PubMed Health⌕ Search

Biomedical subjects

S C Lazarus

Publications and source records attributed to S C Lazarus.

At least 55 records · Page 3Linked to original sources
PubMed1987

Inflammatory mediators, tachykinins and enkephalinase in airways.

Immunologic and nonimmunologic stimuli evoke responses in the airways by complex mechanisms, often involving mast cells and mast cell-derived mediators. These mechanisms can be investigated using isolated mast cell lines for biochemical and physiologic studies. Neuropeptides as well as the enzymes that degrade neuropeptides are present in airway tissues. In the case of substance P, metabolism in the airway has demonstrated physiologic significance. The physiologic response to a stimulus depends upon the interaction between locally released inflammatory mediators and neuropeptides and the enzymes which degrade them.

Endopeptidases↗
PubMed1987

The role of mast cell-derived mediators in airway function.

The airway mast cell appears to play an important role in a number of pathophysiologic responses. Mast cells may be activated directly (e.g., by specific antigen) or indirectly (e.g., by an epithelial cell product such as 15-HETE). When activated, the mast cell releases mediators that may have direct effects or indirect effects. Mast cells and mediators undoubtedly play a role in specific airway responses. The data presented here are intended to serve only as examples of the complex way in which various cells and inflammatory mediators may interact to produce a physiologic response in the airways. Possibilities exist for numerous interactions between additional mediators as well as additional cell types. Because of the complexity of the system, characterization of activation and secretion by isolated pure cells, and studies of cell-to-cell interactions in vitro appear to be important first steps toward understanding the even more complex interactions that occur in vivo.

Animals↗
PubMed1986

Role of inflammation and inflammatory mediators in airways disease.

Recent evidence suggests that airway inflammation is linked to hyper-responsiveness of airway smooth muscle. Increases in airway responsiveness after many stimuli are accompanied by increases in inflammatory cells in bronchoalveolar lavage fluid and in the airway epithelium. Airway epithelial cells may themselves be an important source of inflammatory mediators, producing metabolites that can cause chemotaxis of neutrophils and that can selectively activate other cells in the lungs. Mast cells produce a variety of enzymes and vasoactive, chemotactic, and bronchoconstrictor substances in response to non-immunologic as well as immunologic stimuli. The secretory profile of a mast cell may depend upon the specific stimulus applied. In addition, different populations of mast cells exist and distinct enzymatic pathways may predominate in different cell types. Mediators released by these cells may activate target cells by direct or indirect mechanisms. These inflammatory mediators, together with inflammatory cells, are important in the complex interactions involving airway epithelial cells, neutrophils, mast cells, smooth muscle, respiratory secretory cells, and nerves, which, in concert, are responsible for the pathophysiologic manifestations of obstructive lung disease.

Animals↗
PubMed1986

Cutaneous mast cell heterogeneity: response to antigen in atopic dogs.

Because mast cells (MCs) in skin of atopic dogs are heterogeneous with respect to tissue fixation and staining properties, we determined the effect of antigen on each type of MC in vivo. Skin biopsies were done in anesthetized, ragweed-sensitized dogs before and at 1, 3, 6, and 24 hours after intradermal injections of ragweed antigen (n = 5) or glycerin diluent (n = 4). In each case, one biopsy specimen was fixed with formalin, and a second specimen from an adjacent abdominal site was fixed with basic lead acetate. In sections stained with Alcian blue, 49.7% more MCs (p less than 0.05) were detected in tissue fixed with basic lead acetate ("typical" plus "atypical" MCs: 2916 +/- 581/mm3; mean +/- SEM) than in tissue fixed with formalin ("typical" MCs: 1955 +/- 537/mm3). After antigen, the number of "typical" MCs detectable in tissue sections progressively decreased during the 24-hour period, whereas the number of "atypical" MCs was lowest at 1 hour and had increased at 24 hours. After diluent, MC numbers did not change significantly over time. A late-phase response (LPR), detected clinically as induration and edema, was present 6 hours after antigen in four of five dogs, but LPR was not detected after diluent. The size of LPR was correlated (r = 0.85; p less than 0.05) with the decrease in the number of "typical" MCs at 6 hours. We conclude that the response of the "typical" and "atypical" MC to antigen in vivo differs markedly. The "atypical" MCs participate in the early, acute response to antigen, and the "typical" MCs may be associated with the development of the LPR.

Animals↗
PubMed1986

cAMP immunocytochemistry provides evidence for functional VIP receptors in trachea.

Vasoactive intestinal peptide (VIP), first isolated from porcine intestine (S. I. Said and V. Mutt, Science Wash. DC 169: 1217-1218, 1970), has been identified in postganglionic autonomic axons of many tissues. VIP has potent regulatory effects on the function of various cell types within these tissues, ranging from relaxation of smooth muscle to ion transport. Recently, VIP has been implicated in the regulation of mucus secretion in the respiratory tract, a process involving release of macromolecules from exocrine cells and transport of ions and water across the airway mucosa. However, because airway glands and mucosa both consist of mixed cell populations, it was unclear which specific cells contained VIP receptors and contributed to VIP-evoked responses. We identified these specific cells by using immunocytochemical techniques to monitor concentration changes in adenosine 3',5'-cyclic monophosphate (cAMP), the intracellular compound known to mediate VIP responses. Serous and mucous cells of ferret tracheal submucosal glands and ciliated and basal cells of dog tracheal mucosa all increased cAMP in response to VIP stimulation. We conclude that these cell types possess VIP receptors and thus participate in VIP-stimulated responses. In contrast, ferret tracheal epithelium and dog epithelial goblet cells showed little or no reactivity after VIP, and thus we believe that these cells lack VIP receptors.

Animals↗
PubMed1986

Effects of mast cell-derived mediators on epithelial cells in canine trachea.

We examined the interaction between mast cell-derived mediators and the electrical and ion transport properties of canine tracheal epithelium. We compared the effect of mediators released by immunologic challenge of sensitized lung parenchyma with that of mediators released from canine mastocytoma cells challenged with calcium ionophore A23187. Short-circuit current (Isc) increased by 19.2 +/- 3.0 microA/cm2 in response to mediators released from sensitized lung fragments challenged with ragweed antigen. This effect was not due to histamine. When the epithelial tissues were pretreated with indomethacin, the same mediator supernatant increased Isc by only 3.8 +/- 4.3 microA/cm2. The mediators released from 10(7) mastocytoma cells challenged with calcium ionophore increased Isc by 25.1 +/- 13.6 microA/cm2. In the presence of indomethacin, the Isc increased by 2.0 +/- 0.4 microA/cm2. Mastocytoma-derived mediators produced an increase in net chloride secretion without a significant effect on net sodium absorption. This study provides direct evidence that mast cell-derived mediators can stimulate epithelial ion transport in canine trachea and suggests that the effect is indirect and dependent on intact cyclooxygenase pathways in the tracheal epithelium.

Animals↗
PubMed1986

Isolated canine mastocytoma cells: propagation and characterization of two cell lines.

Five different dog mastocytoma tumors were successfully transplanted and propagated in BALB/c nude mice. Cells from two of these tumors were passaged serially through at least four generations of mice without morphological or functional change. The average yield from a 2-cm tumor harvested from a mouse was 1.2 +/- 2.8 X 10(9) mast cells with greater than 90% viability. Cells of one line were larger and more heavily granulated than the other, and contained 1.29 +/- 0.74 pg histamine/cell (mean +/- SD). Calcium ionophore A23187 and compound 48/80 caused dose dependent histamine release with no significant difference in release from generation to generation. The smaller cells contained 0.06 +/- 0.06 pg histamine/cell. Histamine release after calcium ionophore or compound 48/80 was dose dependent and unchanged through serial passages. Following passive sensitization antigen caused dose-dependent histamine release confirming the presence of IgE receptors on these cells. In both cell lines histamine release was inhibited by terbutaline, dibutyryl adenosine 3',5'-cyclic monophosphate, or isobutylmethylxanthine. These methods provide a morphologically and functionally stable population of nearly pure canine mast cells for biochemical and physiological studies.

Animals↗
PubMed1986

Mast cell-derived mediators and their role in cell-to-cell interactions in the lung.

Mast cells produce a variety of enzymes and vasoactive, chemotactic, and bronchoconstrictor substances in response to nonimmunologic as well as immunologic stimuli. These mast cell-derived mediators may act on airway smooth muscle, submucosal glands, epithelial cells, circulating blood cells, vascular cells, and other cell types. The secretory profile of a mast cell appears to depend on the specific stimulus applied. In addition, different populations of mast cells exist, and distinct enzymatic pathways may predominate in different cell types. The effect of mast cell-derived mediators on the various target cells may be direct or indirect. For example, mediators released by immunologic challenge of sensitized lung fragments or by nonimmunologic challenge of canine mastocytoma cells stimulate the transport of ions and water across the tracheal epithelium. This effect, however, is indirect, is blocked by indomethacin, and therefore appears to be dependent upon an intact cyclooxygenase pathway in the tracheal epithelium. Canine mastocytoma cells resemble normal mast cells in dog lung and skin, and can be propagated to provide a continuous source of large numbers of pure, identical mast cells for biochemical and physiologic studies. Studies of these cells and their inflammatory mediators will increase our understanding of the complex series of cell-to-cell interactions which are responsible for the pathophysiologic manifestations of obstructive lung disease.

Animals↗
PubMed1985

Mast cell heterogeneity in dog skin.

The degree of metachromasia of mast cell granules is known to vary with the type of tissue fixation and among different tissues and species. The present study sought to determine whether mast cells in dog skin are heterogeneous with respect to fixation and staining properties. We performed skin biopsies in six anesthetized, atopic dogs and one mongrel dog. One biopsy was fixed in formalin and a second, from a parallel abdominal site, was fixed in basic lead acetate (Mota's solution). Adjacent sections from each biopsy were stained with alcian blue (1%, pH 0.5) or for chloroacetate esterase activity. In alcian blue-stained sections, one-third fewer mast cells were detected in skin fixed in formalin (1,836 +/- 454 mast cells/mm3, mean +/- SEM) than in skin fixed in basic lead acetate (2,684 +/- 527 mast cells/mm3) (P less than 0.05). The chloroacetate esterase reaction detected the larger number of mast cells regardless of the fixative used. We conclude that mast cell heterogeneity, as demonstrated by metachromatic staining following different types of tissue fixation, exists in dog skin. "Typical" mast cells stain with alcian blue regardless of fixation; however, "atypical" mast cells exhibit metachromasia only after fixation in basic lead acetate. Both the typical and atypical types of mast cells have chloroacetate esterase activity.

Alcian Blue↗
PubMed1985

Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs.

We studied whether antigen-induced airway hyperresponsiveness was associated with pulmonary inflammation in 11 anesthetized ragweed-sensitized dogs. Airway responsiveness to acetylcholine aerosol was determined before and at 2, 6, and 24 h after ragweed or sham aerosol challenge. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) performed at either 2 or 6 h. Total pulmonary resistance increased 11-fold at 5 min after ragweed. Airway responsiveness was unchanged at 2 h but was increased 6.6-fold at 6 h in 8 of 11 dogs (P less than 0.001); hyperresponsiveness persisted from 4 days to 4 mo. Airway responsiveness was unchanged by aerosols of diluent. Neutrophils in BAL fluid increased approximately sixfold at 2 h (P less than 0.02) and at 6 h (P less than 0.02) after antigen challenge. There were fewer eosinophils in fluid recovered at 6 h after antigen compared with 2 h lavages (P less than 0.05). In three nonresponders, BAL showed no significant changes in neutrophils and eosinophils after antigen. Thus antigen-induced hyperresponsiveness is associated with the presence of pulmonary inflammation, presumably arising from the airways and involving both neutrophils and eosinophils.

Acetylcholine↗
PubMed1984

Localization of cAMP in dog and cat trachea: effects of beta-adrenergic agonists.

Adenosine 3',5'-cyclic monophosphate (cAMP) is believed to mediate the transport of ions, water, and mucous glycoproteins in the respiratory tract. Because chemical measurements of total tissue levels of cAMP may not always reflect changes in specific cell types, we adapted standard immunocytochemical methods to examine the cellular localization of cAMP in dog and cat tracheae. The beta-adrenergic agonists terbutaline and isoproterenol increased immunoreactive cAMP in ciliated epithelial cells of dog and cat tracheae and in both serous and mucous gland cells of cat tracheae. Epithelial goblet cells did not respond to beta-adrenergic agonists in either species. This study provides information about the location of beta-receptors on individual cells in the trachea that is not available from chemical assays of either cAMP or beta-receptors in these tissues. Our results support the hypothesis that secretory functions in both serous and mucous submucosal gland cells and ciliated epithelial cells, but not goblet cells, may involve cyclic AMP-dependent mechanisms.

Animals↗
PubMed1984

Prostaglandins and intracellular cyclic AMP in respiratory secretory cells.

Prostaglandins are known to affect ion transport and mucus secretion in the trachea, and at least part of their effect is thought to be mediated by cyclic AMP. Because no prostaglandin receptor assay is currently available, we have used an immunocytochemical probe for the intracellular localization of cyclic AMP to identify those specific cell types in dog and cat trachea that respond to prostaglandins. Using tracheal explants similar to those used by other investigators for in vitro studies of ion transport and glycoprotein secretion, we examined the effect of endogenous and exogenous prostaglandins on immunoreactive cyclic AMP. Endogenous prostaglandins, which may be secreted in response to minor distortion of tissue membranes, stimulated immunoreactive cyclic AMP in ciliated epithelial cells and in both serous and mucous submucosal gland cells. This was not observed in tissues assayed 60 min after dissection, or dissected in the presence of indomethacin or of BW755C. Exogenous prostaglandin E1 increased cyclic AMP in these same cell types. We conclude that prostaglandins stimulate cyclic AMP in specific cell types in the trachea, and that endogenous prostaglandins play a major role in many in vitro preparations.

Animals↗
PubMed1983

Effect of beta-adrenergic stimulation on experimental canine anaphylaxis in vivo.

We studied beta-adrenergic modulation of antigen-induced release of histamine and changes in lung function in natively allergic, anesthetized dogs. After thoracotomy and bilateral cervical vagotomy, samples of peripheral lung frozen in situ were obtained for measurement of adenosine cyclic 3',5'-monophosphate (cAMP) and histamine. In 11 dogs with beta-adrenergic blockade (propranolol), subsequent Ascaris suum antigen (intravenous) decreased lung tissue histamine 21.5% +/- 5.3% (mean +/- SE), with marked physiologic changes of anaphylaxis. In six other dogs, with no pharmacologic treatment before antigen, A. suum decreased lung tissue histamine only 11.5% +/- 1.9%. In six other dogs, terbutaline (1 mg/kg, i.v.) increased concentration of cAMP in peripheral lung, indicating stimulation of beta-adrenergic receptors, and inhibited response to A. suum. When a beta-adrenergic agonist was given 15 sec prior to A. suum, cAMP doubled and inhibition was incomplete. When a beta-agonist was given 150 sec prior to A. suum, cAMP increased fivefold and inhibition was complete.

Adrenergic beta-Agonists↗
PubMed1982

Characterization of tracheal mast cell reactions in vivo. Inhibition by a beta-adrenergic agonist.

In 12 anesthetized dogs, we tested the effects of pharmacologic beta-adrenergic stimulation on the severity of tracheal mast cell reactions in vivo (Am Rev Respir Dis 1979; 119:62). In control dogs, tracheal arterial injections of compound 48/80 produced arteriovenous differences in histamine concentrations across the trachea (35 +/- 15 ng/ml), but not the lung; this finding suggested selective degranulation of tracheal mast cells. Tracheal arteriovenous histamine differences correlated (r = 0.70) with tracheal contractions (12 +/- 4 g/cm) induced by compound 48/80 in these animals. In other dogs, injections of isoproterenol (10 micrograms/kg) before compound 48/80 prevented the development of both tracheal arteriovenous differences and contractions. We concluded that pharmacologic beta-adrenergic stimulation inhibited degranulation of tracheal mast cells. The preparation appears suitable for examining the effects of endogenous stimuli on the severity of mast cell reactions in the central airways of anesthetized dogs.

Adrenergic beta-Agonists↗
PubMed1979

Experimental canine anaphylaxis: cyclic nucleotides, histamine, and lung function.

We studied the effects of Ascaris suum antigen (iv) in 32 natively allergic, anesthetized dogs. After thoracotomy, bilateral cervical vagotomy, and propranolol, samples of peripheral lung frozen in situ were obtained for measurement of cyclic nucleotides and histamine. Following Ascaris, lung histamine decreased 20.4 +/- 3.7% (mean +/- SE), cAMP increased 391 +/- 122%, and cGMP increased 110 +/- 20% with increased plasma histamine and physiological changes of anaphylaxis. No significant changes occurred in 10 control dogs. Release of histamine, reflecting immunological degranulation of mast cells, correlated closely with the physiological effects of anaphylaxis. beta-Adrenergic stimulation with isoproterenol prevented these physiological effects of anaphylaxis in three dogs studied. Furthermore, the level of cAMP induced in lung tissue by beta-adrenergic stimulation in these dogs correlated with the degree of inhibition of immunologically induced histamine release. These results illustrate the suitability of this experimental preparation to study the biochemical and physiological mechanisms of anaphylaxis in vivo.

Anaphylaxis↗
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↗