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Biomedical subjects

G L Snider

Publications and source records attributed to G L Snider.

At least 91 records · Page 5Linked to original sources
PubMed1987

The ultrastructure of hamster bronchial epithelium.

The central intrapulmonary bronchi of adult male Syrian hamsters were examined by electron microscopy to identify the principal types and proportions of epithelial cells. A differential count of cells displaying both a basal lamina and luminal border (transepithelial cells) showed that, on average, ciliated cells constituted 63% and granule-containing (granulated) secretory cells 25% of the total. Other transepithelial cells included nongranulated secretory cells (9%), preciliated cells (1.5%), and indeterminate cells (1%). The most frequent granulated secretory cell (77% of the population) was the Clara cell. It was identified by the presence of prominent apical smooth endoplasmic reticulum and secretory granules. It was subclassified into three types based on the presence or absence of rough endoplasmic reticulum and on granule morphology. Mucous cells (little or no smooth endoplasmic reticulum but with typical mucous granules) constituted approximately 20% of the granulated secretory cells. Serous cells were very infrequent. A differential count of nucleated epithelial cells demonstrated an average of 2% basal cells (hemidesmosomes present) and 20% pseudobasal cells (hemidesmosomes absent). Neuroepithelial bodies and solitary "small-granule" cells were infrequent. Brush cells and apoptotic bodies were rarely found but are noteworthy because their occurrence in hamster airways was not demonstrated previously. These results provide a foundation for subsequent analysis of alterations of epithelial homeostasis induced by injurious agents of exogenous and endogenous origin.

Animals↗
PubMed1987

An ultrastructural study of the response of hamster bronchial epithelium to human neutrophil elastase.

The central intrapulmonary bronchi of hamsters were examined by transmission electron microscopy at varying times following intratracheal instillation of human neutrophil elastase (HNE) or its vehicle, saline. Two hours after HNE treatment, there was a marked irregularity of the surfaces of many nonciliated epithelial cells; a differential count of transepithelial cells (those with both a basal lamina and luminal border) demonstrated a significant decrease in the proportion of granule-containing (granulated) secretory cells and a corresponding increase in nongranulated secretory cells. By 3 days after HNE injection, the differential count had returned to control levels and cell surface alterations were less evident. By 8 days, the proportion of granulated secretory cells had significantly increased, while that of nongranulated secretory cells had decreased. Many Clara cells developed the characteristics of mucous cells so that mucous cells constituted 57% of the secretory cells compared to 14% for the saline controls. The mucous cells contained an increased number of mucous granules including bizarre forms never seen in controls. By day 16, the average mucous cell proportion had increased to 75%; the mucous cells were larger and contained many more secretory granules than at day 8. At no time was there evidence of overt cell injury or alteration of extracellular connective tissue due to HNE. Basal and pseudobasal cells, distinguished by the presence or absence of hemidesmosomes, did not change as a percentage of total nucleated epithelial cells. Saline had no effect on the differential cell count compared to untreated values. Our results indicate a strong likelihood that HNE causes early discharge of secretory granules and alters the phenotypic expression of Clara cells so that they produce abundant, often abnormal mucous granules. The mechanism of HNE-induced disturbance of epithelial homeostasis is unknown, but the early irregularity of nonciliated epithelial cell surfaces may signify an important event in the evolution of the resultant lesion.

Animals↗
PubMed1987

Mediastinal lymph node evaluation by computed tomography in lung cancer. An analysis of 345 patients grouped by TNM staging, tumor size, and tumor location.

To more clearly characterize the role of computed tomography in staging the mediastinal lymph nodes of patients with lung cancer, we analyzed computed tomographic and surgical findings in the chest in 345 consecutive patients with lung cancer who underwent operative staging. Patients were grouped according to the TNM staging system of the American Joint Commission, central or peripheral location of the primary tumor, lobar location of the tumor, and maximum tumor diameter as determined by computed tomography or gross pathology. One third of patients with abnormal findings on the computed tomographic scan did not have mediastinal lymph node metastases. Mediastinal metastases occurred frequently in patients with central cancers (38%). The predictive value of a negative scan in all patients was high (greater than or equal to 90%) except for patients with central T3 lesions (72%), left upper lobe lesions (83%), and central adenocarcinomas (75%). However, only the differences between central T3 and central T2 or T1 lesions, and between central adenocarcinomas and central squamous cell carcinomas, were unlikely to be due to chance alone (p less than 0.05). None of the lobar differences were statistically significant. The frequency of mediastinal metastases in patients with peripheral lesions was 15% (28 of 192 patients); computed tomography correctly identified enlarged mediastinal lymph nodes in all but seven patients. However, there were no true-positive computed tomographic scans in 59 patients with peripheral lesions 2 cm in diameter or smaller; accordingly, we suggest that computed tomography is not indicated for the sole purpose of mediastinal staging in this group. Ninety-four percent of patients in this series undergoing thoracotomy with a curative intent had a curative resection. Only 4% had unresectable lesions; palliative resections were done in 2%.

Adult↗
PubMed1986

Ultrastructural changes in hamster lung 15 min to 3 hr after exposure to pancreatic elastase.

A single endotracheal instillation of porcine pancreatic elastase into hamster lungs induces morphological changes that can be detected as early as 15 min after the instillation of enzyme. Lung tissue from animals sacrificed at six time points between 15 min and 3 hr after enzyme instillation was examined for ultrastructural alterations. There were few of these alterations and they were highly focal, but they included damaged epithelial cells and partially digested elastic fibers that occurred both in the parenchyma and the pleura. A cytochemical technique employing N-t-Boc-L-alanine-p-nitrothiophenyl ester as a substrate for elastase-like enzymes was also used in an effort to locate pancreatic elastase shortly after instillation into the lungs. Reaction product was observed on the alveolar surface and in pinocytotic vesicles of alveolar type I cells, in connective tissue areas, in fibroblasts, and in pinocytotic vesicles of capillary endothelial cells. The location of reaction product coupled with ultrastructural alterations in the tissue suggests that pancreatic elastase instilled into the trachea may reach the interstitium in two ways: First, transport may take place across intact alveolar type I cells via pinocytotic vesicles, and second, a small amount of enzyme may gain access to the connective tissue after the disruption of epithelium in a few highly focal areas.

Animals↗
PubMed1986

Lung mechanics and connective tissue levels in starvation-induced emphysema in hamsters.

The effect of starvation on lung mechanics, morphometry, and levels of connective tissue components was determined in young adult golden Syrian hamsters. A base-line control, fed control, and starved group were studied. Fed group animals increased body weight by 13%, but dry lung weight did not increase above that of the base-line controls. The total lung capacity when transpulmonary pressure was at 25 cmH2O (TLC25) also increased by 20% above base-line controls. The mean TLC25 of the starved group was greater than that of the base-line control group but less than that of the fed control group (P less than 0.05). Volume-corrected air-filled volume pressure (VP) curves of the three groups were similar. Volume-corrected saline-filled VP curves were identical in the three groups. Total lung collagen, elastin, glycosaminoglycan, and protein were similar in the three groups. Air space size was significantly increased and mean internal surface area was significantly decreased in the starved group compared with the base-line and fed controls. No evidence of alveolar wall destruction was evident by light or electron microscopy. We conclude that severe starvation of young adult hamsters produces air space enlargement without changes in lung elastic recoil. The mechanism of alveolar wall remodeling is not yet understood in this model of emphysema.

Air↗
PubMed1986

Effect of varying the time interval between intratracheal administration of eglin-c and human neutrophil elastase on prevention of emphysema and secretory cell metaplasia in hamsters. With observations on the fate of eglin-c and the effect of repeated instillations.

Eglin-c is a naturally occurring polypeptide of 70 amino acids with a molecular mass of 8,100 daltons. It is a strong inhibitor of human neutrophil elastase (HNE) and cathepsin-G, and, when given intratracheally to hamsters 1 h before human neutrophil elastase, it can prevent or ameliorate the emphysema produced by HNE. The present experiments were designed to determine the duration of the effectiveness of eglin-c, prepared by DNA technology from Escherichia coli, in preventing the emphysema and secretory cell metaplasia induced by HNE. Eglin-c (2,000 micrograms in 0.5 ml saline) was effective in ameliorating emphysema, as determined histologically and physiologically, when it was given intratracheally to hamsters 1, 2, 4, and 8 h before the intratracheal instillation of 300 micrograms of HNE. Eglin-c ameliorated bronchial secretory cell metaplasia when given 1 h before HNE but not when the time intervals were 2 h or longer. The clearance of [3H]eglin-c from the lungs was assessed. Four h after intratracheal instillation of 446 micrograms of [3H]eglin-c, 33% of the tritium was found in the lung tissue and bronchoalveolar lavage fluid; 83% of the radioactivity in the lavage fluid supernatant was associated with functionally active eglin-c. No evidence of bronchopulmonary toxicity was seen in hamsters given 4 intratracheal instillations of 2,000 micrograms of eglin-c at 1-wk intervals.

Animals↗
PubMed1986

Interstitial pulmonary fibrosis.

The study of animal models of IPF has demonstrated that there is a stereotyped response of the respiratory airspace walls to a wide variety of injuries. Inflammatory and immune effector cells play a major and complex role in the fibrosing process. They may contribute to the injury of the lung beyond the original insult. These cells secrete substances that play an important role in determining cell traffic in the lungs and in controlling the connective tissue-producing cells. Products derived from the inflammatory response may interfere with protection of normal lung matrix, although injury to lung matrix itself does not lead to fibrosis. Injury to endothelial cells and especially type I epithelial cells appears to play a major role in the fibrogenic response. Further understanding of the factors that injure these cells, the development of methods of protecting them from injury, and a clear understanding of their role in the fibrogenic process appear to be key to developing better methods of preventing and treating interstitial pulmonary fibrosis.

Animals↗
PubMed1986

Staging with CT.

Explore the source record for details and available documents.

Humans↗
PubMed1986

Young hamsters are more resistant than adults to endotracheally instilled porcine pancreatic elastase.

We measured the physiologic and stereologic response to 0.1, 0.2, and 0.4 microgram of porcine pancreatic elastase instilled in a volume of 0.25 ml 0.9% NaCl/100 g body weight into the trachea of groups of young and adult hamsters. The young hamsters averaged 50 g and the adult hamsters 116 g in initial body weight. Twenty-one days after administration of elastase, lung volumes, static lung compliance, maximum expiratory flow, the whole section mean linear intercepts (MLI) were measured. The degree of emphysema increased in all animals as a function of dose. Examination of the lung volume and compliance dose-response characteristics indicated that young hamsters developed less physiologic change with increasing elastase dose than did adult hamsters. Maximum expiratory flow and whole section MLI dose-response were similar in the young and adult elastase-treated groups. However, the MLI in young hamsters treated with the 0.4 microgram elastase dose was decreased in the outer third of the lung compared to adult emphysematous hamsters. Also, mean airspace density relative to saline control values in young hamsters was double that found in adult hamsters treated with the 0.4 microgram elastase dose. Although serum alpha 1-globulin levels were equivalent in both young and adult normal hamsters, values normalized for lung elastin content were significantly increased in young animals. We conclude that young hamsters show less change in lung function as a function of elastase dose twenty-one days after elastase instillation. Possible reasons for this include an increased ratio of lung alpha 1-globulin/lung elastin in young hamsters, their continued ability to grow new alveoli, and age related differences in airway size favoring a central distribution of enzyme.

Aging↗
PubMed1986

Serine proteases stimulate mucous glycoprotein release from hamster tracheal ring organ culture.

The effects of several neurohumoral agents and serine proteases on glycoconjugate release from hamster tracheal organ cultures were assessed. The beta-adrenergic agonist isoproterenol inhibited glycoconjugate release, and its effect was abolished by the specific beta-blocking agent propranolol. A cholinergic agonist, pilocarpine, marginally increased glycoconjugate release, and its effect was abolished by the antagonist atropine. Human neutrophil elastase and porcine pancreatic trypsin consistently increased glycoconjugate release by 1.8 to 2.8-fold. When the proteases were inactivated, they were no longer effective in stimulating glycoconjugate release. Histologic and electron microscopic analysis of the protease-treated organ cultures revealed no discernible toxic reaction. In addition, organ cultures prelabeled with chromium 51 did not release an increased amount of radioactivity when treated with the proteases. Biochemical analysis of the glycoconjugates released into the culture medium showed them to be of high molecular weight (90% eluted in the void volume of a Sepharose 6B column) and to be resistant to digestion with hyaluronidase and heparinase, properties consistent with mucous glycoproteins. The mechanism of protease-induced glycoconjugate release is unknown. We speculate that stimulation of airway secretory cells by serine proteases of neutrophilic or other inflammatory cell origin may play a role in the increased airway secretion that is characteristic of acute tracheobronchitis.

Animals↗
PubMed1986

Experimental studies on emphysema and chronic bronchial injury.

The discovery of the association of emphysema and homozygous alpha-1-proteinase inhibitor deficiency gave rise to the hypothesis that emphysema was caused by an imbalance between endogenous proteases and antiproteases. Experimental studies with enzymes have confirmed that emphysema is induced only by enzymes with elastolytic properties. The lesion produced is similar anatomically and physiologically to human emphysema. Genetic and nutritional models of emphysema that appear to be caused by elastic fiber degradation are also known. Alpha-1-protease inhibitor is normally present in the lung; alpha-2-macroglobulin which can loosely complex with elastases, may enter the injured lung and participate in its defense. Alpha-1-protease inhibitor may be inactivated by oxidants derived from cigarette smoke or endogenous phagocytes. The elastase/antielastase hypothesis of emphysema is also believed to be relevant in emphysema caused by cigarette smoking because cigarette smoke gives rise to increased numbers of neutrophils and macrophages in the lung thus increasing the elastase burden of the lung. The precise role of oxidation of alpha-1-protease inhibitor in-vivo by cigarette smoke is not yet clear. In-vitro and experimental data suggest that oxidants can also interfere with repair of lung matrix. A variety of injuries, including proteases, can give rise to secretory cell metaplasia in the central airways. Peripheral airways injury is produced by gases with oxidant properties such as ozone and NO2. The presence of a low molecular weight protease inhibitor in airway epithelial secretory cells when considered with enzyme-induced secretory cell metaplasia raises the possibility of a protease/antiprotease hypothesis of chronic bronchial injury. Although information on the pathogenesis of emphysema is still incomplete, efforts are being made to develop antiproteases which might be used in the prevention of emphysema and chronic bronchial injury.

Animals↗
PubMed1985

Serum antielastase and neutrophil elastase levels in PiM phenotype cigarette smokers with airflow obstruction.

In order to assess blood factors which might explain why some cigarette smokers develop airflow obstruction while others do not, we compared two groups of PiM phenotype volunteers matched for age, sex and total pack-years of cigarette smoking; one group had airflow obstruction and the other did not. Functional levels of alpha-2-macroglobulin (alpha-2-M) and alpha-1-protease inhibitor (alpha-1-PI) were separately assessed by a protease binding procedure. Neutrophils were isolated from blood by counterflow centrifugation, and their elastase content was assayed with 3H-elastin-SDS (sodium dodecyl sulfate). The obstructed and nonobstructed groups were not different with respect to functional or immunoreactive levels of alpha-1-PI and alpha-2-M or elastase levels in their neutrophils. We do not find imbalances of circulating elastase or antielastase levels in PiM phenotype smokers with airflow obstruction.

Adult↗
PubMed1985

Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes.

To determine whether purified human neutrophil cathepsin G (Cat-G) can act by itself or in concert with purified human neutrophil elastase (HNE) in the induction of emphysema and bronchial secretory cell metaplasia (SCM), we gave golden Syrian hamsters 100 micrograms of HNE alone or in combination with either 100 or 200 micrograms of Cat-G. Other groups of animals received intratracheal doses of up to 600 micrograms of Cat-G alone. The severity of emphysema was determined from measurements of lung volumes, compliance, forced expiratory flow, and the mean linear intercept. The severity of SCM in the main airways was graded on sections stained by the alcian blue and periodic acid-Schiff reaction. The Cat-G was a weak inducer of SCM; significant SCM was produced by 400 and 600 micrograms but not by 100 or 200 micrograms or 200 micrograms of Cat-G. The Cat-G (100 and 200 micrograms) did not potentiate the SCM induced by 100 micrograms of HNE. The Cat-G alone did not produce emphysema, and neither 100 nor 200 micrograms of Cat-G potentiated the mild emphysema induced by 100 micrograms of HNE. These results were not consonant with a report that Cat-G and HNE were synergistic in solubilizing human lung elastin. We therefore measured the ability of Cat-G and HNE to solubilize several radiolabeled elastins. The combination of Cat-G and HNE did not solubilize significantly more hamster lung elastin (23%) than the sum of their individual activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Alveolar wall basement membranes in bleomycin-induced pulmonary fibrosis.

The ultrastructural characteristics of alveolar wall basement membranes (BM) were defined in an experimental model of pulmonary fibrosis. Lungs of adult hamsters were examined 2 to 60 days after a single intratracheal instillation of 0.5 units of bleomycin sulfate. Sections of lung fixed with tannic acid and glutaraldehyde were analyzed for epithelial basement membrane (EPI-BM) thickness and duplication, and tissue incubated in ruthenium red prior to fixation was evaluated for distribution of EPI-BM anionic sites. There were no major alterations in capillary EPI-BM. Six days after bleomycin, during acute inflammation, there was focal injury to alveolar epithelial cells and resultant denudation of EPI-BM. Denuded EPI-BM was folded with the lamina densa 60% thicker than in control animals, suggesting its active or passive retraction. Despite type 2 cell hyperplasia and repopulation of the epithelium, there was no duplication of EPI-BM. Thirty and 60 days after bleomycin, the epithelium was intact, inflammation had subsided, and widespread but focal fibrosis was present. This stage was characterized by thickening and duplication of the EPI-BM; 10% of EPI-BM on the thin side of the alveolar wall were duplicated at 30 days and 30% at 60 days. Duplication and thickening, although worse in fibrotic areas, also occurred in normal-appearing areas of lung, showing that EPI-BM changes may be the only residuum of previous damage. Duplication of EPI-BM in this model of pulmonary fibrosis is a late rather than an early feature of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Premorbid ventilatory response to hypercapnia is not related to resting arterial carbon dioxide tension in hamsters with elastase-induced emphysema.

Marked variability in resting steady-state arterial PCO2 (PaCO2) values are observed among patients with chronic obstructive pulmonary disease (COPD), independent of severity of their obstructive airways defect. The reasons for the development of hypercapnia in some but not in the others remain unclear. One hypothesis states that the level of morbid resting PaCO2 may be related to the premorbid hypercapnic ventilatory response (HCVR); accordingly, subjects who were relatively insensitive to CO2 breathing (low responders) develop CO2 retention in the face of lung disease. The present study investigated this hypothesis in the hamster model of elastase-induced emphysema. After obtaining steady-state HCVR in 19 unanesthetized unrestrained hamsters, emphysema was induced by intratracheal instillation of pancreatic elastase. Forty-five days later, minute ventilation and PaCO2 measurements were done, and lung function tests were obtained. The slopes of HCVR and morbid PaCO2 values varied from -0.09 to 2.36 ml/min/mmHg inspired PCO2 and 48.7 to 63.1 mmHg, respectively. There were no significant correlations between morbid PaCO2 values and premorbid HCVR or lung function test abnormalities caused by emphysema. These animal model studies do not support the hypothesis that the level of PaCO2 in patients with COPD is related to their premorbid HCVR.

Animals↗