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R F Lemanske

Publications and source records attributed to R F Lemanske.

At least 91 records · Page 5Linked to original sources
PubMed1987

The biologic activity of mast cell granules. VIII. In vivo and in vitro characterization of mast cell granule-derived inflammatory factors involved in rat late-phase reactions.

Intradermal injections of isolated mast cell granules (MCGs), as well as solubilized high-molecular-weight (HMW) (greater than 10,000 daltons) and low-molecular-weight (LMW) (10,000 greater than MW greater than 500 daltons) fractionated granule constituents, can produce inflammatory responses termed late-phase reactions (LPRs). The identity and mechanism of action of various inflammatory factor(s) contained within these fractions is incompletely established. Since rat LPRs are neutrophil-dependent responses, we analyzed the inherent neutrophil chemoattractant potential of HMW and LMW granule fractions using a 48-well microchemotaxis chamber. Although both HMW and LMW fractions attracted rat neutrophils, the LMW fraction was less active at equivalent protein concentrations. Checkerboard analysis demonstrated that the HMW fraction enhanced random migration of neutrophils, indicating that the HMW fraction contains factors that are primarily chemokinetic. To analyze further the HMW fraction, solubilized MCGs were sequentially fractionated with XM300 (MW greater than 300,000 daltons), and YM100 (300,000 greater than MW greater than 100,000 daltons), XM50 (100,000 greater than MW greater than 50,000 daltons), and YM10 (50,000 greater than MW greater than 10,000 daltons) ultrafiltration membranes. This process revealed that most in vivo inflammation-provoking activity as well as the in vitro chemoattractant activity resided in the XM300 and YM100 retentate fractions. Two of the major constituents of the HMW fraction, heparin and chymase, were evaluated for their contribution to the chemoattraction. Purified MCG heparin did not evoke neutrophil migratory responses in vitro or in vivo. Sepharose 4B chromatography of solubilized MCG demonstrated a peak of inflammation-provoking activity beginning at the void volume and tapering off near the 400,000 MW range. This in vivo activity was clearly separable from the chymase activity and represents the HMW inflammatory factors. These results demonstrate that both HMW and LMW granule fractions contain inflammatory activities capable of producing LPR in vivo and suggest that enhancement of neutrophil migration at sites of mast cell degranulation is one mechanism of action.

Animals↗
PubMed1987

Food allergens: structure and immunologic properties.

Few of the food allergens have been purified and characterized. Complex mixtures of allergens seem to exist in some commonly allergenic foods. Much further research will be necessary to develop any detailed understanding of the chemistry of food allergens.

Administration, Oral↗
PubMed1986

In vivo and in vitro assessment of the role of leukotriene B4 as a mediator of rat cutaneous late-phase reactions.

Mast cell-dependent late-phase reactions (LPR) occur in rat skin and are characterized histologically by an early (1 to 8 hours) neutrophil-rich infiltrate, which is essential to a later (24 hours) infiltration by mononuclear cells. Although the ability of preformed mast cell-granule constituents alone to elicit LPR is clearly established, the relative pathogenetic contributions of newly generated lipid mediators to rat LPR are unknown. Leukotriene B4 (LTB4) may be generated by stimulated mast cells in a number of species and might potentially contribute to the neutrophil ingress. In order to examine this possibility in a well-characterized animal model of LPR, the capacity of LTB4 to influence rat cutaneous inflammation was studied. LTB4 (0.1 to 100 ng) alone did not induce vasopermeability in rat skin nor potentiate the blueing response to histamine. Intracutaneous LTB4 (0.1 to 100 ng) did not cause significant infiltration of neutrophils 3 to 4, 6 to 8, or 24 hours after injection; increased numbers of mononuclear leukocytes were not appreciated through 24 hours. In the same animals intracutaneous anti-IgE and intact mast cell granules both produced intense biphasic infiltration characteristic of rat LPR. In order to examine if rat polymorphonuclear leukocytes were capable of responding to LTB4, several in vitro studies were performed. Rat peritoneal and peripheral blood neutrophils migrated toward formyl-methionyl-leucyl-phenyl-alanine in vitro but not to purified human or synthetic LTB4. Rat peripheral blood and elicited peritoneal neutrophils bound only 32% and 27%, respectively, of the quantity of [3H]LTB4 bound by human neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

IgE antibody mediated inflammation of rat lung: histologic and bronchoalveolar lavage assessment.

Pulmonary antigen challenge in sensitized individuals elicits immediate and late phase responses (LPR). While mast cells and tissue inflammation are thought to be vital to the development of the LPR, the precise pathogenesis of these responses remains under investigation. Using the Sprague-Dawley rat as a model to study cutaneous LPR, we have previously demonstrated that rat cutaneous LPR are mast cell-dependent and are histologically characterized by early (1-8 h) neutrophil-rich and late (8-24 h) mononuclear cell-rich infiltrates. To compare and contrast this cutaneous response with IgE-dependent pulmonary inflammatory responses, we performed bronchoalveolar lavage (BAL) analyses of pulmonary inflammation following specific antigen challenge in actively immunized [IgE anti-ovalbumin (OA) antibody] and BAL and histologic analyses in passively sensitized [mouse hybridoma anti-dinitrophenyl (DNP) IgE antibody] rats. Following direct insufflation of OA into the trachea, actively sensitized animals demonstrated an increased number of polymorphonuclear leukocytes (PMNs) at 4 h in BAL fluid. These cell numbers were significantly increased over controls by 24 h following challenge. In addition, rats passively sensitized for 72 h with anti-DNP IgE hybridoma antibody (PCA = 1:10,000) were challenged with DNP-BSA aerosols. Examination of BAL fluid 1 to 2 h following challenge revealed significantly increased numbers of PMNs which returned to normal levels by 24 h. Numbers of lymphocytes and macrophages were unchanged compared to controls. Microscopic examination of lung tissue revealed alveolar and interstitial edema at 2 h following challenge and a focal peribronchiolitis characterized by a predominantly mononuclear cell infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The biologic activity of mast cell granules. V. The effects of antihistamine treatment on rat cutaneous early- and late-phase allergic reactions.

Mast cell-dependent late-phase allergic reactions (LPR) as sequelae of immediate hypersensitivity responses (IR) occur in both human and rat skin; thus the rat has served as a useful model to investigate the pathogenesis of cutaneous LPR. To analyze the roles that histamine might play in the generation of rat LPR, the effects of H1 and/or H2 antihistamines on both LPR and antecedent blueing responses (IR) were investigated. Systemically administered diphenhydramine and cimetidine, alone or in combination, reduced blueing reactions to histamine. However, blueing responses to anti-IgE were only partially abrogated by antihistamine treatment with diphenhydramine alone or the combination of antihistamines. Diphenhydramine treatment alone partially inhibited the histologic intensity of LPR in a dose-dependent manner. Although cimetidine treatment alone had no inhibitory effect, it potentiated the diphenhydramine-induced inhibition of LPR. The inhibitory action of antihistamine treatment was apparent only in reactions elicited by anti-IgE or mast cell granules containing histamine, since LPR caused by histamine-free mast cell granules were not affected by antihistamines. This observation suggests that the inhibitory effect of antihistamines on LPR was the result of a specific blockade of histamine receptors rather than the result of a nonspecific suppressive effect. Our findings demonstrate that cutaneous inflammation generated as a result of mast cell degranulation can be significantly reduced by treatment with H1 and H2 histamine receptor antagonists.

Animals↗
PubMed1983

Gastrointestinal mast cells in health and disease. Part I.

The mast cell granule provides three distinct sources of mediators: (1) preformed and rapidly released (histamine), (2) secondarily formed and generated by the interaction of primary mediators and nearby cells and tissues (leukotrienes), and (3) granule matrix-derived, which are preformed but remain associated with the granule proteoglycans after discharge (proteases) (Table). The granule matrix and its associated mediators may remain in the tissue for hours until removed through degradation, dissolution, or phagocytosis. The events initiated by the mediators depend on the tissues into which they are released. Mediator discharge clearly initiates the events associated with immediate hypersensitivity; however, late-phase reactions occur in response to granule-derived mediators as well. Several manifestations that may result from the introduction of mast cell-derived products within the gastrointestinal tract are shown in Fig. 5. These include increased vascular permeability and secretion of mucus, effects on cell surface receptors, chemotaxis of various cell types, and smooth muscle contraction. Thus the mast cell, because of its unique anatomic location and mediators, may serve both as an initiator of acute inflammation and a propagator of chronic changes as well.

Animals↗
PubMed1983

The biologic activity of mast cell granules. IV. The effect of complement depletion on rat cutaneous late phase reactions.

Cutaneous late phase reactions (LPR) in rats can be induced by the intradermal injection of anti-IgE antibody or isolated rat peritoneal mast cell granules. Rat LPR are characterized by neutrophil-rich infiltrates at 2 to 8 hr followed by mononuclear cell-rich infiltrates thereafter. Rat Arthus reactions are histologically similar and are complement (C) dependent. To determine the importance of C in the pathogenesis of rat LPR compared with its role in Arthus reactions, rats were treated with cobra venom factor (CVF) (250 U/kg i.v.), and the effects of this treatment on total hemolytic complement (CH50), C3 titers, LPR, and Arthus reactions were assessed. CVF treatment produced profound decreases in both CH50 (from 197 +/- 20 to less than 1.0 U/ml) and C3 (from 44,240 +/- 2840 to less than 5 U/ml) titers after 6 hr, which persisted through at least 30 hr. The inflammatory intensity of heterologous reverse passive Arthus reactions was significantly decreased in CVF-treated animals. In contrast, the intensity of LPR was unaffected by CVF treatment. Therefore, although LPR and Arthus reactions share certain histologic characteristics, these similarities are not due to a mutual requirement for the presence of C.

Animals↗
PubMed1983

The biologic activity of mast cell granules. VI. The effect of vinblastine-induced neutropenia on rat cutaneous late phase reactions.

Type I immediate hypersensitivity reactions in human and rat skin may be followed by late phase reactions (LPR). A consistent feature of both human and rat LPR is the early histologic appearance of neutrophils, which, in rats, is followed by the later appearance (8 to 24 hr) of mononuclear cells. To determine the importance of the neutrophil in the development of LPR, rats were depleted of neutrophils using parenteral injections of vinblastine sulfate (VS). VS produced a dose-dependent neutropenia, with the maximal effect on day 4. LPR that were induced with anti-IgE, isolated mast cell granules (MCG), or purified high (greater than 10,000 daltons) and low (500 to 10,000 daltons) m.w. fractions obtained from MCG were significantly abrogated in VS-treated rats. In neutropenic rats previously immunized with complete Freund's adjuvant, the intensity of inflammatory reactions produced by skin testing with purified protein derivatives was also significantly reduced. Administration of exogenous neutrophils to neutropenic animals partially reconstituted the reduced LPR. These data confirm and extend previous observations on the contribution of neutrophils to delayed hypersensitivity reactions and provide evidence that the neutrophil is critical for the development of rat cutaneous LPR as well.

Agranulocytosis↗
PubMed1983

The biologic activity of mast cell granules. VII. The effect of anti-neutrophil antibody-induced neutropenia on rat cutaneous late phase reactions.

Mast cell-dependent late phase reactions (LPR) occur in rat skin and are characterized histologically by an early (1- to 8-hr) neutrophil-rich and later (8- to 24-hr) mononuclear cell-rich infiltrate. To extend previous observations on the role of the neutrophil in the sequential histologic development of cutaneous LPR, rats were selectively depleted of circulating neutrophils using rabbit anti-rat neutrophil antibody (anti-neut), and the effects of this treatment on the histologic intensity of LPR were analyzed. In addition, the effects of neutrophil depletion on cutaneous delayed-type hypersensitivity (DTH) reactions produced by immunization with Freund's complete adjuvant followed by intradermal challenge with purified protein derivative (PPD) were assessed. Following anti-neut treatment, cutaneous DTH reactions were unaffected. In contrast, selective neutrophil depletion resulted in significant reductions in the intensity of cutaneous LPR at both 6 to 8 and 24 hr following anti-IgE or rat mast cell granule injection. Further, statistical comparison of circulating neutrophil counts with the capacity of the animal to express LPR revealed a highly significant direct correlation. These data confirm the previous observations that rat LPR are neutrophil-dependent reactions.

Agranulocytosis↗
PubMed1982

The experimental production of increased eosinophils in rat late-phase reactions.

The effects of peripheral eosinophilia on the intensity, kinetics and cellular characteristics of rat cutaneous late-phase reactions (LPR) have been investigated. Two distinct methods of inducing peripheral eosinophilia did not alter either the intensity or the kinetics of LPR produced by the intradermal injection of anti-IgE, Compound 48/80, or isolated mast cell granules. Hypereosinophilic animals exhibited increased numbers of tissue eosinophils in LPR tissue sites which correlated with the elevations in their respective peripheral eosinophil counts; however, the absolute number of eosinophils present, although significant, was not impressive (less than 10% of total). Our data suggest that, although rat LPR can be modulated to involve increased tissue eosinophils by increasing the numbers of peripheral blood eosinophils, no effects of these procedures on altering either the intensity or the kinetics of these reactions can be appreciated.

Animals↗
PubMed1981

Analysis of granulocyte beta-adrenergic response in cystic fibrosis: correlation of decreased responsiveness with disease severity.

Granulocytes from 21 nonasthmatic cystic fibrosis (CF) patients were isolated and the effects of isoproterenol, histamine, and prostaglandin E1 upon zymosan-induced beta-glucuronidase release was measured. Granulocytes from CF patients contained significantly less total beta-glucuronidase activity compared with those from control subjects, but response to zymosan stimulation was normal. Compared with those from control subjects, the granulocytes from CF patients with severe airway disease (% predicted FEV1 less than 60) had significantly reduced responsiveness to isoproterenol, which correlated with both the % predicted FEV1 values and the NIH clinical score. In this same population of CF patients, granulocyte responsiveness to PGE1 was also decreased compared with that of the control subjects, but the degree of impairment was not as severe as that observed with isoproterenol nor did it correlate with disease severity. Histamine responsiveness, however, was normal. Our findings suggest that abnormal beta-adrenergic responses may reflect the severity of airway disease and clinical score.

Adolescent↗
PubMed1980

Impaired in vitro beta-adrenergic granulocyte response in chronic obstructive pulmonary disease.

Isoproterenol (ISO), histamine (HIS), and prostaglandin E1 (PGE1) inhibit the in vitro release of the lysosomal enzyme, beta-glucuronidase, from polymorphonuclear leukocytes (PMN) during incubation with complement-coated zymosan particles. In asthma, this granulocyte response to ISO and HIS is impaired. Using this in vitro cell model to assess granulocyte beta-adrenergic response, we studied 23 patients with chronic obstructive pulmonary disease (COPD). All had long-standing disease and severe obstruction (FEV1 = 37.5% of predicted). The granulocyte response to HIS challenge in patients with COPD was normal when compared to control subjects, in contrast to the response from the asthmatic group. The granulocyte response to ISO challenge in patients with COPD, however, was reduced compared to control subjects, but not to the degree found in the asthmatics. This demonstrated that reduced granulocyte response to ISO is not limited to asthmatics, but can be found as well in other obstructive diseases of the lung.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Administration, Inhalation↗
PubMedDate not supplied

Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Administration, Inhalation↗
PubMedDate not supplied

Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.

BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Adolescent↗