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Biomedical subjects

C G Persson

Publications and source records attributed to C G Persson.

At least 145 records · Page 8Linked to original sources
PubMed1989

Inflammatory passage of plasma macromolecules into airway wall and lumen.

Anaesthetised guinea-pigs received tracer macromolecules 70-340 kDa intravenously and their erythrocytes were labelled in vivo with 99mTc. Superfusion of tracheal mucosa (via oral catheter) with control solutions and inflammatory agents, was followed by sampling of tracheal surface liquids and tracheal tissue. Under baseline conditions no 125I-fibrinogen (340 kDa) and minimal amounts of erythrocytes, 131I-albumin (70 kDa), and FITC-D (150 kDa) were found in tracheal lavage fluids. Undisturbed baseline conditions with negligible leakage of plasma into airway tissue and lumen were thus obtained with the present provocation and sampling techniques. Superfusion during 2 min with bradykinin 2-10 nmol, histamine 2-8 nmol, capsaicin 0.1-0.4 nmol, PAF 4-8 nmol, ovalbumin 3-6 pmol (in sensitised animals) produced, within 1-10 min, a significant and dose-dependent accumulation of plasma in tracheal tissue and lavage fluids. PAF also induced a late phase plasma leakage response at 5 h. At 10 min PAF given intra-arterially produced a similar leakage into the tissue but less into the lumen compared to topical PAF. Intravenous PAF produced additional effects such as pulmonary oedema. Carbachol 8-16 nmol had only minimal effects on 'leakage' but produced severe bronchoconstriction. Toluene diisocyanate (0.003-0.03 microliter) produced dose-dependent and very sustained (17 h) plasma leakage. Recovery of plasma tracers in airway tissue and surface liquids, respectively, was significantly correlated. As examined with capsaicin, absorption of luminal macromolecules increased only slightly during the exudation process. It is suggested that the consistent inflammatory stimulus-induced passage of plasma into the lumen is a consequence of a load on the basal side of the epithelium induced by the extravasated plasma and its derived peptides. An increased interstitial pressure may transiently separate many epithelial cells allowing a mainly uni-directional almost unrestricted flow of large solutes into the lumen.

Allergens↗
PubMed1989

The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 5'-monophosphate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma.

The contribution of adenosine antagonism to the anti-bronchoconstrictor effect of xanthines was examined in 7 atopic asthmatic subjects. On separate occasions the effect of intravenous infusions of theophylline, enprofylline and saline placebo was observed on bronchoconstriction provoked by increasing inhaled concentrations of histamine and adenosine 5'-monophosphate (AMP). Airway calibre was followed as the maximum expiratory flow at 70% below total lung capacity (Vmax30) and FEV1. Both active drugs produced a similar 6-8% increase in FEV1 and 28-41% increase in Vmax30 at steady state plasma concentrations of theophylline 11 mg/ml and enprofylline 3 mg/ml respectively. During the placebo infusion histamine and AMP caused dose-related reductions in both indices of airway calibre, with AMP being approximately 10 times less potent than histamine in molar terms. Theophylline and enprofylline produced similar protection against histamine induced reductions in FEV1 and Vmax30. Whereas enprofylline afforded a similar degree of protection against the airway effect of AMP and histamine, theophylline produced significantly greater protection against AMP whether airway calibre was assessed as Vmax30 or FEV1. The differential effects of theophylline and enprofylline against AMP, but not histamine or baseline airway calibre suggest that adenosine antagonism has little role to play in the acute bronchodilator actions of xanthines.

Adult↗
PubMed1989

Reversibility and reproducibility of histamine induced plasma leakage in nasal airways.

Plasma exudation is one cardinal factor in airways defence and inflammation. In inflammatory airway diseases such as rhinitis and asthma, however, plasma leakage may also have a pathogenetic role. Experimental data from animals indicate that highly sensitive, active, and reversible processes regulate the vascular and mucosal permeability to macromolecules. With the use of a nasal lavage model for the recovery of liquids on the mucosal surface the effect of histamine on the macromolecular permeability of the airway endothelial-epithelial barriers was studied in normal subjects. The concentrations of albumin, kinins, and N-alpha-beta-tosyl-L-arginine-methyl esterase (TAME) in nasal lavage fluid were measured and nasal symptoms assessed by a scoring technique. The reproducibility of three repeated challenges with 30 minute intervals on the same day was studied in 12 subjects and compared with the same procedure (three challenges) on a different day. Sneezing decreased significantly (p less than 0.05) after the first histamine challenge but was maintained thereafter. Otherwise, the mean values for symptoms and for markers of vascular leakage were very similar both for the three challenges in the same session and for the two challenge sessions on a different day. Sneezing, blockage, and secretions were associated with increased concentrations of TAME esterase (maximum 9000 cpm/ml), kinins (1.4 ng/ml), and albumin (0.3 g/l) in lavage fluid. Both the symptoms and the measures of plasma exudation were reversible and reproducible in the three repeat histamine challenges and at two challenge sessions on different days. These findings support the view that non-injurious, active processes regulate the inflammatory flow of macromolecules across airways endothelial-epithelial barriers. The present experimental approach would be suitable for studies of the modulatory effects of inflammatory stimulus induced plasma leakage and symptoms in human airways.

Adult↗
PubMed1989

Effect of three weeks' treatment with budesonide on in vitro contractile and relaxant airway effects in the rat.

An investigation was carried out to determine whether the sensitivity of rat tracheal smooth muscle to contractile and relaxant drugs was affected by three weeks' treatment with subcutaneous budesonide before death. Budesonide treatment was associated with a lower thymus weight and a smaller gain in body weight than in control animals. There was, however, no difference in the carbachol concentration-response curves or maximum responses to carbachol of tracheal smooth muscle from control and budesonide treated rats. Isometric and isotonic recordings agreed in these respects. Glucocorticoid treatment did not increase the sensitivity of tracheal smooth muscle to the relaxant drugs terbutaline and enprofylline; if anything there was a tendency for terbutaline and enprofylline to be less potent after budesonide treatment. The data suggest that in vivo effects of glucocorticoids on airway responsiveness to bronchodilating and bronchoconstricting drugs are unlikely to be due to a direct effect on bronchial smooth muscle.

Animals↗
PubMed1989

Budesonide reduces sensitivity to antigen but does not alter baseline tone or responsiveness to carbachol, terbutaline, and enprofylline in IgE-sensitized guinea-pig tracheae.

In vitro incubation of IgE-sensitized guinea-pig tracheal rings with 10(-7) M budesonide for 24 h significantly shifted the concentration-response curve to antigen by 5-fold to the right. Smooth muscle characteristics such as baseline tone, muscarinic contraction or relaxation to beta 2-receptor agonists and xanthines were not or only marginally affected by this exposure of airway tissue to a glucocorticoid drug. It is concluded that budesonide reduced anaphylactic IgE-driven release of contractile mediators.

Airway Resistance↗
PubMed1989

Antiinflammatory therapy with glucocorticoids in intrinsic asthma.

The pioneering study by Bordley et al. (John Hopkins Hosp. 1949) contains information on glucocorticoids in asthma that has stood the test of time: These drugs do not distinguish between intrinsic and extrinsic asthma. The beneficial effect can be seen in 4-48 h. The full effect is obtained in a week or longer. After stopping therapy in "cured" patients, symptoms may gradually return. Studies carried out by Swedish, English and German workers in the mid-1950s appear to be the first successful uses of topical glucocorticoids in asthma. As shown with beclomethasone dipropionate during the 1970s, and expanded during the 1980s with the more lung-selective drug, budesonide, inhaled glucocorticoids have a broad clinical efficacy in mild and severe asthma and are very safe to use. They improve baseline airway resistance and reduce "non-specific" hyperreactivity. They inhibit not only late phase responses but also immediate type reactions in the airways including exercise-induced asthma. It has been suggested that long-term treatment with glucocorticoids may have significant effects on the progression of the disease. Clinical efficacy, increased lung selectivity, and improved delivery (a breath-actuated multi-dose pure drug powder device will soon be available for inhalational glucocorticoid therapy) would speed up the current trend towards using glucocorticoids as primary and prophylactic treatment of asthma. Bordley et al. (1949) also gave factual hints about the mode of action of glucocorticoids in asthma: Sputum (eosinophilic) production ceased entirely; paleoedematous airway mucosa covered with thick purulent mucus turned into a pink normal mucosa with a clear mucus. Glucocorticoids have taught us about asthma and taken the attention away from smooth muscle and single inflammatory mediator or cell hypotheses to a focus on complex inflammatory mucosal/submucosal events involving many target cells. Of particular interest is the ability of glucocorticoids to reduce plasma exudation into airway wall and lumen. Exuded plasma is a multipotential pathogenetic factor in asthma and anti-plasma leakage actions may contribute significantly to the general clinical efficacy of glucocorticoids in this disease.

Anti-Inflammatory Agents↗
PubMed1988

Xanthines--symptomatic or prophylactic in asthma?

Perhaps xanthines should not be classified as bronchodilators because their clinical efficacy may reflect their antiinflammatory properties more than smooth muscle relaxation. Xanthines inhibit late phase airway reactions induced by allergen or chemical sensitizers. But, they offer little protection against methacholine-, histamine, or allergen-induced immediate bronchoconstriction and any protection seen is unrelated to the extent of the initial bronchodilatation. The antiinflammatory effects of xanthines include stabilization of a variety of inflammatory cells that are present in asthmatic airways. Another potentially important effect is the increase in number, and activity, of "suppressor" T-lymphocytes. Xanthines may also stabilize the barrier functions of both the airway epithelium and the airway microvessel (venular) wall. As a result less cellular and plasma-derived mediators are released, less plasma is exuded into the airway wall and less plasma enters the airway lumen. Penetration of inhaled macromolecules across the epithelium and into the airway wall may also be reduced. Future prospects for xanthines are interesting. A novel xanthine which lacks adenosine antagonist activity, enprofylline, has been shown to exert potent antiasthma actions without producing several of the excitatory, extrapulmonary, theophylline-like effects. We are only now starting to learn how xanthines actually work in the inflamed asthmatic and bronchitic airway. Nevertheless, the currently available data show that xanthines are likely to be more prophylactic than symptomatic in the treatment of asthma and chronic obstructive airway disease.

Adenosine↗
PubMed1988

Developments in anti-asthma glucocorticoids.

Studies carried out by Swedish and English workers in the mid 1950s appear to be the first successful uses of topical glucocorticoids in asthma. As shown with beclomethasone dipropionate during the 1970s, and expanded with budesonide during the 1980s, inhaled glucocorticoids have a very broad clinical efficacy and are safe to use. With increasing lung selectivity glucocorticoid drugs may well become a primary treatment for asthma. Even prolonged treatment with large doses of budesonide may not affect the contractile and relaxant characteristics of airway smooth muscle suggesting that this tissue is not a direct target for glucocorticoid actions. In IgE-sensitized guinea-pigs, as in atopic asthmatics, inhalational budesonide and other glucocorticoids inhibit both immediate and late phase pulmonary reactions occurring after allergen provocation. The anti-anaphylactic lung effects of glucocorticoids are not necessarily associated with inhibition of histamine and leukotriene release and, although PAF release was reduced by budesonide, the importance of this effect is as yet unknown. Airway eosinophilia is seen at the late phase reaction but may not consistently be reduced by glucocorticoids. These drugs reduce plasma leakage that is associated with both atopic and non-atopic asthma. Hence, a stabilising effect on airway endothelial-epithelial barriers may be one of the significant actions of glucocorticoids in the inflamed airways of patients with asthma or chronic obstructive pulmonary disease.

Administration, Inhalation↗
PubMed1988

Plasma exudation and asthma.

Several pieces of evidence support the view that exudation of plasma into the airway wall and into the airway lumen occurs in asthma. Vascular leakage of plasma results from inflammatory mediator-induced separation of endothelial cells in postcapillary venules belonging to the tracheobronchial circulation. Whereas proposed mediators of asthma induce reversible leakage, several antiasthma drugs exhibit antileakage effects in animals and humans. Potential consequences of plasma exudation are many. Mucosal/submucosal edema might contribute to airway hyperresponsiveness. Plasma exudate in the airway lumen in asthma may contribute to sloughing of epithelium, impairment of mucociliary transport, narrowing of small airways, and mucus plug formation. Exuded plasma may cause airway inflammation and constriction because of its content of powerful mediators, and chemoattractant factors and plasma proteins may condition the inflammatory cells abundant in asthmatic airways to release mediators in response to stimuli that otherwise would be innocuous to the cells. It is concluded that inflammatory stimulus-induced increase in macromolecular permeability of the tracheobronchial microvasculature and mucosa may be a significant pathogenetic mechanism in asthma and that the postcapillary venular endothelium and airway epithelium that regulate leakage of plasma are important effector cells in this disease.

Asthma↗
PubMed1988

Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in the guinea-pig.

Neural pathways involved in cough and reflex bronchoconstriction and the effects of drugs on these airway reflexes have been studied in unanaesthetised guinea-pigs exposed to aerosols of citric acid (0.13-0.78 M), capsaicin (30 microM), nicotine (9.2 mM) and histamine (0.9 mM). The number of coughs was counted during the first 3 min of exposure and the time to onset of signs of dyspnea, as an indication of bronchoconstriction, was measured. Citric acid produced bronchoconstriction and dose-dependently increased the number of coughs. Capsaicin produced both cough and bronchoconstriction. Nicotine mainly produced cough and histamine bronchoconstriction. Pretreatment of adult guinea-pigs with capsaicin (50 mg kg-1 s.c.) produced a long-lasting (greater than or equal to 10 weeks) depletion of substance P- and calcitonin gene related peptide-like immunoreactivities in the sensory nerves of the larynx, tracheobronchial tree and lung. In capsaicin-treated animals, citric acid (0.39 M) and capsaicin (30 microM) caused neither cough nor bronchoconstriction. Nicotine (9.2 mM) and mechanical stimulation still produced cough, and histamine (0.9 mM) bronchoconstriction. It is concluded that in guinea-pigs both capsaicin-sensitive (probably C-fibre endings) and capsaicin-resistant (probably rapidly adapting stretch receptors) afferent neurons may be involved in cough and reflex bronchoconstriction.

Animals↗
PubMed1988

Adenosine-induced bronchoconstriction in the guinea-pig isolated lung: interaction with theophylline and enprofylline.

Effects of purine nucleosides and asthma mediators on airway tone have been examined in the guinea-pig isolated perfused lung preparation. Acetylcholine (10 pmol-0.3 nmol), histamine (1-10 nmol), adenosine (10 nmol-0.3 mumol), ATP (10 nmol-0.3 mumol) and inosine (10 mumol-0.1 mmol) all produced a dose dependent increase in lung resistance (RL) and a decrease in dynamic compliance (CDYN). ATP was equipotent with adenosine whereas inosine was about 500 times less potent. The adenosine-induced bronchoconstriction was affected neither by disodium cromoglycate (150 microM) nor by the histamine H1-receptor antagonist, mepyramine (1 microM) suggesting that histamine is not involved in this response. Furthermore, it was studied whether the xanthines theophylline and enprofylline specifically interacted with the adenosine induced bronchoconstriction. Theophylline significantly (P less than 0.01-0.001) and concentration dependently prevented both acetylcholine and adenosine-induced increase in RL. The response to 0.1 nmol acetylcholine was reduced by 32.8 +/- 8.4% (mean +/- SEM) and 58.1 +/- 4.0%, respectively, by 75 and 150 microM theophylline. Theophylline, 75 and 150 microM, also inhibited the increase in RL caused by 0.1 mumol of adenosine by 61.4 +/- 9.6% and 83.4 +/- 5.2%, respectively. Theophylline, was significantly (P less than 0.05-0.01) more potent in preventing the RL increase produced by adenosine than that by acetylcholine. Enprofylline, 30 microM, equally well as 75 microM theophylline reduced the acetylcholine-induced bronchoconstriction by 41.8 +/- 7.6% (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1988

The epithelium and the pharmacology of guinea-pig tracheal tone in vitro.

1. Epithelium removal did not influence the development of spontaneous tone in guinea-pig tracheal smooth muscle mounted as open ring preparations with two adjoining cartilaginous rings in vitro. 2. Epithelium removal did not change the potency of carbachol but tended to reduce the maximal contraction. In the presence of epithelium the EC50 of carbachol was not different in tracheal open ring compared with intact tube preparations (comprising four cartilaginous rings), suggesting that the size of continuous epithelium in vitro was not critical for the potency of carbachol. 3. Substance P produced the same response in intact and rubbed tracheae. The enkephalinase inhibitor thiorphan (0.1 mM) by itself contracted the trachea and appeared to potentiate the substance P response five times more in the absence than in the presence of epithelium. Capsaicin (1 microM)-induced contractions did not differ between intact and rubbed preparations. 4. Arachidonic acid, 22 microM, variably produced small relaxations and contractions in intact as well as in rubbed tracheae. The mean effects of arachidonic acid were not significantly altered by epithelium removal. 5. Adenosine produced small contractions and dose-dependent relaxations in the presence and absence of epithelium. 6. Epithelium removal had no effect on the potency of the relaxant agonists theophylline and enprofylline. The isoprenaline curve was shifted 2 fold to the left and the terbutaline curve 1.5 fold to the right. The maximal relaxations were generally reduced in epithelium-free tissue. The reduction reached statistical significance with theophylline. 7. The present results suggest that epithelium removal is of little consequence for the pharmacology of the guinea-pig tracheal open ring preparation in vitro.

Animals↗