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Biomedical subjects

G L Snider

Publications and source records attributed to G L Snider.

At least 37 records · Page 2Linked to original sources
PubMed1996

Differential expression of elastin and alpha 1(I) collagen mRNA in mice with bleomycin-induced pulmonary fibrosis.

Interstitial pulmonary fibrosis is characterized by increased production of connective tissue components, including collagen and elastin. The role of elastin turnover in pulmonary fibrosis is not clear, and it is not known whether elastin and collagen are regulated separately or together during the inflammatory process. Mice with bleomycin-induced pulmonary fibrosis were investigated to determine the temporal and spatial changes in localization of elastin mRNA expression, as well as to compare elastin mRNA expression with that of alpha 1(I) collagen mRNA expression. In control (saline-treated) lungs, elastin mRNA was detected by in situ hybridization in arterial walls. No signal was found in alveolar or airway walls or in pleura; alpha 1(I) collagen mRNA was detected in the tissue underlying the airway epithelium. An increase in elastin mRNA expression in muscular arteries was observed 3 days after bleomycin instillation. Expression was also seen in the adventitia of terminal airways and adjacent small blood vessels. Expression of alpha 1(I) collagen mRNA increased in the tissue underlying the airway epithelium. In the pleura, alpha 1(I) collagen mRNA expression was found, although no pleural thickening was evident. The alpha 1(I) collagen mRNA expression was particularly increased in the adventitia of terminal airways and in associated small blood vessels. Obvious in areas of fibrosis, elastin mRNA expression was occasionally increased in the pleura and airway wall 7 days after bleomycin treatment; alpha 1(I) collagen mRNA expression was generally stronger than elastin mRNA expression in areas of fibrosis and was frequently intense in the adventitia of airways and associated blood vessels. The fibrotic areas showed increased elastin mRNA expression 14 and 30 days after bleomycin treatment. The arteries in fibrotic areas showed normal elastin mRNA levels. In the areas of fibrosis and in the adventitia of airways and adjacent blood vessels, alpha 1(I) collagen mRNA expression was very high. In conclusion, lung elastin biosynthesis is markedly altered by bleomycin treatment. The localization and intensity of elastin mRNA expression is different from the expression of alpha 1(I) collagen mRNA.

Animals↗
PubMed1995

Cross-linked elastin and collagen degradation products in the urine of patients with scleroderma.

OBJECTIVE: To measure the urinary excretion of specific cross-link amino acid markers for mature elastin (desmosine [DES] and isodesmosine [IDES]) and fibrillar collagen (hydroxylysylpyridinoline [HP] and lysylpyridinoline [LP]) in systemic sclerosis (SSc) patients and healthy controls. METHODS: Urine specimens from 20 patients with SSc and 22 controls were assessed for DES, IDES, HP, and LP using high performance liquid chromatography and ultraviolet absorption spectroscopy, in combination with an isotope dilution technique in which the urine specimen was spiked with isotopically labeled cross-link amino acids. RESULTS: Mean +/- SD levels of urinary DES and IDES were elevated in SSc patients by 2-3-fold, and urinary HP and LP by 3-4-fold, compared with controls (DES 21.0 +/- 9.4 versus 7.5 +/- 1.4 micrograms/gm creatinine; HP 109.0 +/- 72.9 versus 24.9 +/- 5.7 nmoles/mmole creatinine). Nineteen of the 20 SSc patients had urinary DES and HP values that were > 3 SD above the control mean. A significant elevation in the HP:LP ratio in SSc patients as compared with controls (mean +/- SD 6.9 +/- 1.5 versus 5.5 +/- 1.3) indicated a soft tissue origin for much of the increased HP. CONCLUSION: Patients with SSc have higher levels of urinary cross-link amino acids specific for the degradation of mature collagen and elastin. These markers distinguish most SSc patients from healthy controls.

Adult↗
PubMed1995

Preliminary evidence that augmentation therapy diminishes degradation of cross-linked elastin in alpha-1-antitrypsin-deficient humans.

It is hypothesized that emphysema develops in some severely alpha 1-antitrypsin (AAT)-deficient persons because endogenous elastases are not adequately controlled by AAT, and accelerated elastin degradation occurs. It is not known whether augmentation therapy with AAT diminishes degradation of lung elastin in severely deficient persons with lung disease. Two severely deficient, PiZ patients were studied, a 63-year-old never-smoking woman with bronchiectasis and a 41-year-old smoking man with emphysema. Urinary desmosine (DES) was determined before and after augmentation therapy with AAT, 260 mg/kg/month. Mean +/- SEM pretreatment urinary DES was elevated in both patients, 19.7 +/- 0.9 (n = 2) and 10.8 +/- 0.2 (n = 2) micrograms/g creatinine, respectively, compared to normal values of 7.5 +/- 0.3 (n = 22) micrograms/g creatinine. Following augmentation therapy, urinary DES values decreased 40 and 36%, respectively, to 11.9 +/- 0.3 (n = 8) and 6.9 +/- 0.4 (n = 7) microgram/g creatinine (p < 0.05). We conclude that monthly AAT augmentation therapy decreased DES excretion in the urine of these PiZ patients. We speculate that since there was lung disease in both patients, a decrease in degradation of lung elastin is the most likely explanation for this observation.

Adult↗
PubMed1995

Elastin and collagen degradation products in urine of smokers with and without chronic obstructive pulmonary disease.

It has been hypothesized that emphysema results from damage to the elastic fiber network of the lungs as a result of elastase-antielastase imbalance. We used a new assay for urinary desmosine (DES) and isodesmosine (IDES), specific markers for the degradation of mature crosslinked elastin, and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), specific markers for the degradation of mature crosslinked collagen, in order to examine elastin and collagen degradation in relation to current cigarette smoking and the presence of chronic obstructive pulmonary disease (COPD). The study sample consisted of 22 never-smokers (NSM group), 13 current smokers without airflow obstruction (SM group), and 21 patients with COPD (COPD group), including both current and former smokers. The relation between the creatinine-height index and FEV1 was used to correct for possible loss of muscle mass and decreased excretion of creatinine in the COPD group. Mean urinary excretion of elastin-derived crosslinks in the COPD group (DES, 11.8 +/- 5.1 [mean +/- SD]; IDES, 11.3 +/- 5.0 micrograms/g creatinine) and in the SM group (DES, 11.0 +/- 4.2; IDES, 10.2 +/- 2.5 micrograms/g creatinine) was significantly higher than in the NSM group (DES, 7.5 +/- 1.4; IDES, 6.9 +/- 1.3 micrograms/g creatinine). In multivariate analysis, current smoking and the presence of COPD were significantly and independently associated with higher urinary excretion of elastin degradation products, and there was no significant interaction between current smoking and the presence of COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Elastin and collagen degradation products in urine of patients with cystic fibrosis.

Elastin degradation has been reported to be increased in patients with cystic fibrosis (CF). In order to further explore evidence for elastin degradation in a group of 18 patients with CF with a wide range of disease severity, we used an isotope dilution method to measure urinary desmosine (DES) and isodesmosine (IDES), amino acids derived exclusively from cross-linked elastin, and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), amino acids derived exclusively from cross-linked collagen. Urinary DES and IDES (mean +/- SD) were 23.9 +/- 30.7 and 18.5 +/- 22.4 micrograms/g creatinine, respectively, in the patients with CF versus 7.5 +/- 1.7 and 6.8 +/- 1.4 micrograms/g creatinine, respectively, in 10 healthy control subjects (p < 0.001); only two patients with CF had DES values within the control range. The values of urinary HP and LP in the CF group were 54.9 +/- 39.1 and 12.3 +/- 8.6 nmol/mmol creatinine, respectively, versus 24.5 +/- 5.8 and 5.1 +/- 2.7 nmol/mmol creatinine, respectively, in the controls (p < 0.005). Both HP and LP were highly correlated (r = 0.71, p < 0.0001). Patients with CF had active pulmonary inflammation; neutrophils were abundant in the bronchoalveolar lavage fluid of the CF group and correlated with elastase activity measured with methoxysuccinyl Ala-Ala-Pro-Val paranitroanilide (r = 0.61, p < 0.05). Airway neutrophils had decreased expression of the complement receptor CR1 (CR1/CR3 of 0.17 +/- 0.15 versus 1.0 for blood neutrophils), a change known to be caused by uninhibited neutrophil elastase. We conclude that lung elastin is the most likely source of the increased DES and IDES in CF.

Adult↗
PubMed1994

Effect of diet on urinary excretion of desmosine and hydroxylysyl pyridinoline.

To help validate the use of urinary desmosine (DES), isodesmosine (IDES), and hydroxylysyl pyridinoline (HP) as specific markers of host elastin and collagen degradation, respectively, a study was carried out on the effect of dietary elastin and collagen on urinary DES, IDES, and HP. Ingestion of a meal of calf ligamentum nuchae containing 33 g elastin, 500 mg DES, and 400 mg IDES produced a 10-fold increase in urinary DES and an 8-fold increase in IDES. The urinary DES values remained elevated for more than 10 days following the ingestion. We estimate that about 0.3 mg, or < 0.1%, of the ingested DES was excreted in the urine. Since ligamentum nuchae is not a usual ingredient of human diets, we also determined whether a more typical source and amount of DES, IDES, and HP might affect urinary DES, IDES, or HP values. Lean ground beef (454 g) was ingested. Our analysis showed that this meal contained 4 mg DES, 2 mg IDES, and 0.9 mg HP. The meat-rich diet caused a significant increase of 16 and 34% in the creatinine and DES content of the urine, respectively. When DES, IDES, and HP values were normalized for the urine creatinine content, diet had no effect on the measured amounts. The baseline values (mean +/- SE) for the volunteers before ingestion of the beef were 8.3 +/- 0.7 micrograms DES/24 h, 8.3 +/- 0.6 micrograms IDES/24 h, and 340 +/- 48 nmol HP/24 h; 5.7 +/- 0.5 micrograms DES/g creatinine, 5.6 +/- 0.4 micrograms IDES/g creatinine, and 26.9 +/- 2.2 nmol HP/mmol creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1994

CT and COPD.

Explore the source record for details and available documents.

Aged↗
PubMed1994

Pitfalls in antiprotease therapy of emphysema.

Many individuals with emphysema are unable to stop smoking despite the best efforts of specialists in smoking cessation. Because emphysema is a slowly progressive disease, it is rational to attempt to develop drugs for it. The hope is that drug therapy will slow the rate of decline of lung function, thereby delaying the onset of disability and prolonging life. The major emphasis in drug development has been on antiproteases having the ability to inhibit neutrophil elastase. There are a number of potential pitfalls in the development of such drugs. Although there is gathering evidence that elastin degradation is a part of the development of human emphysema, it is evident from studies in experimental emphysema that protease-antiprotease imbalance is not the only pathogenetic mechanism that gives rise to emphysema. There is strong evidence that human centrilobular and panacinar emphysema are different in pathogenesis. Indeed, airspace enlargement may be considered one of the stereotyped ways that the lung heals after a variety of injuries. There is accumulating evidence that macrophages as well as neutrophils may participate in elastolysis; antiproteases designed to inhibit neutrophil elastase may not inhibit the metalloproteases produced by macrophages. Some antiproteases may serve to transport elastase into the interstitium of the lung and actually increase the risk of emphysema. A process study of antiprotease therapy, using a measure of alteration of elastase burden of the lungs and urinary elastin peptides and desmosine measurements as markers of elastin degradation is now feasible. An outcome study of antiprotease therapy of emphysema should not be undertaken unless there is evidence from a process study that an antiprotease has biochemical efficacy and no unacceptable side effects.

Animals↗
PubMed1993

Oxidants from neutrophil myeloperoxidase do not enhance elastase-induced emphysema in the hamster.

Alpha-1-protease inhibitor is susceptible to oxidative impairment by the neutrophil myeloperoxidase (MPO) system. The purpose of this study was to assess the effect of the MPO oxidant system on elastase-induced emphysema in the hamster. Intratracheal instillation of 200 micrograms of human neutrophil elastase (HNE) induced a significant secretory cell metaplasia (SCM) and airspace enlargement [23% increase in mean linear intercept (MLI) as compared with control values]. Instillation of MPO system components [0.6 international units (U) of MPO, 5.5 U of glucose oxidase and glucose (0.02 M)] along with 200 micrograms HNE failed to enhance the severity of the SCM or emphysema induced by HNE alone. A second experiment was carried out using 50 micrograms of porcine pancreatic elastase (PPE) to induce emphysema. PPE produced a significant 45% increase in MLI, but the MPO system combined with PPE failed to enhance the emphysema induced by PPE alone. The MPO system alone had no measurable effect on airspace size or SCM. In vitro studies showed that PPE was partially inactivated by the MPO system; a 56% loss of elastolytic activity occurred during a 6-min incubation of PPE with the MPO system. This may explain why the MPO system did not exacerbate PPE-induced injury, but it does not explain the lack of enhancement for HNE. A 6-minute incubation of HNE with the MPO system resulted in a nonsignificant 10% decrease of elastolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Relationship of secretory granule content and proliferative intensity in the secretory compartment of the hamster bronchial epithelium.

We have previously shown that normal hamster airway epithelial secretory cells have a lower proliferative intensity than basal cells, but because of their high frequency are a major contributor to cell renewal (Am. J. Respir. Cell Mol. Biol. 1990; 2:51-58). In the present experiment, the relation between proliferative intensity and secretory granule content in bronchial epithelial cells is studied. [3H]thymidine (2 microCi/g wt) was given intraperitoneally, 1 h before killing, to 5 hamsters treated 21 days earlier with intratracheal saline and to six hamsters in which secretory cell metaplasia had been induced by intratracheal treatment with 300 micrograms of human neutrophil elastase given 21 days earlier. Light microscopic autoradiograms were prepared from 2-microns-thick Epon sections of left intrapulmonary hilar bronchi. Cells were categorized as basal, ciliated, secretory, or indeterminate. Secretory cells were classified as either: S1, with 0 to 4 granules; S2, with > or = 5 granules with intervening cytoplasm; or S3, with abundant granules and no apparent supranuclear cytoplasm. Proliferative intensity was defined by the categorical labeling index (LIc) at 1 h after [3H]thymidine injection. LIc was determined by the number of labeled cells in a category as the percent of labeled and unlabeled cells of that category. LIc of each of the cell categories were similar in the elastase and saline groups. LIc was highest for basal cells, reflecting their proliferative intensity, and lowest for ciliated cells. In the saline group, LIc of S1 (0.25%) was significantly higher compared with S2 (0.13%); S3 cells were rare (0.2%) and none were labeled.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Electron microscopic study of human lung tissue after in vitro exposure to elastase.

Much of the experimental evidence supporting the hypothesis that pulmonary emphysema results from an imbalance between elastases and anti-elastases in the lung comes from animal models. The present study was designed to examine the effects on human lung tissue of the two elastases that have been most widely used to produce these animal models. Lung tissue was exposed in vitro to human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE). Although both enzymes solubilized protein at similar rates, PPE solubilized elastin five times faster than did HNE. Ultrastructurally, HNE-exposed tissue exhibited fewer damaged elastic fibers as well as some fibers that were damaged at the edges, whereas the interior of the fiber appeared intact. Elastic fibers showing damage only at the periphery were not seen in tissue exposed to PPE. Immunocytochemical studies in which antibodies to HNE and PPE were applied to thin sections of Lowicryl-embedded tissue indicated that both of these elastases could be detected in association with elastic fibers, but only in areas of the fiber that showed morphological evidence of elastase injury. Both HNE and PPE removed fibronectin from basement membranes (as determined by loss of binding of fibronectin antibodies after exposure to elastase), but neither elastase was detected on basement membrane. Loss of epithelial cells usually accompanied elastic fiber damage by HNE but not PPE.

Animals↗