- 1.7% vs 25.1 +/- 15.4%; p less than 0.005), with no statistical difference in nasal resistance. Present data indicate that upper airway patency is variable in normals during voluntary mouth breathing. We suggest that habitual mouth breathing with absence of nasal obstruction may be associated with velopharyngeal narrowing.
Adult↗