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Biomedical subjects

G L Snider

Publications and source records attributed to G L Snider.

At least 73 records · Page 4Linked to original sources
PubMed1990

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters.

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.

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PubMed1989

Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis.

Chronic obstructive pulmonary disease (COPD) is defined in this chapter, and the relation between its two major components, (a) chronic bronchitis and emphysema and (b) nonremitting asthma, is discussed. Intensity of tobacco smoking and age are the major risk factors for the development of chronic airways obstruction. Environmental air pollution, childhood infections, and familial factors other than alpha-1 protease inhibitor deficiency appear to play only small roles. Emphysema is the major cause of severe airways obstruction; bronchiolitis is a contributing factor and likely is responsible for the minor reversible element of airways obstruction. The elastase-antielastase hypothesis, which is based mainly on indirect evidence, is the best explanation for the pathogenesis of emphysema. Extensive airspace enlargement with fibrosis is infrequently observed; this mechanism may play a role in the pathogenesis of the centrilobular emphysema of smokers.

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PubMed1989

Human neutrophil elastase causes glycoconjugate release from the epithelial cell surface of hamster trachea in organ culture.

It is known that human neutrophil elastase (HNE) treatment of hamster tracheal explants causes the release of glycoconjugates, most of which appear to have the characteristics of mucus glycoproteins. This study was designed to determine the origin of HNE-induced glycoconjugate release from 1-day-old cultures of adult hamster trachea. After confirming that HNE treatment released glycoconjugates from cultures labeled with tritiated glucosamine, light microscopic autoradiograms and electron micrographs were prepared. Untreated cultures and cultures treated with inactivated HNE served as controls. HNE treatment caused a 40 to 50% decrease in the silver grain count on the external apical surfaces of secretory cells (p less than 0.05) and ciliated cells (p less than 0.01). Silver grain counts in secretory and ciliated cell cytoplasm, submucosa, and nontissue background were not significantly different from controls. The percentage of nongranulated secretory cells and the number of secretory granules in granulated secretory cells were similar in the HNE-treated and untreated controls. There was no evidence of constitutive release of radiolabeled glycoproteins, or of discharge of secretory granules from the secretory cells. We conclude that HNE releases mucins and other glycoconjugates from the external surfaces of both secretory and ciliated cells in tracheal organ culture.

Animals↗
PubMed1989

Chronic obstructive pulmonary disease: a definition and implications of structural determinants of airflow obstruction for epidemiology.

Chronic obstructive pulmonary disease (COPD) may be defined as a process characterized by the presence of chronic bronchitis or emphysema that may lead to the development of airways obstruction; airways obstruction need not be present at all stage of the process and may be partially reversible. The pathologic changes in the lungs due to smoking affect three regions: the bronchi, bronchioles, and parenchyma. The bronchi show enlargement of the submucosal glands with dilation of their ducts; infiltration with neutrophils and lymphocytes is present but not prominent. Respiratory bronchiolitis is observed in persons smoking for only a few years; the membranous bronchioles show a mix of inflammation, luminal mucus, goblet cell metaplasia, and distortion due to fibrosis and loss of alveolar attachments. The lung parenchyma shows centrilobular emphysema. Bronchial changes are only weakly related to airflow obstruction but bronchiolar changes are also related. The relation between airflow limitation and bronchiolitis is progressively harder to show as the severity of emphysema increases because of the dominant role of emphysema in causing airflow obstruction. Emphysema is the predominant lesion in persons with severe airflow obstruction due to COPD. The diffusing capacity for carbon monoxide is related to the severity of emphysema but is nonspecific and is mildly abnormal in smokers without emphysema. The compliance of the lungs of smokers is decreased even when a emphysema and airflow limitation are mild. Standard epidemiologic tools do not differentiate emphysema from other causes of airflow obstruction. Most persons dying of COPD will have severe emphysema.

Bronchi↗
PubMed1989

Regional difference in airway epithelial response to neutrophil elastase: tracheal secretory cells discharge and recover in hamsters that develop bronchial secretory-cell metaplasia.

Human neutrophil elastase (HNE) causes secretory granule discharge and conversion of many Clara cells to mucous cells in hamster bronchi. We investigated whether the trachea responds to HNE in a similar manner because of its abundance of Clara cells. By light microscopy, the tracheal epithelium of animals exposed to a single intratracheal injection of HNE was normal at 21 days, although bronchial secretory-cell metaplasia (SCM) was present. An ultrastructural differential cell count showed no increase in the proportion of granulated secretory cells in HNE-treated animals at 8 and 21 days postinjection compared to saline or untreated controls. At 2 h, the percentage of granulated secretory cells was lower and that of granulated secretory cells was higher in HNE-treated animals than in controls. The HNE-treated animals had fewer secretory granules per cell profile and more surface undulation than controls. By 1 day, the differential cell count and number of granules per cell profile were normal. Saline did not affect the differential cell count or granule number at any time. Ultrastructural study of untreated trachea disclosed the same three types of Clara cell that are found in the bronchus, but their frequencies, with one exception, are significantly different in the two regions. We conclude that HNE acts as a secretagogue in both trachea and bronchus but that an amount of enzyme sufficient to cause bronchial SCM does not induce a similar lesion in trachea. Heterogeneity of Clara cell types in hamster airways may explain the regional variation in secretory-cell modulation by HNE.

Animals↗
PubMed1989

Amelioration of human neutrophil elastase-induced emphysema in hamsters by pretreatment with an oligopeptide chloromethyl ketone.

Human neutrophils are a likely source of elastase in the pathogenesis of human pulmonary emphysema. A study was undertaken to determine whether emphysema, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be ameliorated by intratracheal instillation of succinyl-alanyl-alanyl-prolyl-valine-chloromethyl ketone (CMK). One mg of CMK was given to hamsters 1 h before 300 or 360 micrograms HNE or 1 h or 4 h after 360 micrograms HNE. The animals were studied eight weeks after treatment. The CMK given 4 h after HNE did not ameliorate the emphysema. The CMK given 1 h before HNE, ameliorated the development of emphysema but not bronchial secretory cell metaplasia. A molar ratio of instilled CMK to HNE of 128 was required for 50% in vivo effectiveness in ameliorating emphysema. Clearance studies indicated that 6.9% of the instilled CMK could be lavaged from the lungs 1 h after instillation. Therefore, an 8.9 to 1 molar ratio of lavageable CMK to HNE, at the time of HNE instillation, resulted in 50% protection. Using an in vitro assay with 3H-elastin as substrate, a 3 to 1 molar ratio of CMK to HNE was required to inhibit 50% of the elastolytic activity; 14% of the activity remained with an 18 to 1 molar ratio of CMK to HNE. Study of the in vivo effectiveness of anti-elastases, given as pretreatment in ameliorating HNE-induced emphysema and secretory cell metaplasia, is a reasonable bioassay, which may be used as a step in evaluating such agents for possible use in the prevention of human disease.

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PubMed1988

Acid-induced secretory cell metaplasia in hamster bronchi.

Hamsters were exposed to an intratracheal instillation of 0.5 ml of 0.08 N nitric, hydrochloric, or sulfuric acid to determine their airway epithelial response. Three weeks after exposure, the left intrapulmonary bronchi in Alcian blue/PAS-stained paraffin sections were evaluated for the amount of secretory product in the airway epithelium as a measure of secretory cell metaplasia (SCM). Compared to saline-treated control animals, all three acids caused statistically significant SCM. In addition to the bronchial lesion, all three acids caused similar interstitial fibrosis, bronchiolectasis, and bronchiolization of alveoli that varied in individual animals from mild to severe. In a separate experiment to study the persistence of the SCM, hamsters treated with a single instillation of 0.1 N nitric acid showed significant SCM 3, 7, and 17 weeks after exposure. There was a high correlation (r = 0.96) between a subjective assessment of SCM and objective assessment using a digital image-analysis system. We conclude that protons induce SCM independently of the associated anion; the SCM persists at least 17 weeks. Sulfuric acid is an atmospheric pollutant and nitric acid may form locally on the mucosa of lungs exposed to nitrogen dioxide. These acids may contribute to the development or maintenance of the SCM seen in the conducting airways of humans with chronic obstructive pulmonary disease.

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PubMed1988

Defenses of the hamster lung against human neutrophil and porcine pancreatic elastase.

Instillation of human neutrophil elastase (HNE) into hamster lungs produces milder emphysema but more pulmonary hemorrhage than an equivalent amount of porcine pancreatic elastase (PPE), whether equivalence is determined by elastolytic units or moles. We undertook a study of the mechanisms of these differences. 125I-HNE or 3H-PPE were instilled intratracheally into hamsters. The partitioning of radioactivity between bronchoalveolar lavage fluid (BAL) and lung tissue was similar for HNE and PPE as were the half-lives, 45 and 51 min, respectively, for uncomplexed, enzymatically active HNE and PPE. In BAL there was preferential binding and inactivation of HNE by the hamsters' alpha-1-protease inhibitor (a-1-PI) whereas PPE was preferentially bound by alpha-2-macroglobulin (a-2-M). This was also observed in vitro when HNE and PPE were incubated with plasma from untreated hamsters. Nevertheless, when the sum of the elastase binding capacity of a-1-PI and a-2-M was considered, hamster plasma had similar binding capacities for HNE and PPE. It is known that the enzymatic activity of elastases is inhibited by formation of a stable complex with a-1-PI. On the other hand, elastases bound to a-2-M are protected against a-1-PI inhibition but can free themselves by proteolysis and exhibit elastolytic activity. Preferential inactivation of HNE by a-1-PI may be one mechanism that accounts for the lesser emphysema-inducing potency of HNE than of PPE.

Animals↗
PubMed1988

Cadmium-chloride-induced air-space enlargement with interstitial pulmonary fibrosis is not associated with destruction of lung elastin. Implications for the pathogenesis of human emphysema.

To determine whether lung elastin is lost during the evolution of cadmium-induced air-space enlargement with pulmonary fibrosis, the lung elastin of 5- to 7-day-old golden Syrian hamster pups was radiolabeled by giving [3H]valine. At maturity, a single intratracheal instillation of 0.5 ml of 0.025% CdCl2 solution was given. Lung mechanics, histologic examination, and biochemistry were studied 5, 10, 21, 42, 105, and 180 days after the cadmium treatment. The animals developed fibrosis and air-space enlargement with decreased lung volumes, compliance, and forced expiratory flow; their functional residual capacity was increased. The total lung collagen and total lung elastin were increased, but there was no loss of radiolabel in lung elastin. We conclude that CdCl2-induced air-space enlargement with pulmonary fibrosis is not accompanied by loss of neonatally formed lung elastic fibers. We hypothesize that air-space enlargement with fibrosis represents a stereotyped response of the lung to fibrosing injuries, which we hypothesize is due to forces from more fibrotic and atelectatic areas causing overdistension of less abnormal air spaces. The air-space enlargement of fibrosing human diseases such as sarcoidosis and eosinophilic granuloma may have a similar basis. Evidence is reviewed that human centrilobular emphysema may be a form of focal air-space enlargement with interstitial fibrosis; there may be mechanisms in addition to elastase-antielastase imbalance that cause human emphysema.

Animals↗
PubMed1988

An 18-month study of the effects on hamster lungs of intratracheally administered human neutrophil elastase.

A study was made of the evolution of emphysema and airway injury induced in the lungs of male golden Syrian hamsters by a single intratracheal injection of 350 micrograms human neutrophil elastase (HNE). Saline control and HNE-treated groups of 8 animals were studied 1, 3, 6, 12, and 18 months posttreatment. HNE treatment caused a significant increase in all lung volumes and a significant decrease in maximum expiratory flows at all study times. The mean linear intercept (MLI) values of the left lung were significantly increased over control values. There was no progression with time in MLI values, lung volumes, or lung compliance. Secretory-cell metaplasia was present at 1 month and persisted throughout the study. The HNE-treated lungs showed clusters of ferric iron-containing macrophages in the terminal airspaces. The amount of iron in the lungs, determined morphometrically, was greatest at 1 month, was decreased by 6 months, and then did not change further to 18 months. At 18 months the amount of iron was still significantly above control amounts. We conclude that the airway and parenchymal lesions induced by HNE persist without progression for 18 months. Clearance of ferric iron, which was probably a result of the hemorrhage induced by HNE treatment, continued for 6 months with no evident subsequent clearance.

Animals↗
PubMed1987

An ultrastructural morphometric analysis of elastase-treated hamster bronchi shows discharge followed by progressive accumulation of secretory granules.

An ultrastructural morphometric analysis of bronchial secretory cells was carried out on hamsters treated intratracheally with 300 micrograms of human neutrophil elastase (HNE) in 0.5 ml saline, saline alone, or left untreated. Five to 6 animals were killed at 2 h and at 3, 8, and 16 days after treatment. Electron micrographs were prepared from the hilar region of the left main intrapulmonary airway; 125 +/- 16 (mean +/- SE) granulated secretory cells extending from basement membrane to lumen were analyzed for each group. The number (Ng) and area (Ag) of granular profiles per cell, the area of cell profiles (Ac), and the volume density of secretory granules per cell (Vv) were determined using an electronic image analyzer. There were significant decreases in Ng, mean Ag, and Vv in the 2-h HNE group when compared with the saline group. Values of Ng, mean Ag, and Vv were similar for HNE and saline groups at 3 days, but were significantly increased at 8 and 16 days. The Ac of HNE-treated groups was similar to their saline control groups at all time points except at 16 days when the HNE-treated group enlarged to double that of its saline control group. An ultrastructural differential cell count showed a decrease in frequency of granulated secretory cells at 2 h and an increase at 8 and 16 days; there was an inverse change in the frequency of nongranulated secretory cells at these times. The proportion of ciliated, preciliated, and indeterminate cells remained constant over time in all treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of the elastase inhibitor, eglin-c, on antibacterial mechanisms in experimental pneumonia. Description of a system to quantitate phagocytic and bactericidal activity of resident murine alveolar macrophages in vivo.

To evaluate the influence of the elastase inhibitor, eglin-c, on lung host defense, normal CD-1 mice were challenged intratracheally with type 3 Streptococcus pneumoniae suspended in phosphate-buffered saline alone or containing 10 mg/ml eglin-c. After infection with 5 X 10(3) colony-forming units (cfu), animals given eglin-c demonstrated a significant enhancement in their capacity to clear viable pneumococci from the lungs at 24 h after challenge; the augmented pulmonary clearance was associated with an increased influx of granulocytes at 6 and 24 h. After challenge with higher inocula (5 X 10(4) and 5 X 10(5) cfu), animals treated with eglin-c exhibited a significant impairment in pulmonary clearance at 6 h; however, in the presence of larger numbers of granulocytes within the bronchoalveolar spaces, the attenuation in pulmonary clearance resolved between 6 and 24 h. Changes in the kinetics of pulmonary clearance that were similar to those noted after infection with high pneumococcal inocula were also observed after challenge with 1 X 10(6) cfu Staphylococcus aureus. In addition, although it did not influence the in vivo phagocytic capacity of resident alveolar against S. aureus, eglin-c depressed the bactericidal activity of these cells. We conclude that in the mouse, high doses of eglin-c alter pulmonary antimicrobial mechanisms important for preventing and eradicating bacterial infection of the lower respiratory tract.

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