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Biomedical subjects

I Erjefält

Publications and source records attributed to I Erjefält.

At least 37 records · Page 2Linked to original sources
PubMed1992

Increased sensitivity to toluene diisocyanate (TDI) in airways previously exposed to low doses of TDI.

Repeated airway exposures to toluene diisocyanate (TDI) may cause sensitization and asthma. This study has examined the acute inflammatory response to TDI in guinea-pig tracheobronchial airways, the development of increased sensitivity to TDI and the effects of xanthines and a glucocorticoid on these responses to TDI. A restricted surface area of the tracheobronchial mucosa of Ketalar-Xylazin anaesthetized guinea-pigs was exposed to TDI, dissolved in olive oil, by means of 1 min infusions through an oral catheter. The TDI-induced inflammatory process was quantified by determination of airway luminal entry of plasma. Already 3 nl (approximately 20 pmol) of TDI produced a significant and sustained exudation response (P less than 0.001 to P less than 0.01, 5 and 17 hr after exposure). Pretreatment with intravenous enprofylline (25 mumol/kg) intraperitoneally or 26 mumol/kg by tracheal superfusion) was without effect. Two repeated exposures to TDI 3 nl (on days 1 and 8) made the animals hyperresponsive to TDI so that on day 15 a previously subthreshold dose of TDI (0.3 nl) produced significant exudation both at 5 and 17 hr after exposure (P less than 0.001 to P less than 0.01). Similarly, two repeated dermal exposures to a large dose of TDI (20 microliters) lowered the threshold for tracheal provocation with TDI. Budesonide (2.6 mumol/kg orally) given daily during the topical airway 'sensitization' regimen (days 1-14) significantly reduced the response to the subsequent 0.3 nl challenge dose of TDI (P less than 0.05). The effects of daily treatments with either theophylline (100 mumol/kg) or enprofylline (50 mumol/kg) were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1991

Plasma exudation as a first line respiratory mucosal defence.

A great variety of provocations of the airway mucosa produce extravasation of plasma from the abundant subepithelial microvessels. A plasma exudate has important actions through its volume, its specific and unspecific binding proteins, its enzyme systems, and its potent peptides (of kinin, complement, coagulation, fibrinolysis and other systems). If allowed to operate on the surface of an intact mucosa the plasma exudate would have important roles in normal airway defence. Recent observations in guinea-pig tracheobronchial airways and in human nasal airways suggest that the mucosal exudation of plasma into the airway lumen is a non-injurious fully reversible process. Threshold exudative responses thus resulted in the appearance of an 'unfiltered' plasma exudate not only in the lamina propria but also on the surface of an undisrupted mucosa. Even after extensive luminal entry of exudate the epithelial lining was intact, as judged by light, fluorescence and electron microscopy. Hence, the epithelial barrier was reversibly permeable when approached from beneath by the plasma exudate. This was a distinct increase in outward permeability, because even during the exudation of plasma the mucosa remained a barrier to luminal solutes. It is possible that the exudate itself, by a slight compressive action on the basolateral aspect of epithelial cells, creates intercellular pathways for its entry into the lumen. Contrary to current beliefs, we propose that plasma exudation should be considered a first line respiratory defence mechanism operating together with other systems of the mucosal surface.

Absorption↗
PubMed1991

Allergen, bradykinin, and capsaicin increase outward but not inward macromolecular permeability of guinea-pig tracheobronchial mucosa.

When inflammatory stimuli are applied on the airway mucosa, plasma is promptly extravasated from the subepithelial microvessels. The plasma exudate distributes in the lamina propria and much of it is soon transmitted across the epithelial lining. The rapid luminal entry of large plasma solutes must reflect a dramatic change in mucosal permeability. Previously it has been thought that such a perviousness of the mucosal barrier would be bidirectional in nature. This study in anaesthetized guinea-pigs examines whether absorption across the mucosa is increased (above control) during, and immediately after, the plasma exudation process. An oral catheter, introduced into the tracheal lumen, was used to superfuse the lower airways with 0.04 ml of a solution containing the absorption tracer 131I-albumin and a selected dose of a provocating agent: allergen, 3 pmol (ovalbumin in IgE-sensitized animals); bradykinin, 5 nmol; capsaicin, 0.4 nmol; or carbachol, 8 nmol. The superfusate had a desired distribution on the tracheobronchial mucosa so that specific airway and not bronchoalveolar exudation:absorption ratios could be determined. In separate experiments it was confirmed that the present provocations, except carbachol (P greater than 0.05), moved significant amounts of plasma into the airway lumen (P less than 0.001). This was distinctly an increase in the outward mucosal permeability because the absorption of luminal 131I-albumin into circulating plasma was not significantly different from control with any of the provocations (P greater than 0.05). The present data support our notion that unfiltered plasma exudates can operate on the mucosal surface, in first-line defence reactions, without compromising the integrity of the epithelial lining as a barrier to luminal material.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Toluene diisocyanate produces an increase in airway tone that outlasts the inflammatory exudation phase.

Toluene diisocyanate (TDI) is a causative agent in occupational asthma. Through an oral catheter TDI, 0.03 microliters, dissolved in 0.02 ml olive oil, was superfused on the tracheobronchial mucosa of anaesthetized guinea-pigs. TDI induced plasma exudation into both airway tissue and lumen (peak effect: 5 hr; duration approximately 17 hr). Light microscopy examinations demonstrated that the epithelium was not disrupted by this process (and that microvessels are abundant just beneath the epithelium). At days 6 and 21 after exposure to TDI PAS-positive cells were increased, but no other histological alterations were found. Also, the occurrence of peptide-containing nerve fibres was not altered by TDI. After TDI-exposure the airway smooth muscle tone was elevated as examined in vitro at base-line and at concentration-response to carbachol. The largest increases in tone were recorded 21 days after exposure to TDI. The abnormally large tone was not associated with an increased thickness of the smooth muscle layer nor was it associated with reduced effects of either beta 2-agonist (terbutaline) or xanthine- (theophylline) relaxants. It is concluded that TDI-induced plasma exudation into guinea-pig airways occurs for 17 hr without disrupting the epithelial lining and without causing major changes in the airway peptidergic innervation. Both the airway tone, and the number of mucous cells, are increased for at least 3 weeks after exposure to TDI.

Airway Resistance↗
PubMed1991

Effects of airway luminal concentration of albumin on histamine-induced mucosal exudation of radio-iodine labelled albumin.

In an in vivo study of guinea-pig airway barriers we have examined the effects of the luminal concentration of albumin on exudation (outward) and absorption (inward) permeabilities to radio-iodine labelled albumin. Previously validated techniques for superfusion of solutes onto the tracheobronchial mucosal surface and for subsequent tracheal lavage were employed. [125I]albumin was administered intravenously as plasma tracer and [131I]albumin was superfused topically as absorption tracer. Histamine (5.0 nmol) was superfused onto the mucosal surface together with the absorption tracer and in the presence of different albumin concentrations (0.3, 3.0 and 30 mg ml-1). The experiment was terminated 10 minutes after the tracheal mucosal superfusion and samples of plasma and tracheal lavage fluid were collected. The mucosal exudation response was calculated from the detection of [125I]albumin in the airway lumen. The absorption ability of the mucosa was determined by the detection of [131I]albumin in circulating plasma. Histamine induced a significant mucosal exudation of [125I]albumin. This effect was unaffected by the level of albumin on the mucosal surface. There was a small but significant absorption of [131I]albumin in the presence of 0.3 and 3.0 mg ml-1 of albumin in the luminal liquid. An albumin concentration of 30 mg ml-1 markedly increased the rate of absorption of [131I]albumin. However, the absorption rate was not affected by the histamine-induced mucosal exudation process at any level of luminal albumin. The present data further demonstrates that plasma exudation and mucosal absorption are independent processes. The data are in keeping with the view that an increased subepithelial hydrostatic pressure moves the plasma exudate across the mucosa as a distinct outward process.

Absorption↗
PubMed1991

Effects of histamine, ethanol, and a detergent on exudation and absorption across guinea pig airway mucosa in vivo.

This study examined effects of three substances that cause mucosal provocation (histamine, ethanol, and the detergent dioctylsodium sulphosuccinate (DOSS] on the flux of solutes across airway vascular mucosal barriers in anaesthetised guinea pigs. The inward flux was assessed as absorption of iodine-131 labelled albumin (MW 69,000) from the tracheobronchial surface into the circulation and the outward flux as the exudation of two intravenously administered plasma tracers--125I albumin (MW 69,000) and fluorescein isothiocyanate conjugated (FITC) dextran (MW 70,000)--into the airway. The absorption of technetium-99m labelled DTPA (MW 492) from the tracheobronchial airways was determined in separate experiments. Histamine (5.0 nmol) dissolved in 40 microliters saline and superfused on the tracheobronchial mucosal surface caused significant and similar entry of 125I albumin and FITC dextran into the airway lumen. This dose of histamine did not, however, alter the absorption of small (99mTc DTPA) or large (131I albumin) solutes across the airway mucosa. Ethanol (0.17 mumol), superfused in the same way, also caused significant exudation of the plasma tracers into the airway lumen. In addition, ethanol increased the absorption of 131I albumin without causing change in the disappearance rate of 99mTc DTPA. The detergent, DOSS (0.28 nmol), dissolved in ethanol (0.17 mumol), caused a pronounced increase in exudation and much increased absorption of small and large tracer solutes. Thus three patterns of change in airway mucosal barriers were found. The agents that are toxic to membranes, ethanol and DOSS, caused a bidirectional increase in permeability across the mucosa, whereas histamine caused only an outward exudative flux. The results obtained with histamine are similar to those seen previously with bradykinin, capsaicin, and allergen, suggesting that endogenous inflammatory mediators have a role in mucosal defence, producing entry of plasma exudates into the airway lumen without increasing the mucosal absorption of luminal material.

Absorption↗
PubMed1991

Laser-Doppler measurement of tracheal mucosal blood flow: comparison with tracheal arterial flow.

Blood flow in the tracheal mucosa (Qm) has been measured by laser-Doppler flowmetry in anesthetized sheep and dogs. The values have been compared with tracheal arterial inflow (Qtr) by use of an electromagnetic flow probe and with tracheal arterial perfusion pressure (Ptr) produced by mechanical perfusion. Changes in blood flow were caused by injections of methacholine, phenylephrine, and histamine into the perfusion circuit. These interventions produced a range of measurements for each animal. Correlations of Qm against Qtr were significant in two of five animals (R = 0.03-0.93); correlations of Qm against Ptr were significant in two of four animals (R = 0.56-0.96). Percent changes in Qtr were generally much larger than those of Qm, and there was considerable variability between Qm and either Qtr or Ptr. Qm reflected the same vascular changes as Ptr or Qtr in 28 interventions and showed an opposing change in 4 cases. In 11 interventions, changes measured by Ptr or Qtr were not reflected by any changes in Qm. Thus qualitative changes in tracheal perfusion measured with these methods were usually the same; quantitatively the three methods showed great differences. These differences may reflect different regulatory mechanisms in various components of the tracheal vasculature or different technical aspects of the methods used.

Animals↗
PubMed1991

Pharmacologic control of plasma exudation into tracheobronchial airways.

We have employed anesthetized guinea pigs to examine effects of nonsteroidal antiasthma drugs on airway plasma exudation, which is a process of potential pathogenetic importance in asthma. This study focused on exudation of plasma into the airway luman (circumventing problems with a changing blood pool in tissue samples). Topical tracheal superfusions with a neurogenic agent (capsalcin), bradykinin, and histamine increased mucosal blood flow (Laser Doppler flowmetry) and produced significant exudation of macromolecular plasma tracers (fluorescein-labeled dextran 156000 D; 131I-albumin 70,000 D). Lidocaine 3 x 10(-5) M, applied topically, inhibited capsalcin- but not bradykinin-induced plasma exudation. Intravenously administered terbutaline, enprofylline, and theophylline and topical cromoglycate dose-dependently inhibited the inflammatory stimuli-induced mucosal exudation of plasma. Cromoglycate did not alter airway blood flow, and both terbutaline and enprofylline increased the blood flow. Hence, these three types of drugs did not inhibit exudation by stopping flow. Further, both neural and non-neural exudative responses were inhibited, suggesting that the drugs may have acted directly on the permeability-regulating microvascular endothelial cells. It is proposed that antiexudative actions may contribute to the antiasthma effects of beta 2-agonists, xanthines, and cromoglycates.

Animals↗
PubMed1991

Long duration and high potency of antiexudative effects of formoterol in guinea-pig tracheobronchial airways.

Inflammatory stimulus-induced luminal exudation of plasma proteins is potentially pathogenic in asthma. This study of plasma exudation into tracheobronchial airways examines antiexudative effects (potency and duration of action) of two beta 2-agonists in anesthetized guinea pigs. The exudative response to airway provocations with bradykinin 1.25 x 10(-4) M (5 nmol) was determined in different groups of animals 10, 300, 450, and 600 min, respectively, after the mucosa had been treated topically with salbutamol 10(-6) to 10(-4) M (0.1 to 10 nmol), formoterol 10(-9) to 10(-7) M (0.1 to 10 pmol), or saline (control). Exuded plasma in tracheal lavage liquids was calculated from their contents of the plasma tracer, 125I-albumin, given intravenously 10 min before provocation with bradykinin. Salbutamol (1 and 10 nmol) and formoterol (1 and 10 pmol) promptly inhibited the mucosal exudation (p less than 0.001). Propranolol, 0.1 nmol, reduced (p less than 0.01) the antiexudative effects of both drugs. Only formoterol (1 and 10 pmol) maintained its effect at 300 min, abating gradually at 450 and 600 min. In a group of sensitized guinea pigs, formoterol (1 and 10 pmol) was demonstrated to inhibit also allergen-induced luminal exudation of plasma (p less than 0.001). It is suggested that an antiexudative action may contribute to the long duration of formoterol's antiasthma effect.

Adrenergic beta-Agonists↗
PubMed1990

On the use of absorbing discs to sample mucosal surface liquids.

A common technique to sample airway mucosal 'surface' liquids is with absorbing discs of filter paper. The present study examined the efficacy of this technique by analysing tracheal liquids of control and capsaicin (0.1 nmol)-exposed guinea-pig airways. Mucosal fluids, obtained by topically applied discs or by a specific lavage procedure, and tracheal tissue were sampled. The animals had received FITC-dextran (MW 70 kDa) intravenously and this specific plasma tracer was analysed in the sampled material. Under control conditions significantly more FITC-dextran was found in the discs than in the tracheal lavage fluids (P less than 0.001) despite the fact that the lavaged mucosal surface was much larger than that covered by the discs. Capsaicin significantly increased the content of FITC-dextran in all fluids sampled as well as in the airway tissue. In all cases concentrations of FITC-dextran in the disc fluids did not differ much from that in the tissue samples. These data suggest that absorbing discs severely disturb the epithelial-barrier function and sample subepithelial fluid and solutes including macromolecules. As demonstrated in this study by the elevated content of a plasma tracer molecule an inflammatory process may, nevertheless, be traced in the mixture of surface and tissue fluids that is sampled by the discs.

Absorption↗
PubMed1990

Clearance of 99mTc DTPA from guinea pig nasal, tracheobronchial, and bronchoalveolar airways.

Technetium-99m labelled diethylenetriamine penta-acetate (99mTc-DTPA) was used to compare small solute absorption (clearance) from nasal, tracheobronchial, and bronchoalveolar airways in anaesthetised guinea pigs. 99mTc DTPA dissolved in saline was superfused through nasal and orolaryngeal catheters on to nasal and tracheobronchial airways; a small particle aerosol of nebulised 99mTc DTPA was delivered to the bronchoalveolar airways through a tracheostomy. Radioactivity over the appropriate region was then determined with a gamma camera. Mucociliary transport of 99mTc DTPA appeared not to contribute to the disappearance of 99mTc DTPA. Time-activity curves were obtained and half life values calculated by fitting a monoexponential equation to the experimental data. A progressive reduction in 99mTc DTPA was recorded from the nasal and tracheobronchial airways and from the bronchoalveolar airway, suggesting that absorption was occurring. The disappearance of 99mTc DTPA was fastest from the bronchoalveolar region, which also had the largest mucosal surface. The similar shape of the retention curves for the nasal and tracheobronchial regions suggests that the characteristics of nasal absorption of 99mTc DTPA could prove applicable to the tracheobronchial region. It is proposed that the present methods are suited for comparing the pharmacology of small solute absorption across nasal, tracheobronchial, and bronchoalveolar airway mucosa.

Absorption↗
PubMed1990

The airway epithelial lining in guinea pigs is intact promptly after the mucosal crossing of a large amount of plasma exudate.

In the present study of anaesthetized guinea pigs, we have confirmed by chemical analyses that 10 min after topical mucosal provocation with capsaicin 0.4 nmol of platelet-activating factor 8 nmol plasma macromolecular tracers (FITC-dextran, molecular weight 156 kD, previously injected intravenously) have been significantly exuded into airway tissue and lumen. We have also examined the airway mucosa and the mucosal surface material using fluorescence, light, and electron microscopy. Thus we have demonstrated by histological techniques that promptly after the induction of large exudative responses plasma macromolecules are abundant in the lumen as well as in the lamina propria. Furthermore, the exudate is seen on the surface of a mucosa that has an intact epithelial lining. These observations are evidence in favour of the possibility that plasma exudation into the lumen is a first-line defense mechanism of the normal airway mucosa.

Animals↗
PubMed1990

Subepithelial hydrostatic pressure may regulate plasma exudation across the mucosa.

This study demonstrated in guinea pig tracheal tubes in vitro that small increases in serosal hydrostatic pressure caused significant mucosal crossing of serosal macromolecules. Reversibility and repeatability of this passage agree with inflammatory stimulus-induced appearance of exuded plasma in airway lumen in vivo. Bradykinin, histamine, and terbutaline, which induce and inhibit, respectively, plasma exudation in vivo, were without effect on the present in vitro permeability. Carbachol, similar to histamine, contracted the trachea, and did not increase, but rather decreased the pressure-induced luminal entry of serosal macromolecules. It is proposed that a plasma-exudation-induced hydrostatic pressure load transiently separates epithelial cells, providing a direction-selective and non-injurious intercellular pathway for passage of bulk plasma exudate into the airway lumen. This mechanism would allow potent plasma protein systems to operate on mucosal surfaces at sites of insults without compromising the mucosa as a barrier to luminal solutes.

Animals↗
PubMed1990

Early and late tracheobronchial plasma exudation by platelet-activating factor administered to the airway mucosal surface in guinea pigs: effects of WEB 2086 and enprofylline.

The effects of the platelet-activating factor (PAF) antagonist, WEB 2086, and the xanthine, enprofylline, on PAF-induced plasma exudation in tracheobronchial airways has been studied in guinea pigs. Superfusion of PAF (4 nmol) onto the tracheal mucosal surface caused a significant exudation of the i.v. plasma tracers [131I]albumin and fluorescein isothiocyanate-dextran (fluorescein-labeled dextran MW 156 kDa) during the first 15 min after PAF (early response) and also 5 hr later (late response). The early, but not the late, response could be identified histologically by a particulate tracer (carbon given i.v.) which was trapped in submucosal leaky vessels. WEB 2086 [3 mg (6.6 mumol)/kg] caused significant attenuation of both the early plasma exudative response (with loss of carbon-labeled vessels) and the late plasma exudative response to PAF. The late response was equally well attenuated by enprofylline [4.85 mg (25 mumol)/kg] given before PAF. It is concluded that PAF-induced late (as well as early) plasma exudative responses in guinea pig tracheobronchial airways are the result of specific receptor activation by topical PAF and that the antiasthma xanthine enprofylline can inhibit this PAF-induced late response. Our data suggest that particulate tracers, such as carbon, cannot detect microvessels involved in the ongoing late phase exudative response to PAF.

Animals↗
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↗
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↗