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G L Larsen

Publications and source records attributed to G L Larsen.

At least 109 records · Page 6Linked to original sources
PubMed1985

Distribution of cysteine conjugate beta-lyase in gastrointestinal bacteria and in the environment.

A cysteine conjugate beta-lyase was detected in 24 of 43 gastrointestinal bacteria tested, and from mixed populations of bacteria obtained from lake, river and soil samples. These bacterial cysteine conjugate beta-lyases catalyse the cleavage of the thioether linkage of both an S-alkyl- and an S-aryl-linked cysteine conjugate (2-S-cysteinyl-N-isopropylacetanilide (cysteine conjugate of propachlor) and S-(2-benzothiazolylcysteine), respectively). A cysteine conjugate beta-lyase was isolated from Eubacterium limosum at levels at least 16-fold greater than those from any other gastrointestinal bacterial tested. This enzymic activity was present from the late lag phase through the stationary phase of growth of the bacteria. Maximum activity occurred in the mid log phase. A cysteine conjugate beta-lyase isolated from animal and plant tissues cleaved only the S-aryl-linked cysteine conjugate (S-(2-benzothiazolyl)cysteine) and generally had less enzymic activity than enzymes isolated from the bacteria. Glutathione-S-transferase activity was not detected in the 43 gastrointestinal bacteria tested, except for a low level (0.6 nmol/min per mg) of activity in Escherichia coli. No S-methyl transferase activity was detected in the gastrointestinal bacteria or mixed populations of bacteria tested.

Animals↗
PubMed1985

The late asthmatic response.

Since LARs are associated with increases in airways reactivity, their significance may go well beyond the increase in symptoms due just to the allergen exposure. This is especially true since the increase in non-specific airways reactivity can last for weeks after a single exposure to allergen. Every effort should be made to search for possible allergic triggers in patients suspected to have LARs. Careful attention to historical information and skin test reactivity are critical in this evaluation. In situations where this approach is not revealing and where serious concerns remain about potential environmental triggers, a bronchial challenge to the suspected antigen can be considered. Since the nonspecific airways reactivity in patients with LAR may possibly be due to inflammation in the airways, the potential risk of transient induction of airways inflammation must be carefully weighed against the value of information that can be obtained from this procedure. Bronchial challenge should be performed only in an inpatient setting by experienced personnel under the supervision of a physician. A full explanation of the potential risks and benefits of this type of evaluation must be given to the patient and family. Treatment is primarily directed at allergen avoidance with use of a prophylactic drug, such as cromolyn sodium, when allergen avoidance is not possible.

Allergens↗
PubMed1984

Modulation of the late asthmatic response by antigen-specific immunoglobulin G in an animal model.

The late asthmatic response (LAR) occurs 4 to 12 h after antigenic challenge and has been related to the severity of asthma. In addition, improvement of asthmatic symptoms after immunotherapy has also been related to loss of the LAR. Because the LAR seems to be a critical component of asthma, we employed an animal model of the LAR to study its immunopathogenesis, concentrating on the role of antigen-specific rabbit homocytotropic (IgE) and heterocytotropic (IgG) antibodies to Alternaria tenuis. Serum samples from rabbits previously immunized with Alternaria extract were infused into age-matched previously nonimmunized recipients. Groups of recipients were categorized according to the immune status of the transfused serum: E-only, E/G, subdivided into E/low G (1:256 to 1:512) and E/high G 1:2,048), G (serum heat-treated to minimize IgE), and Control (transfused with serum from nonimmunized rabbits). Subsequently, pulmonary function was measured before and for 6 h after challenge with aerosolized Alternaria tenuis by recording pulmonary resistance, functional residual capacity by helium dilution, specific conductance, and dynamic compliance. The E-only recipients showed an immediate asthmatic response followed by a marked LAR comparable in magnitude to actively immunized animals. The E/G recipients showed blunting of the LAR in a dose-dependent fashion, with increasing titers of IgG antibody. The G recipients showed no immediate or late responses. Immunofluorescent studies in selected animals from each group failed to show any granular deposition of immunoglobulin or C3 in either the airways or blood vessels of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Pulmonary response of fifth component of complement-sufficient and -deficient mice to hyperoxia.

The fifth component of complement, C5, can form fragments that cause neutrophil chemotaxis, oxygen radical production, and lysosomal enzyme release. The purpose of this study was to determine if C5 and these fragments contribute to the inflammation seen in pulmonary oxygen toxicity as defined by histology and analysis of bronchoalveolar lavage fluid (BALF). In addition, the role of C5 in producing mortality in the animals was addressed. Pairs of C5 deficient (C5-) and C5 sufficient (C5+) mice, 6 mo or older, were placed in a chamber and challenged with 95% oxygen at ambient pressure. A significant difference in mortality was observed after 200 h of exposure, i.e., 90% mortality in C5+ mice vs. 25% mortality in C5- mice (P less than 0.001). This difference in mortality was not seen when C5- mice were transfused with plasma that contained C5 derived from C5+ mice. Morphometric analysis of histologic sections with light microscopy revealed earlier pathologic changes in C5+ mice that was characterized by increased cellularity due in part to neutrophil influx into the alveolar-capillary wall. Transmission electron microscopy also confirmed an earlier inflammatory response in the C5+ mice with evidence of injury to alveolar epithelial cells, interstitial edema, and an increase in the cellular component of the interstitium. Analysis of BALF also demonstrated earlier abnormalities in C5+ mice, which included a significantly greater percentage of neutrophils in the C5+ mice at 117 h. Similar studies in younger mice of these strains again showed earlier neutrophil accumulation in C5+ mice, but the time course of the injury was more protracted. This study shows that the presence of C5 is associated with a greater mortality and an earlier influx of neutrophils into murine lungs. However, in the absence of C5, neutrophils will still immigrate into the lung and hyperoxic damage will occur at a later time point, which demonstrates the inherent redundancy of the inflammatory process.

Animals↗
PubMed1984

Resolution of pulmonary inflammation.

Mononuclear phagocytes are suggested to play a major orchestrating role in the resolution of inflammatory processes in the lung. Particular emphasis is placed on their participation in the progression from a lesion with neutrophils as the dominant infiltrating cell to one that contains macrophages, on the macrophage's role in removing neutrophils and cell debris, and on their promotion of repair mechanisms. It is suggested that monocytes must mature into macrophages before they are capable of active participation in the resolution of inflammation.

Animals↗
PubMed1983

Respiratory response to intraesophageal acid infusion in asthmatic children during sleep.

Nocturnal asthma has been associated with nighttime gastroesophageal reflux (GER). To establish whether the presence of acid in the lower esophagus causes bronchoconstriction, nine children with nocturnal asthma and GER underwent intraesophageal acid-infusion challenges during sleep. The patients were divided into two groups on the basis of presence or absence of a positive Bernstein test for esophagitis. The test was considered positive if acid infusion produced symptoms of heartburn. On two occasions, at approximately midnight and 4 to 5 A.M., 30 ml of normal saline was infused over 15 min into the distal esophagus followed by a similar infusion of 0.1N HCl. Respiration was continuously monitored by inductance plethysmography along with clinical evaluation. The saline and midnight acid infusions had no effect in either patient group; however, with the 4 to 5 A.M. acid infusion, all the patients with a positive Bernstein test developed significant changes in their respiratory pattern indicative of bronchoconstriction as well as overt clinical wheezing. In the patients with a negative Bernstein test, the 4 to 5 A.M. acid infusion had no effect. It is concluded that during sleep the presence of acid in the lower esophagus can trigger bronchoconstriction in asthmatic children with a positive Bernstein test and that these children appear to be more susceptible to the bronchoconstrictive effects of intraesophageal acid at 4 to 5 A.M. than at midnight.

Adolescent↗
PubMed1983

Cysteine conjugate beta-lyase in the gastrointestinal bacterium Fusobacterium necrophorum.

A cysteine conjugate beta-lyase from the anaerobic gastrointestinal bacterium Fusobacterium necrophorum was purified 51-fold by heat treatment, ammonium sulphate fractionation, gel-filtration chromatography, and anion-exchange chromatography. This enzyme catalyses the cleavage of the thioether linkage in cysteine conjugates of the following S-alkyl- or S-aryl-linked compounds: cysteine conjugate of propachlor (2-S-cysteinyl-N-isopropylacetanilide); 1,2-dihydro-1-hydroxy-2-S-cysteinylnaphthalene and S-(2-benzothiazolyl)cysteine. 2-Mercapto-N-isopropylacetanilide, pyruvic acid and ammonia were produced from the beta-lyase cleavage of the cysteine conjugate of propachlor in equimolar ratios. The apparent Km values for the cysteine conjugate of propachlor and S-(benzothiazolyl)cysteine were 1.1 and 1.0 mM, respectively. Pyridoxal phosphate was required for enzymic activity. Ammonium ion activated enzymic activity, while hydroxylamine completely inhibited the enzyme. Dithiothreitol and bovine serum albumin had no effect on enzymic activity.

Carbon-Sulfur Lyases↗
PubMed1983

Metabolism of mercapturic acid-pathway metabolites of 2-chloro-N-isopropylacetanilide (propachlor) by gastrointestinal bacteria.

1. Mercapturic acid pathway metabolites of propachlor, labelled with 14C, were incubated with pig caecal contents, small and large intestinal contents, and pure cultures of gastrointestinal bacteria. 2. The glutathione, cysteine, N-acetylcysteine, and the S-oxide of the N-acetylcysteine conjugates of propachlor (2-chloro-N-isopropylacetanilide) were each metabolized by mixed pig caecal micro-organisms to 2-mercapto-N-isopropylacetanilide. 3. The extent of formation of 2-mercapto-N-isopropylacetanilide by mixed pig caecal micro-organisms from mercapturic acid-pathway metabolites of 14C-propachlor was as follows: glutathione (43.4%), cysteine (32.6%), N-acetylcysteine (5.2%), and the S-oxide of the N-acetylcysteine conjugate of propachlor (6.1%). The S-oxide of the N-acetylcysteine conjugate of propachlor was converted by the mixed pig caecal micro-organisms to N-acetylcysteine and cysteine conjugates of propachlor. 4. Small intestinal contents metabolized the glutathione conjugate of propachlor to the cysteine conjugate; little C-S lyase activity was present in the small intestinal contents. 5. The cysteine conjugate of propachlor was metabolized to 2-mercapto-N-isopropylacetanilide by Fusobacterium necrophorum, Bacteroides vulgatus, Megasphaera elsdenii and Eubacterium aerofaciens.

Acetanilides↗
PubMed1983

Studies on the re-establishment of the intestinal microflora in germ-free rats with special reference to the metabolism of N-isopropyl-alpha-chloroacetanilide (propachlor).

Conventional rats metabolize 2-chloro-N-isopropylacetanilide (propachlor) mainly to various 2-methylsulphonylacetanilides and to residues in the faeces that are unextractable. Mercapturic acid pathway (MAP) metabolites of propachlor are the source of the methylsulphonyl sulphur and the insoluble faecal residues. Germ-free and antibiotic-treated rats quantitatively metabolized propachlor only to MAP metabolites, which were excreted in the urine and faeces (all water-soluble). Germ-free rats given enemas of caecal contents from conventional rats were qualitatively similar to conventional rats with respect to the metabolism of propachlor within 56 days of the inoculations i.e. they excreted 2-methylsulphonyl acetanilides in the urine and insoluble residues in the faeces. They approached quantitative similarity within 180 days. Antibiotic-treated rats spontaneously recovered the ability to metabolize propachlor as conventional rats, qualitatively within 6 days and quantitatively within 21 days. While differences occurred in the faecal metabolites of propachlor, biliary secretion of metabolites by germ-free rats was not different from that of conventional or antibiotic-treated rats.

Acetanilides↗
PubMed1982

Metabolism of 2,4',5-trichlorobiphenyl by the mercapturic acid pathway.

Carbon-14-labeled 2,4',5-trichlorobiphenyl was found to be metabolized by the mercapturic acid pathway to metabolites that are excreted in bile. About 57 percent of the carbon-14 was excreted in the bile; 30 to 35 percent was present as mercapturic acid pathway metabolites. Mercapturic acid was also isolated from the urine (0.3 percent of the dose).

Acetylcysteine↗
PubMed1982

Pulmonary microvascular alterations and injury induced by complement fragments: synergistic effect of complement activation, neutrophil sequestration, and prostaglandins.

Fragments of C5 that are generated at, or administered to, extravascular sites in the pulmonary parenchyma induced neutrophil infiltration, edema, tissue damage, and a complete inflammatory response. Generation of C5 fragments within the vascular system induced leukocyte sequestration in the pulmonary vasculature, but without detectable increased vascular permeability or neutrophil migration. By contrast, the combination of short episode of hypoxemia with the intravascular C5 activation led significant increases in pulmonary vascular permeability, mild endothelial alterations, and emigration of neutrophils. Infusion of 10 micrograms PGE2 into animals in which intravascular complement had been activated produced changes in the lungs that were similar to, though less severe than, the combination of hypoxia and complement activation.

Animals↗
PubMed1982

Absence of inflammatory lung injury in rabbits challenged intravascularly with complement-derived chemotactic factors.

Systemic activation of the complement system results in the generation of chemotactic factors that have been suggested to play a role in the pathogenesis of inflammatory pulmonary diseases such as the adult respiratory distress syndrome. This led us to ask whether systemic complement activation by cobra venom factor (CVF) or intravascularly administered zymosan-activated rabbit plasma (ZAP) or rabbit C5a would result in lung injury. As had been described previously for CVF and ZAP, intravenously administered rabbit C5a also caused an acute neutropenia along with sequestration of neutrophils within the pulmonary vasculature. However, no significant lung inflammation as measured by neutrophil emigration or increased vascular permeability occurred with any of the three stimuli. Only when these agents were combined with anesthesia, surgical manipulation, and intubation did significant neutrophil emigration into alveoli occur, but again without any change in vascular permeability. After administration of ZAP, a decrease in dynamic compliance and an increase in pulmonary resistance as well as a transient period of hypoxemia occurred that was not observed after CVF or rabbit C5a treatment. Thus, our studies suggest that changes in lung function after ZAP instillation may not represent changes from complement activation alone in that they are not reproduced with CVF or rabbit C5a. We conclude that complement activation, as an isolated event, may be an insufficient insult in the lung to produce significant lung injury.

Airway Resistance↗
PubMed1982

The pulmonary response of C5 sufficient and deficient mice to Pseudomonas aeruginosa.

Neutrophils have been shown to be important in the clearance of Pseudomonas aeruginosa from murine lungs. The mechanisms responsible for the neutrophil influx into the lungs, however, remain poorly defined. This study was undertaken to define the contribution to this inflammatory process by the C5 molecule or its fragments. Congenic C5 sufficient (B10.D2/nSn) and CS deficient (B10.D2/oSn) mice were challenged by intrapulmonary administration of Pseudomonas aeruginosa. Differences in survival of the 2 strains of mice were noted over a 6-day period. In addition, host response was assessed at 6-, 24-, and 48-h time points by histologic examination, analysis of cells from pulmonary lavage, analysis of cells in the peripheral blood and culture of the lungs and blood of challenged mice. Mortality was consistently higher in C5 deficient mice. Neutrophil accumulation within the lung was greater at the 6-h time point in the C5 sufficient mice, and greater at the 48-h time point in the C5 deficient mice as demonstrated by both lavage and histologic examination. Differences in neutrophil accumulation could not be explained by differing blood neutrophils concentrations in the mice before challenge, or a lack of mobilization of neutrophils into the peripheral circulation after challenge in the C5 deficient mice. An early lack of clearance of the bacteria from the lungs of the C5 deficient strain was documented. We conclude that the C5 molecule and its phlogistic fragments are important neutrophil chemotaxins in murine lungs exposed to Pseudomonas aeruginosa, and, quantitatively, may be the most important early stimulus for neutrophil accumulation in this model.

Animals↗
PubMed1982

An animal model of late pulmonary responses to Alternaria challenge.

The pathogenesis of the late asthmatic response to allergen inhalation is unknown; IgE as well as IgE- and IgG-dependent mechanisms have been proposed. This study was undertaken to determine whether rabbits immunized to produce only IgE to Alternaria tenius would develop immediate and late phase pulmonary responses to Alternaria aerosol challenge, and to compare this response in "IgE only" rabbits with the response in rabbits producing multiple antibody isotypes to the allergen. Neonatal rabbits immunized with Alternaria tenius extract produced only IgE to that allergen, whereas rabbits first immunized at 7 days of age made multiple antibody isotypes. After aerosol challenge, the rabbits with only IgE antibody to the Alternaria developed biphasic change in lung function, as assessed by changes in pulmonary resistance and dynamic compliance, whereas rabbits with anti-Alternaria IgG as well as IgE had blunted biphasic pulmonary responses. Intravenously administered isoproterenol did not reverse the late phase response. Transfusion with serum containing anti-Alternaria IgG into "IgE only" rabbits reduced both the early and late phase changes in pulmonary mechanics. Transfusion of plasma containing anti-Alternaria IgE into nonimmunized control rabbits produced, upon challenge, both early and late phase responses in pulmonary mechanics, which were lost in retesting 4 wk later. We conclude that in this system IgE-allergen interaction can result in both the immediate and late pulmonary responses, that the presence of IgG results in blunting rather than in enhancing of this responsiveness, and that the response can be seen in the absence of cellular immune mechanisms.

Aerosols↗
PubMed1982

In vivo clearance and tissue distribution of C5a and C5a des arginine complement fragments in rabbits.

We have previously shown a marked difference in the inflammatory response to human C5a or C5a des arginine (Arg) instilled in rabbit lungs. These studies raised the question of where C5a and C5a des Arg are processes in vivo and what role neutrophils may play in the tissue distribution of these two mediators. After intravenous injection of purified, biologically active 125I-C5a or 125I-C5a des Arg, adult rabbits were serially bled and then killed at various time intervals. Although greater than 50% of the injected radioactivity was cleared from the circulation within 2 min for both mediators, C5a des Arg persisted in the circulation longer than C5a. C5a instillation caused an acute neutropenia, whereas C5a des Arg caused a less severe and more prolonged neutropenia, preceding a neutrophilic response observed with both mediators. Clearance of the mediators was primarily seen in the highly vascularized organs: the lung, spleen, liver, and kidney. A time-dependent accumulation was seen initially in the lung, followed by the spleen, liver, and kidney. Histologic examination showed a marked increase in the number of neutrophils within the lung and spleen. Depletion of circulating neutrophils by nitrogen mustard pretreatment of rabbits showed no change in the amount of labeled mediator bound in the lung, whereas splenic accumulation was dependent on the presence of neutrophils. These results indicate that C5a and C5a des Arg are rapidly removed from the circulation by specific accumulation in vascularized tissues. Clearance by the lung was not affected by neutrophil depletion, whereas clearance by the spleen was dependent on neutrophils. These experiments further suggest there are neutrophil-dependent and neutrophil-independent mechanisms involved in the removal of C5a and C5a des Arg from the circulation and that binding of C5 fragments in the pulmonary vasculature may precede and then induce neutrophil sequestration.

Animals↗