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Biomedical subjects

G L Larsen

Publications and source records attributed to G L Larsen.

At least 91 records · Page 5Linked to original sources
PubMed1989

New concepts in the pathogenesis of asthma.

Heightened airways reactivity is a major characteristic of asthma. Several stimuli capable of producing an inflammatory reaction within the respiratory tract can increase airways reactivity in both normal and asthmatic subjects. The association between lower airways inflammation and alterations in airways function has been studied most extensively after antigen exposure leading to an immediate and/or late asthmatic response in atopic subjects. The late asthmatic response (LAR) is of special interest because it lasts for hours, is prevented by corticosteroids and not adrenergic agents, and is associated with more severe asthma as well as increases in airways responsiveness. While late phase reactions in the lung and skin were initially thought to be Arthus reactions, more recent observations in man and animal models suggest they may be initiated when antigen-specific IgE is present, and may be blunted by antigen-specific IgG. In terms of pathology, immediate reactions are characterized primarily by edema while late phase reactions are associated with infiltration of the involved tissues with inflammatory cells. The potential importance of granulocytes to the reactions in the skin of rats and the lungs of rabbits was suggested when cytotoxic drugs that produced granulocytopenia prevented late phase responses. Several other factors also appear to be important in determining if an LAR will occur. These include the antigen load, level of airways reactivity, histamine releasing factors, lymphocyte populations within the lung, and endogenous corticosteroid levels. While various mediators of inflammation and hypersensitivity such as platelet activating factor and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism produce some of the clinical features seen in asthma, one mediator is unlikely to be responsible for all the manifestations of this disorder. Rather, a series of cell-to-cell interactions mediated through the products they release are likely to produce the pathologic and physiologic features of the disease.

Asthma↗
PubMed1989

Penetration of corticosteroids into the lung: evidence for a difference between methylprednisolone and prednisolone.

Little is known about the penetration of corticosteroids, such as methylprednisolone and prednisolone, into the lung, despite their common use in the treatment of inflammatory lung diseases. To compare methylprednisolone and prednisolone concentrations in the bronchoalveolar space, we administered these two corticosteroids in a randomized, crossover fashion to 17 adult rabbits. A loading dose was administered and was followed by a continuous infusion for 180 minutes to achieve steady-state plasma concentrations between 200 to 2000 ng/ml. Serial plasma samples were obtained during the infusions. Bronchoalveolar lavages (BAL) were performed at 180 minutes with sterile saline. Plasma and BAL fluid (BALF) were assayed for methylprednisolone and prednisolone concentration by high-performance liquid chromatography. Corticosteroid concentrations were normalized to urea concentrations in plasma and BALF. Generally, BALF corticosteroid concentration increased as plasma concentration increased. At plasma concentrations greater than 800 ng/ml, BALF methylprednisolone concentrations increased exponentially, whereas the increase for prednisolone remained linear. BALF methylprednisolone was five times as high as that of prednisolone when plasma corticosteroid concentration was in the 2000 ng/ml range. With this continuous infusion technique, methylprednisolone has a higher degree of bronchoalveolar penetration than prednisolone, and these differences are greater at higher plasma concentrations.

Adrenal Cortex Hormones↗
PubMed1989

Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups. An alteration in the ratio of bronchoconstrictive to bronchoprotective mediators.

Prostanoids have been implicated in the pathogenesis of asthma because of their potential role in the modulation of airway tone. In the present study, the bronchoconstrictors prostaglandin D2 (PGD2) and thromboxane (TX), and those prostanoids able to protect against bronchoconstriction, prostaglandin E2 (PGE2), and the stable metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), were measured in bronchoalveolar lavage fluid (BALF) before and 5 min after endobronchial allergen challenge in four subject groups: nonatopic nonasthmatics (n = 6), nonatopic asthmatics (n = 3), atopic nonasthmatics (n = 9), and atopic asthmatics (n = 8). There were no significant differences in prechallenge prostanoid levels between the four groups, with the potentially bronchoprotective mediators present in highest concentration. Allergen challenge in atopic asthmatics resulted in significant increases (p less than 0.05) in PGD2 (97.4 +/- 19.4 to 1,053.2 +/- 338.6 pg/ml, mean +/- SEM) and TX (45.5 +/- 7.5 to 150.7 +/- 37.8 pg/ml) over prechallenge levels and control groups. Similarly, histamine increased in the atopic asthmatics after challenge (0.36 +/- 0.22 to 6.84 +/- 1.86 ng/ml; p less than 0.05). Atopic nonasthmatics had slight increases in PGD2 (96.9 +/- 25.4 to 219.7 +/- 47.5 pg/ml; p greater than 0.1) after challenge, whereas PGD2 and TX did not change in nonatopic subjects. A significant positive correlation was found between histamine, PGD2, and TX levels after challenge among all groups (p less than 0.001). There were no significant changes among the four groups after allergen challenge in 6-keto-PGF1 alpha or PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

In vitro metabolism of the methylthio group of 2-methylthiobenzothiazole by rat liver.

1. When 2-methylthiobenzothiazole and 35S-labelled glutathione (GSH) were incubated with rat liver homogenates, both 35S-labelled S-(2-benzothiazolyl)-glutathione and 2-mercaptobenzothiazole were isolated from the reaction mixtures. Glutathione-S-transferase appears to be involved in the S-(2-benzothiazolyl)glutathione (GBZ) formation. 2. The evidence indicates that 2-methylthiobenzothiazole is oxidized to its corresponding methylsulphoxide and/or methylsulphone which becomes a substrate for GSH conjugation. 3. Degradation products identified from the methylthio group were formaldehyde and sulphate. 4. Although sulphur is exchanged in this pathway, the net result of this pathway which involves oxidation of the methylthio group and GSH conjugation is an apparent S-demethylation of the methylthio group. 5. Another S-demethylation pathway which does not involve GSH conjugation also functioned in vitro.

Animals↗
PubMed1988

A kidney perfusion method for metabolism studies with chickens using propachlor as a model.

1. A procedure for directly perfusing chicken kidneys in situ with xenobiotics is described. 2. When propachlor (2-chloro-N-isopropylacetanilide) or the glutathione, cysteine and mercapturic acid conjugates of propachlor were individually perfused through chicken kidneys, propachlor mercapturate was isolated from the urine and identified as an end product, indicating that all enzymes necessary for mercapturic acid formation were present in chicken kidney.

Acetanilides↗
PubMed1988

Metabolism of 2,6-dichlorobenzamide in rats and mice.

1. Oral doses of 2,6-dichlorobenzamide (DCB) were excreted by rats as DCB, two monohydroxy-DCBs, 2-chloro-5-hydroxy-6-(methylthio)benzamide and 2-chloro-5-hydroxy-6-[S-(N-acetyl)cysteinyl]benzamide (mercapturic acid). 2. Biliary excretion (33% of the dose), enterohepatic circulation and intestinal micro-floral metabolism were involved in formation of 2-chloro-5-hydroxy-6-(methylthio)benzamide, and the mercapturic acid served as a precursor. 3. Whole body autoradiography and microautoradiography showed the accumulation of non-extractable residues from DCB in the nasal mucosa and contents of the large intestines of rats and mice dosed with 14C-labelled DCB.

Animals↗
PubMed1988

Metabolism of 2,6-dichlorobenzonitrile, 2,6-dichlorothiobenzamide in rodents and goats.

1. Twelve 14C-labelled metabolites were isolated from either urine or bile from either rats (11 metabolites) or goats (7 metabolites) given single oral doses of 2,6-dichlorobenzo[14C]nitrile (DCBN). Five of these metabolites were also excreted in urine from rats dosed orally with 2,6-dichlorothiobenz[14C]-amide (DCTBA). 2. All metabolites from either DCBN or DCTBA were benzonitriles with the following ring substituents: Cl2, OH (three isomers); Cl2, (OH)2; Cl, (OH)2; Cl, OH, SH; Cl, OH, SCH3; SCH3, SOCH3, OH; Cl2, S-(N-acetyl)cysteine; Cl, S-(N-acetyl)cysteine; Cl, OH, S-(N-acetyl)cysteine. 3. The thiobenzamide moiety of DCTBA was converted to the nitrile in all the excreted urinary metabolites. No hydrolysis of the nitrile in DCBN to either an amide or an acid was detected. 4. Urine was the major route for excretion; however, enterohepatic circulation occurred. 5. Whole-body autoradiography of 14C-DCBN and 14C-DCTBA in mice showed the presence of bound residues in the mucosa of the nasal cavity, trachea, tongue, oesophagus, the kidney, liver and the intestinal contents.

Amides↗
PubMed1987

Comparison of the evolving histopathology of early and late cutaneous and asthmatic responses in rabbits after a single antigen challenge.

Histopathologic changes during the immediate cutaneous response (ICR) and late cutaneous response (LCR) to antigen challenge in allergic humans include dermal edema in the ICR (15 to 30 minutes) followed by increasing cellular infiltration in the LCR (6 hours and more). No description of the evolving histopathologic changes that occur during an immediate asthmatic response (IAR) followed by a late asthmatic response (LAR) exists in either clinical studies or animal models. We examined cutaneous and pulmonary histopathology at 1/2, 6, 24, and 48 hours as well as 7 days after simultaneous intradermal and aerosol antigen challenge of rabbits immunize with Alternaria tenuis extract. Nonimmunized rabbits challenged with Alternaria tenuis extract and immunized rabbits challenged with normal saline served as controls. Immediate wheal and flare responses followed by a LCR were seen in immunized but not control animals. Pulmonary function tests documented immediate and LAR in immunized but not control animals. Thirty minutes after antigen challenge of sensitized animals (ICR and IAR), both dermal sites and large airway submucosal sites had interstitial edema and vessel dilatation while small airways were essentially normal. At 6 hours after challenge, the dermal and large airway submucosal sites of immune animals (LCR and LAR) demonstrated a moderate mixed leukocyte infiltrate as well as residual edema. Additionally, bronchioles and pulmonary vessel adventitia from these responding animals had an intense and widespread leukocyte infiltration. At 24 and 48 hours, immune challenged animals but not controls had a marked mixed cellular infiltrate near skin vessels and near the bronchioles and pulmonary vessels with little or no residual interstitial edema. At 7 days, three of four animals showed resolution of the inflammation while the fourth showed minimal residual changes. Morphometric analysis of airway inflammation substantiated these qualitative observations and demonstrated that the granulocytes around airways of immune rabbits were a mixture of neutrophils and eosinophils at 6 hours, but were predominantly eosinophils at 48 hours. Immunofluorescent studies of skin and lung tissue did not demonstrate any granular or linear deposition of immunoglobulin or complement at the sites of inflammation, however, fibrin deposition was noted in the skin and lungs of immune rabbits. These observations show that immunized rabbits challenged with antigen develop cutaneous and pulmonary inflammation.(ABSTRACT TRUNCATED AT 400 WORDS)

Alternaria↗
PubMed1987

The inflammatory reaction in the airways in an animal model of the late asthmatic response.

The late asthmatic response is defined as airway obstruction that occurs hours after antigen exposure in some atopic asthmatics. The importance of this reaction is that the airway obstruction may be severe, prolonged, and difficult to control unless corticosteroids are employed. In addition, this response may lead to an increase in airway reactivity. To investigate the immunopathogenesis of this disorder, an animal model in rabbits was developed. In this model, antigen-specific IgE was associated with the late asthmatic response and antigen-specific IgG was associated with blunting of the reaction. Antigen challenge of immune rabbits led to edema within the large airways shortly after antigen exposure, with infiltration of inflammatory cells (neutrophils and eosinophils) into the large and small airways during the late response. The infiltrates became more mononuclear with time and resolved over 10 days. As in humans, the late response was associated with an increase in airway reactivity and correlated temporally with infiltration of the airways with neutrophils and eosinophils. The contribution of granulocytic cells to the airway responses to antigen was studied by granulocyte depletion, which prevented both the late response and the heightened airway reactivity. In addition, transfusion of a neutrophil-rich population of white cells into granulocytopenic immune rabbits restored both responses. Thus, in this animal model, the antigen-induced late asthmatic response and subsequent increase in airway reactivity were dependent on the presence of granulocytes at the time of exposure to antigen.

Airway Obstruction↗
PubMed1986

The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model.

The antigen-induced late asthmatic response (LAR) and subsequent heightened airways reactivity after this response have been associated with increased airways inflammation. Employing an animal model of the LAR in rabbits previously developed in our laboratory, 3 phases of experiments were performed to investigate the role of polymorphonuclear leukocytes (PML) in the LAR and heightened reactivity. In all 3 phases, airways reactivity to histamine and bronchoalveolar lavage analysis were performed 3 days before and 3 days after bronchial challenge with ragweed extract. In Phase 1, 2 groups of rabbits receiving nitrogen mustard were studied: an immune group received immune serum containing antiragweed IgE, and a control group received nonimmune serum. In Phase II, nitrogen mustard was administered to immune rabbits during aortic occlusion to allow the lungs to be exposed to nitrogen mustard while limiting exposure of the bone marrow to this drug, preventing depletion of PML. In Phase III, both an immune and a nonimmune group of rabbits received nitrogen mustard as in Phase I; however, prior to antigen challenge, they were repleted with a neutrophil-rich population of PML. In all experiments, no group of control (nonimmune) rabbits, whether depleted or repleted of PML, developed an immediate asthmatic response (IAR) or a LAR. In addition, no significant increases in lavage cells or airways reactivity occurred after ragweed challenge. In contrast, those animals receiving immune serum and nitrogen mustard developed an IAR; however, no LAR occurred, and no significant change in airways reactivity was observed. Rabbits receiving immune serum and nitrogen mustard with aortic occlusion developed an IAR and LAR, and airways reactivity increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Cysteine conjugate beta-lyase in the gastrointestinal bacterium Eubacterium limosum.

A cysteine conjugate beta-lyase (beta-lyase) from the gastrointestinal bacterium Eubacterium limosum has been isolated and characterized. This organism has the highest specific activity for cysteine conjugate beta-lyase of the gastrointestinal bacteria studied. The beta-lyase was found to cleave the thioether linkage of S-alkyl- and S-aryl-L-cysteine conjugates. Stoichiometric amounts of 2-mercaptobenzothiazole, pyruvic acid, and ammonia were produced from the beta-lyase cleavage of S-(2-benzothiazolyl)-L-cysteine. The enzyme activity was inhibited by hydroxylamine, iodoacetic acid, or KCN. The enzyme appears to be a 75,000-Da dimer of two 38,000-Da subunits. A natural substrate, cystathionine, was cleaved by this enzyme, indicating that this beta-lyase has beta-cystathionase activity. These data suggest that a beta-cystathionase from E. limosum may be an important enzyme in the metabolism of a wide range of cysteine conjugates of xenobiotics to thiol-containing products.

Animals↗
PubMed1986

Inflammation and the late phase reaction in asthma: the effect of polymorphonuclear leukocyte depletion on airways obstruction and bronchial hyperreactivity in an animal model.

Increases in airway reactivity noted after antigen exposure in which a late asthmatic response (LAR) develops may be related to pulmonary inflammation. Employing an animal model of the LAR developed in our laboratory, we conducted experiments to determine if depletion of polymorphonuclear leukocytes (PMLs) would ablate the LAR and inhibit subsequent increases in airways reactivity. Four groups of ten animals each were studied. The first group was given immune sera (I) containing anti-ragweed IgE. The second group received non-immune sera (NI). A third group of animals received immune sera plus nitrogen mustard (I + NM), while a fourth group received non-immune sera plus nitrogen mustard (NI + NM). Airways reactivity to histamine and the evaluation of different cell types in bronchoalveolar lavage fluid (BALF) were determined three days before and three days after bronchial challenge with ragweed extract (RWE). No control rabbit (NI or NI + NM) developed either an immediate asthmatic response (IAR) or an LAR, and no significant increases occurred in their airways reactivity or cells in lavage fluid after bronchial challenge with RWE. In contrast, the sensitised rabbits not given nitrogen mustard developed an LAR and airways reactivity increased markedly three days later. Those animals receiving immune sera and nitrogen mustard developed an IAR; however, no LAR occurred and no significant change in airways reactivity ws observed. BALF analysis seventy-two hours after ragweed challenge in the animals that received immune sera showed a significant increase in PMLs. However, there was no significant increase on BALF PMLs in the animals receiving immune sera and nitrogen mustard.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Obstruction↗
PubMed1985

Increases in airway reactivity to histamine and inflammatory cells in bronchoalveolar lavage after the late asthmatic response in an animal model.

An increase in airway reactivity after the late asthmatic response (LAR) has been noted in humans. Although these alterations in reactivity have been proposed to be associated with inflammation, no clinical study of the LAR has shown both increased airway reactivity and evidence of pulmonary inflammation. Employing an animal model of the LAR in rabbits developed in our laboratory (Am Rev Respir Dis 1982; 126:493-498), we examined changes in airway reactivity and pulmonary inflammation in rabbits having a late asthmatic response. Two groups of rabbits were studied: a control group (n = 10) received nonimmune serum, and a sensitized group (n = 10) received serum containing homocytotropic antibody (IgE) to ragweed extract (RWE) from rabbits previously immunized from birth with ragweed. Airway reactivity to histamine and the evaluation of different cell types in bronchoalveolar lavage fluid were determined 3 days before and 3 days after bronchial challenge with RWE in all rabbits. No control rabbit developed a LAR, and no significant changes occurred in this group's airway reactivity or cells in lavage fluid after bronchial challenge with RWE. In contrast, all sensitized rabbits developed a LAR, and airway reactivity for this group was markedly increased 3 days later. In addition, the total number of cells including both polymorphonuclear and mononuclear cells in lavage fluid increased significantly 3 days after the LAR. Ten days after the LAR in the sensitized group (n = 8), as airway reactivity returned towards baseline, so did the cells in lavage. We conclude that increased airway reactivity to histamine is temporally associated with pulmonary inflammation as defined by cells in lavage after the LAR in this model.

Animals↗
PubMed1985

Additive effect of intravascular complement activation and brief episodes of hypoxia in producing increased permeability in the rabbit lung.

Systemic complement activation with intravascularly administered cobra venom factor (CVF) or infusion of either zymosan-activated rabbit plasma or a fifth component of complement fragment with anaphylatoxin activity in the rabbit have not caused significant increases in bronchoalveolar lavage albumin in rabbits (Webster, R. O., G. L. Larsen, B. C. Mitchell, A. J. Goins, and P. M. Henson. 1982. Am. Rev. Respir. Dis. 125:335-340). To assess if another stimulus (hypoxia) acting in concert with complement activation can produce significant lung injury, rabbits were challenged with CVF alone, 10 min of 12% oxygen alone, or CVF followed by a 10-min exposure to 12% oxygen. Either stimulus alone caused no significant changes in arterial oxygen, pulmonary resistance, or dynamic compliance during the 240 min of observation after either stimulus, and neither stimulus alone caused increased albumin accumulation in bronchoalveolar lavage over a 30-min period at the end of the experiment. However, the combination of insults significantly altered arterial oxygen, pulmonary resistance, and dynamic compliance while also increasing albumin and neutrophils recovered by lavage. The increase in lavage albumin did not appear to be due to hemodynamic events in that the pulmonary artery pressure increased acutely after CVF infusion and again during the hypoxic exposure, but was normal when albumin accumulation in the lung was measured. Neutrophil depletion with nitrogen mustard abolished all of these changes induced by CVF plus hypoxia. In addition, meclofenamate pretreatment and infusion during the 4-h study abolished the increases in lavage albumin and neutrophils as well as the increase in pulmonary artery pressure after CVF. Meclofenamate pretreatment did not, however, block accumulation of albumin in the lung (interstitium). We conclude that complement activation, as an isolated event, will not cause a significant increase in lavage albumin in this model. However, combining complement activation with an episode of hypoxia will lead to an increase in lavage albumin that is dependent on the presence of neutrophils for its expression. Meclofenamate treatment will prevent increases in lavage albumin and neutrophils while not preventing albumin accumulation in the lung (interstitium), suggesting a product of the cyclooxygenase pathway of arachidonic acid metabolism is needed to produce movement of albumin and/or neutrophils across the alveolar epithelium in this model.

Albumins↗