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Biomedical subjects

G Weinbaum

Publications and source records attributed to G Weinbaum.

At least 19 recordsLinked to original sources
PubMed1998

Experimental study of acid burden and acute oesophagitis.

BACKGROUND: The relationship of the pH of oesophageal refluxate and its pepsin content to injury of oesophageal mucosa remains unclear. A study was made of the earliest morphological alterations in the oesophageal mucosa secondary to varying concentrations of hydrochloric acid with or without pepsin. METHODS: Adult cats had varying concentrations of acid with and without 1 per cent porcine pepsin infused into the oesophagus through a paediatric feeding tube placed 5 cm above the oesophagogastric junction at a rate of 1 ml/min for 30 min. At autopsy 24 h later, the oesophagus was removed intact and scored by an expanded modification of a previously published histopathological scoring system. This included estimates of the intensity and distribution of four morphological features: basal cell hyperplasia (BCH), intraepithelial leucocytes (IELs), subepithelial leucocytes and ulcers. Each of these four categories was scored from 0 to 4, with a maximum injury score of 16. RESULTS: Mean(s.e.m.) scores were as follows: pH 1, 15.0(1.0); pH 1 with pepsin, 13.3(1.4); pH 2, 15.3(0.7); pH 2 with pepsin, 11.7(1.1); pH 3, 1.8(1.6); pH 3 with pepsin, 3.7(1.9); pH 4 with or without pepsin, 0.6(0.2). Differences between pH 3 and 4 versus pH 1 and 2 were significant (P < 0.05). CONCLUSION: Injury to the oesophagus is more dependent on the pH of refluxate than on the presence of pepsin. Peptic injury appears to occur at a critical threshold of acid burden (pH < 3) as opposed to a graded level of injury based on a pH scale.

Acute Disease↗
PubMed1993

Production of chemoattractant by Helicobacter pylori.

Helicobacter pylori is present in the antral region of the stomach in a majority of patients with gastritis type B. The specific mechanism whereby the organism participates in the development of disease remains uncertain. Since the organism is not invasive, we postulate that H. pylori produces a chemoattractant that recruits inflammatory cells to the antral region of the stomach. H. pylori was grown under microaerophilic conditions at 37 degrees C for 72 hr in Brucella broth containing 1% fetal bovine serum. Culture supernates were harvested after removal of organisms by centrifugation and filtration. The putative chemoattractant in culture supernates as well as that which might be present endogenously in the growth medium (negative control) was assayed against human neutrophils (PMN) in modified Boyden blind-well chambers using 3.0-microns membranes. We found that H. pylori supernates are chemotactic and showed up to 130% activity when compared to the positive chemoattractant control (zymosan-activated serum, a source of C5a). Minimal activity was observed with virgin growth medium. The chemoattractant activity is proportional to the number of colony forming units (CFU) of H. pylori. Preliminary characterization of the activity shows that the chemoattractant is stable in a boiling water bath for 15 min, activity is lost within 1 hr in acid or alkali, and the chemotactic factor has an approximate molecular weight of 8500 daltons. The factor has no amino-sugar and is negative for the lipid A portion of lipopolysaccharide.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1992

Specificity and sensitivity of the assay for elastin-derived peptides in chronic obstructive pulmonary disease.

One prediction of the protease-antiprotease hypothesis of chronic obstructive pulmonary disease (COPD) pathogenesis is the appearance of elastin-derived degradation products in the plasmas of affected patients that are due to the breakdown of alveolar interstitial elastin by an excess of elastolytic activity in the lung. We previously demonstrated a significant elevation of plasma elastin-derived peptides (EDP) in subjects with COPD in comparison with asymptomatic smokers with normal spirometry or normal nonsmokers. To better determine the selectivity of the assay for EDP as a marker of COPD, we measured plasma EDP levels in different patient populations. These included subjects with COPD, subjects with diseases that may involve accelerated elastolysis (pneumonia, atherosclerotic vascular disease, and inflammatory arthritis), subjects with diseases hypothesized to involve pulmonary inflammation without elastolysis (asthma and acute tracheobronchitis), asymptomatic smokers with normal spirometry, and healthy, nonsmoking subjects. Mean plasma EDP levels in subjects with COPD were elevated above those in all other subjects (p less than 0.01). The prospective analyses of specificity and sensitivity of plasma EDP levels as markers of COPD gave values of 91 and 65%, respectively. Utilizing receiver operating characteristic curve analysis to assess the diagnostic and screening performance of plasma EDP as a test for COPD (perfect test equals an area under the curve of 1.0), the area under the curve was 0.87, which compares favorably with many widely used clinical tests. These data demonstrate that the assay for plasma EDP is a quantitative, easily measured, and highly specific marker for subjects with COPD.

Adult↗
PubMed1991

Size distribution of human lung elastin-derived peptide antigens generated in vitro and in vivo.

The protease-antiprotease hypothesis of emphysema development suggests that degradation of elastin in the lung interstitium may give rise to abnormal quantities of circulating elastin-derived peptides (EDP) during periods of inflammation. Recent studies have shown a relationship between emphysema and high levels of EDP in human plasma. This report characterizes elastin digests on the basis of antigenicity, size, and method of preparation, as well as the size distribution of EDP found in the plasmas of nonsmokers, smokers, and emphysema patients. Gel filtration of elastin digests prepared by hydrolysis of human lung elastin using a low (1:500) ratio of neutrophil elastase to elastin generated a broad protein peak of approximately 70,000 daltons. In contrast, a high (1:25) ratio of neutrophil elastase to human lung elastin gave a broad protein peak, with a size distribution in the 10,000 to 30,000 dalton range. This digest showed distinct immunochemical properties. A polyclonal antibody directed against the low-ratio digest showed a minimum detection of 2 ng/ml for the homologous antigen but required 1,000 ng/ml of the high-ratio digest for detectable inhibition in an indirect ELISA assay. Gel filtration of plasmas from normal nonsmokers and the majority of normal smokers revealed a single immunoreactive EDP fraction of approximately 70,000 daltons. Plasmas from selected normal smokers and emphysema patients with high levels of circulating EDP (greater than 90 ng/ml) fractionated into a complex pattern of peptides in which the 70,000 dalton component represented 50% of the immunoreactive material and several lower molecular weight peptides represented the remaining circulating elastin antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens↗
PubMed1991

Induction of unilateral pulmonary fibrosis in the rat by cadmium chloride.

Intralobar instillation of cadmium chloride (CdCl2) into the left lungs of rats initiated a sequence of events that culminated in massive unilateral intraluminal fibrosis. Early events (days 1 and 2) after CdCl2 administration included infiltration of the treated lung with polymorphonuclear leukocytes, an increase in the number of alveolar macrophages, activation of the macrophages as assessed by the induction of cathepsin L mRNA, and the induction in liver of mRNA for the acute-phase response protein, alpha 1-acid glycoprotein. By days 5 to 7 in the treated lungs, mRNA for procollagen alpha 1(I) increased 20- to 60-fold, and mRNA for procollagen alpha 1(III) increased 4- to 14-fold. These increases were correlated with the almost complete filling of the alveolar spaces with fibroblasts and collagen. The contralateral lung exhibited no significant change in histology but showed a similar induction of collagen gene expression. These increases were tissue-specific, as the livers of these animals showed no change from the control levels of collagen gene expression. Procollagen messages in the treated and contralateral lungs were equally competent for translation into pro-alpha 1(I) and pro-alpha 2(I) polypeptides. Both the treated and contralateral lungs increased hydroxyproline content about 1.5- to 2-fold over 14 days. The contralateral lung, but not the treated lung, showed a 2-fold increase in lung volume. As a result, the collagen density (mg collagen/ml lung volume) doubled in the treated lung but remained constant in the contralateral lung. These data indicate that CdCl2 caused a rapid induction of pulmonary fibrosis in the treated lungs of rats and stimulated histologically normal growth of the contralateral lung.

Actins↗
PubMed1991

Effects of simulated extracorporeal circulation on human leukocyte elastase release, superoxide generation, and procoagulant activity.

Activated leukocytes are thought to contribute to respiratory dysfunction, alterations in microvascular permeability, disseminated intravascular coagulation, and thrombosis, all of which can complicate extracorporeal circulation. The purpose of this work was to determine the effects of extracorporeal circulation on leukocyte functions likely to mediate organ damage. White blood cell counts in the bubble circuits (n = 5) fell to 51% +/- 7% (mean +/- standard error of the mean; p less than 0.05) of initial levels within 2 hours of recirculation. In contrast, counts from both the spiral coil (n = 5) and hollow-fiber (n = 5) groups remained at 91% +/- 12% and 100%, respectively. Plasma levels of human neutrophil elastase rose from 0.28 +/- 0.06 micrograms/ml to 3.14 +/- 0.36 micrograms/ml (p less than 0.05) and 0.20 +/- 0.02 micrograms/ml to 1.61 +/- 0.35 micrograms/ml (p less than 0.05) in bubble and spiral coil circuits, respectively, but from only 0.20 +/- 0.03 micrograms/ml to 0.96 +/- 0.42 micrograms/ml in the hollow-fiber circuit despite 2 hours of recirculation. Consistently, in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine, a chemotactic peptide, cells from spiral coil and bubble circuits released and generated significantly less elastase and superoxide anion, respectively. In contrast, neutrophils from the hollow-fiber circuits demonstrated enhancement of N-formyl-L-methionyl-L-leucyl-L-phenylalanine-induced elastase release and superoxide generation. Finally, mixed leukocytes from all circuits expressed procoagulant activity reaching statistical significance in bubble circuits. In conclusion, extracorporeal circulation has pronounced effects on neutrophil elastase release, superoxide anion generation, and leukocyte procoagulant activity. Spiral coil and bubble oxygenators cause granule release and, subsequently, reduced sensitivity to soluble agonists. In contrast, hollow-fiber oxygenators "prime" cells, actually enhancing reactivity. Recirculation through all circuits induces leukocyte procoagulant activity that is likely to contribute to surface-induced thromboses and excessive bleeding.

Blood Coagulation↗
PubMed1990

Release of lactoferrin and elastase in human allergic skin reactions.

Our previous skin chamber studies have shown prominent accumulation of viable neutrophils in human allergic skin reaction sites. To determine whether such neutrophils release components that may be pathogenic in allergic reactions, we have compared the patterns of release of five components: 1) lactoferrin, present in specific granules; 2) and 3) elastase and myeloperoxidase, present mainly in azurophilic granules; 4) lactic dehydrogenase, a cytosolic component generally released during cell damage; 5) histamine, present in mast cells and basophils but not in neutrophils. In 13 pollen-sensitive subjects we found that continuous antigen challenge for 5 h lead to a peak of histamine release into overlying skin chambers during the 1st h, followed by a plateau of low level histamine release over the succeeding 4 h. In contrast, there was no significantly increased released of lactoferrin or elastase during the first h, but significantly increased accumulation of these components at Ag challenge sites over the next 4 h. There was no significant difference at Ag vs buffer control sites in the levels of either myeloperoxidase or lactic dehydrogenase. The increased levels of lactoferrin and elastase at antigen challenge sites in the 2nd to 5th h were not simply a reflection of the greater numbers of neutrophils present in such sites because the levels of these components did not correlate significantly with the number of neutrophils in chamber fluids obtained from individual sites. However, such lactoferrin levels did correlate significantly with the amount of histamine released earlier during the 1st h of Ag challenge at individual sites. These findings suggest a selective in vivo release of neutrophil components in IgE-mediated human allergic skin reactions, possibly related in degree to earlier mast cell activation. Inasmuch as lactoferrin likely plays a role in reactive oxidants effects and elastase is a potent nonspecific protease, release of these agents could play a pathogenic role in late phase allergic reactions.

Adult↗
PubMed1990

Intraluminal fibrosis induced unilaterally by lobar instillation of CdCl2 into the rat lung.

Lung injury induced by intratracheal instillation of cadmium chloride (CdCl2) into the rat lung may serve as a model of human interstitial lung disease. In this study, CdCl2 solutions were instilled through a lobar bronchus into the left lung of the rat. Two doses (400 micrograms or 50 micrograms of CdCl2, each in 400 microliters of neutral saline) were used and the morphologic changes occurring during the first 7 days after a single exposure were documented by light and electron microscopy. With the higher dose, inflammatory cells appeared in the alveolar interstitium 1 day after CdCl2 administration. Edema and thickening of the alveolar walls were evident, as were damaged type I epithelial cells and denuded basement membranes. Fibrin was found in the air spaces. Within 2 days, inflammatory cells were seen in large numbers and fibroblasts were observed passing through gaps in the alveolar basement membranes into the air spaces. By 4 and 7 days after CdCl2, various forms of intraluminal fibrosis, including intrabronchiolar budding, mural incorporation, and obliterative changes, were observed. The contralateral lungs had normal-appearing architecture for all the time points investigated. In the lower dose exposure, gradients of alveolar damage were observed in which normal lung, interstitial fibrosis, and/or intraluminal fibrosis were seen within treated lungs. In the mildly damaged regions, interstitial fibrosis predominated, while in the more severely damaged regions, mural incorporation of the convoluted basement membranes was observed. The pulmonary fibrosis that developed appeared to be similar to some human interstitial lung diseases and may offer a system in which to study the regulation of collagen deposition and fibrosis development in these pathologic conditions.

Animals↗
PubMed1989

Alpha 1-antitrypsin levels predict mortality from ethionine-induced pancreatitis in mice.

Experimental pancreatitis can be induced by an ethionine-containing, choline-deficient diet in mice. We investigated the role of circulating alpha 1-antitrypsin in this model using two strains of mice: ICR and C57BL-6. A 50% reduction in circulating alpha 1-antitrypsin occurred in all mice by day three of diet exposure. Total protein was reduced by only 9% and albumin was unchanged. Female mice of both strains had significantly lower alpha 1-antitrypsin levels than male mice prior to and after diet exposure. This was associated with significantly greater mortality in both female strains. Interstrain comparisons showed a significantly higher mortality in the C57BL-6 females (100%) compared to the ICR females (58%); this corresponded to significantly lower alpha 1-antitrypsin levels in C57BL-6 females. Regardless of sex or strain, alpha 1-antitrypsin levels prior to and after diet exposure were significantly higher in mice surviving than in mice dying. We conclude that circulating alpha 1-antitrypsin is a predictor of mortality from diet-induced pancreatitis.

Animals↗
PubMed1988

Nitrogen-dioxide-induced emphysema in rats. Lack of worsening by beta-aminopropionitrile treatment.

We evaluated the effect of beta-aminopropionitrile (beta APN) on the nitrogen dioxide (NO2) animal model of emphysema. Rats maintained on a beta APN-supplemented or a regular diet were exposed to 30 ppm NO2 for intervals ranging from 1 to 8 wk. Emphysema development was assessed by histologic evaluation and by changes in lung volume and mean linear intercept values. Evidence of pathologic changes were also documented by clinical and radiographic findings of osteolathyrism. The induction of centriacinar emphysema was attributed specifically to NO2 exposure. Neither the severity of the emphysema nor the time course of its development was altered by the beta APN-supplemented diet. These findings are in marked contrast to those observed with the exogenous elastase model of the disease, and they suggest that elastin synthesis and repair may not modulate elastin destruction in the NO2 model of emphysema.

Aminopropionitrile↗
PubMed1988

Fibronectin degradation products containing the cytoadhesive tetrapeptide stimulate human neutrophil degranulation.

We investigated whether adhesive glycoproteins, such as fibronectin or fibrinogen, could function to provide a nidus for neutrophil degranulation. Elastase release in recalcified plasma was normal in afibrinogenemic plasma, but 73% less in plasma depleted of fibronectin. Proteolytic digests of fibronectin, but not intact fibronectin (50-1,000 micrograms/ml), induced a concentration-dependent release of neutrophil elastase and lactoferrin. MAbs N293, which recognized the mid-molecule of fibronectin, N294, which was directed toward the 11-kD cell adhesive fragment, and N295, generated against the amino terminal of the 11-kD fragment, inhibited the release of elastase by 7, 24, and 60%, respectively. The cytoadhesive tetrapeptide portion of fibronectin, Arg-Gly-Asp-Ser (250-1,000 micrograms/ml), released 1.94 +/- 0.10 micrograms/ml of elastase from 10(7) neutrophils, in contrast to the lack of release by the control hexapeptide, Arg-Gly-Tyr-Ser-Leu-Gly. Plasmin appeared to be the enzyme responsible for fibronectin cleavage, since neutrophil elastase release in plasma that had been depleted of plasminogen was decreased and reconstitution of plasminogen-deficient plasma with purified plasminogen corrected the abnormal release. Plasmin cleaved fibronectin to multiple degradation products, each less than 200 kD. This fibronectin digest released 1.05 microgram/ml of elastase from 10(7) neutrophils. We suggest that the activation of plasminogen leads to the formation of fibronectin degradation products capable of functioning as agonists for neutrophils.

Antibodies, Monoclonal↗
PubMed1988

Acute cigarette smoke exposure in dogs: the inflammatory response.

Acute cigarette smoke causes polymorphonuclear leukocyte (neutrophil, PMN) recruitment to the lung followed by loss of elastase from the recruited cells. Dogs were exposed to cigarette smoke with different oxidant content, bronchoalveolar lavage (BAL) was performed, and the cell distribution in the recovered alveolar lining fluid was analyzed. Exposures were 1, 3, or 6 cigarettes on one or multiple days with a maximum dose of 42 cigarettes. The mean percent PMN present in control lavage was 2.01%, while the mean percent PMN recovered in BAL after a dose of 42 1R1 cigarettes was 13.05%. Recoverable PMN, after a single exposure to three 1R1 cigarettes, also increased from 1.7 to 10.4% by 15 h after cessation of smoke exposure. The cell response for multiple (2 and 7) day exposures was similar. The elastase content per BAL neutrophil decreased relative to peripheral blood PMN from the same animals. No free elastolytic activity was found in BAL, but PMN elastase antigen was present. Increased frequency of cigarette smoke exposure delayed the return to homeostatic cell conditions. The increased PMN accumulation observed may result in an increased proteolytic load in the pulmonary interstitium and contribute to the pathogenesis of emphysema.

Animals↗
PubMed1988

Ultrastructural quantitation of peroxidase- and elastase-containing granules in human neutrophils.

Previous ultrastructural studies of human neutrophils showed two distinctive granule types, the azurophil (peroxidase-positive) and the specific (peroxidase-negative). By identification of granules with peroxidase activity and those immunopositive for elastase antigen, the authors defined two subpopulations of azurophil granules, one that contained peroxidase activity and no measurable elastase antigen and another that contained elastase antigen associated with a small amount of peroxidase activity. They quantitated the peroxidase-positive as well as the elastase-positive granules in human peripheral blood neutrophils and found an average of 1536 +/- 69 peroxidase-positive granules per neutrophil. Of these, 399 +/- 20 were also elastase-positive. The average elastase concentration per neutrophil was 1.59 pg, and the average concentration per granule was 4 X 10(-3) pg. It is concluded that in normal individuals approximately one-third of the azurophil granules contain elastase antigen. Because neutrophil elastase has been implicated in the pathogenesis of emphysema, quantitation of its distribution within the cell presents an approach that may help define selective azurophil granule release and its relationship to the development of emphysema.

Cytoplasmic Granules↗
PubMed1987

Neutrophil recruitment and degranulation during induction of emphysema in the rat by nitrogen dioxide.

Rats exposed to 30 ppm NO2 continuously for 3 to 6 wk developed mild centriacinar air-space enlargement and mild interstitial fibrosis. The emphysematous changes did not become more severe after 6 wk with continued NO2 exposure for as long as 14 additional weeks. Elastase inhibitory capacity (EIC) and the total protein concentration increased acutely in lung lavage fluid, consistent with the histologic evidence of pulmonary edema, then subsided but remained above control levels for the entire exposure period. The ratio of EIC to total protein remained unchanged relative to that in control animals. Neutrophils accumulated in the lung and were recoverable by lavage with the same relative concentration profile as observed for total protein. The average elastase activity per neutrophil in cells recovered from the air space by lung lavage was 60% less than in cells recovered from peripheral blood. This was true for control or NO2-exposed rats. Thus, emphysematous changes in the NO2-exposed rat were accompanied by a marked neutrophil recruitment concomitant with an increased neutrophil elastase burden in the lung, which may have directly contributed to lesion development.

Animals↗
PubMed1987

Human neutrophil degranulation during extracorporeal circulation.

Cardiopulmonary bypass, especially when prolonged, may result in hemostatic failure and pulmonary dysfunction, which has been attributed to changes in platelets and leukocytes, respectively. It has been well documented that contact of blood with synthetic surfaces causes platelet activation. In this report, we explore mechanisms of the activation of neutrophils during simulated in vitro extracorporeal circulation and document the release of neutrophil lactoferrin and elastase during clinical cardiopulmonary bypass (CCB). Inhibition in the simulated circuit by prostaglandin E1 (PGE1) and lidocaine suggests different mechanisms for release of neutrophil-specific proteins. During CCB with a bubble oxygenator it was observed that platelet counts fell to 42% +/- 2% of baseline. In addition, beta-thromboglobulin antigen (beta TG), a platelet-specific, alpha-granule protein marker reflecting the release reaction, increased from 0.15 +/- 0.05 to 0.84 +/- 0.11 microgram/mL. Neutrophil counts decreased to 67% +/- 7% of prebypass levels but then gradually rose as bypass continued. Both lactoferrin, a neutrophil-specific granule marker, and neutrophil elastase, an azurophilic granule marker, increased in plasma threefold to 1.66 +/- 0.33 micrograms/mL and 1.65 +/- 0.68 microgram/mL, respectively, just before bypass was stopped. When fresh heparinized human blood was recirculated within an extracorporeal membrane oxygenator bypass circuit for 120 minutes, plasma beta-TG rose to 5.13 micrograms/mL, lactoferrin increased from 0.13 +/- 0.04 to 1.62 +/- 0.22 micrograms/mL, and neutrophil elastase rose from 0.05 +/- 0.02 to 1.86 +/- 0.41 micrograms/mL. At 120 minutes, lidocaine (100 mumol/L), which inhibits neutrophil activation, delayed release of lactoferrin (1.33 +/- 0.26 micrograms/mL) and markedly inhibited release of elastase (0.24 +/- 0.05 microgram/mL) but did not inhibit release of beta-TG antigen (5.66 micrograms/mL at 120 minutes). PGE1 (0.3 mumol/L) inhibited significantly the release of beta-TG (0.31 microgram/mL) and elastase (0.52 +/- 0.11 microgram/mL) and attenuated the release of lactoferrin (1.57 +/- 0.45 micrograms/mL).

Alprostadil↗