Biomedical subjects

M E Strek

Publications and source records attributed to M E Strek.

8 recordsLinked to original sources

PubMed2001

Consensus guidelines for asthma therapy.

OBJECTIVE: This article provides information on the consensus reached by the Antileukotriene Working Group on the role of leukotriene (LT) modifiers in the treatment of asthma. DATA SOURCES: Relevant and appropriate controlled clinical studies were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals and appropriate reviews. RESULTS: Only limited use of LT-modifying agents has been recommended in recently published guidelines of the National Asthma Education and Prevention Program and the National Heart, Lung, and Blood Institute. Consequently, the Antileukotriene Working Group was convened to arrive at a consensus on the wider use of LT modifiers in the treatment of asthma. The group' s purpose was 2-fold: to review and disseminate information on the role of LT modifiers in clinical practice. As determined by the group, a thorough understanding of the patient's disease, patient education, and an effective patient-clinician relationship are key elements in overall patient management. CONCLUSIONS: Based on evidence from clinical trials and expert opinions of participants comprising the Antileukotriene Working Group, LT-modifying agents potentially may be used as first-line therapy, in combination regimens, and as an alternative to inhaled corticosteroids in the treatment of asthma.

Asthma↗

PubMed1996

Mechanisms of smooth muscle contraction elicited by cationic proteins in guinea pig trachealis.

Cationic proteins elicit contraction of airway smooth muscle, but the mechanisms by which this occurs are not completely understood. We studied potential mechanisms by which eosinophil major basic protein (MBP) and the synthetic cationic proteins poly-L-lysine (PL) and poly-L-arginine (PA) cause contraction of isolated guinea pig tracheal smooth muscle (TSM) in vivo. Topical application of 10(-8) mol/cm2 of each protein to an isolated tracheal segment elicited TSM contraction with potency PL > MBP > PA. Pretreatment with atropine blocked the subsequent response to MBP but did not block the response to either PL or PA. Pretreatment with indomethacin blocked the subsequent response to both MBP and PL but did not block the response to PA. We demonstrate that MBP causes contraction of guinea pig TSM both through stimulation of the parasympathetic nervous system and secretion of a cyclooxygenase mediator. Neither PL nor PA, while of similar molecular weight and charge as MBP, cause TSM contraction via the parasympathetic nervous system, though some cationic proteins may act via a prostanoid mediator. Thus the cationic charge of MBP is not solely responsible for its effects on TSM in the guinea pig.

Acetylcholine↗

PubMed1993

Effect of mode of activation of human eosinophils on tracheal smooth muscle contraction in guinea pigs.

We studied the relationship between mode of activation of isolated human eosinophils and in situ responsiveness in isolated tracheal smooth muscle (TSM) of guinea pigs. Human peripheral blood eosinophils were activated with either 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M formyl-methionyl-leucyl-phenylalanine (fMLP) + 5 micrograms/ml cytochalasin B (CYB), and activation was confirmed by measurement of eosinophil peroxidase (EPO) secretion by kinetic assay. EPO secretion was similar after activation with fMLP+CYB (10.2 +/- 3.2% of total eosinophil content) and PMA (10.0 +/- 2.8% of total content; P = NS). Topical application of 6 x 10(6) eosinophils/cm2 activated with fMLP+CYB to the TSM segment caused 0.51 +/- 0.14 g/cm active tension (AT) in five preparations (P < 0.03 vs. baseline); cells activated with PMA caused no contractile response (0.04 +/- 0.03 g/cm AT, P = NS vs. baseline). Both PMA- and fMLP+CYB-activated cells caused augmentation of muscarinic responsiveness of guinea pig trachealis. The dose of intravenous acetylcholine required to cause a threshold response (ED0.3) was -7.3 +/- 0.1 log mol/kg at baseline vs. -8.7 +/- 0.5 log mol/kg after treatment with fMLP+CYB-activated eosinophils (P = 0.05) and -6.9 +/- 0.1 log mol/kg at baseline vs. -7.5 +/- 0.1 log mol/kg after PMA-activated cells (P < 0.01). Both AT and augmented muscarinic responsiveness were blocked by pretreating the eosinophils with 200 microM A-63162, an inhibitor of 5-lipoxygenase, before activation with fMLP+CYB. We demonstrate that eosinophils activated comparably (as assessed by EPO secretion) cause augmented muscarinic responsiveness and/or direct contraction of guinea pig TSM through secretion of a product of the 5-lipoxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗

PubMed1993

Effects of activated eosinophils cultured from human umbilical cord blood on guinea pig trachealis.

We studied the biochemical indexes and corresponding induction of airway smooth muscle contraction and hyperresponsiveness in guinea pig trachealis in situ caused by cultured eosinophils derived from mononuclear cell fractions of human umbilical cord blood. A method was developed that permitted isolation of large numbers of cells (approximately 2.6 x 10(6)/ml cord blood) having morphological and immunohistological characteristics of human peripheral blood eosinophils. After activation with 10(-6) M formyl-Met-Leu-Phe + 5 micrograms/ml cytochalasin B (fMLP + B), in situ application to the epithelial surface of 6 x 10(6) cord-derived eosinophils (CDE)/surface area (cm2) caused 1.46 +/- 0.24 g/cm maximal active tracheal tension in guinea pig tracheal smooth muscle (P < 0.005 vs. zero baseline). Muscarinic responsiveness also was augmented in situ in trachealis preparations treated with activated 3-wk CDE. Contraction caused by 3 x 10(-7) mol/kg iv methacholine (MCh) was 0.94 +/- 0.18 g/cm at baseline vs. 1.80 +/- 0.24 g/cm after activated CDE (P = 0.02). Control (sham-activated) 3-wk CDE caused neither significant contraction [0.41 +/- 0.16 g/cm active tension (AT); P < 0.05 vs. fMLP+B] nor augmented muscarinic responsiveness. Cells cultured for 5 wk contained fewer granules than 3-wk CDE and also caused less direct contraction of trachealis (0.73 +/- 0.14 g/cm AT) after activation (P < 0.01 vs. 3-wk CDE). Both contraction and muscarinic augmentation were blocked in 3-wk CDE after blockade of leukotriene C4 (LTC4) synthesis by pretreatment with the 5-lipoxygenase inhibitor, A63162 (50 microM). Treatment with A63162 had no effect on the stimulated release of eosinophil peroxidase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Physiologic significance of epithelial removal on guinea pig tracheal smooth muscle response to acetylcholine and serotonin.

We studied the modulatory effect of airway epithelium on guinea pig tracheal smooth muscle (TSM) contraction. Isometric force was measured in vivo before and after removal of the tracheal epithelium. In parallel studies, TSM contraction was also measured isometrically in epithelium-intact and epithelium-denuded TSM strips in vitro. Epithelial removal in vivo did not alter the contractile response of TSM to acetylcholine (ACh) or serotonin. In nine guinea pigs, active tension (AT) caused by 3 x 10(-7) mol/kg of intravenous ACh was 0.74 +/- 0.14 g force per longitudinal length of the segment (g/cm) in the presence of epithelium versus 0.89 +/- 0.16 g/cm after removal of airway epithelium (confirmed histologically) (p NS). The threshold response to ACh was also unchanged (-8.0 +/- 0.3 log mol/kg control versus -8.3 +/- 0.3 log mol/kg after epithelial removal, p NS). In six guinea pigs, the AT caused by 3 x 10(-8) mol/kg of intravenous serotonin was 1.92 +/- 0.63 g/cm with an intact epithelium versus 2.15 +/- 0.70 g/cm after epithelial removal in vivo (p NS). Epithelial removal in vitro increased the sensitivity of TSM contraction to ACh when the data were expressed as the percentage maximal response to ACh. The concentration of ACh causing 50% of the maximal response (EC50) was -5.74 +/- 0.25 log M in eight epithelium-intact TSM strips versus -6.37 +/- 0.16 log M after epithelial removal in controls (n = 8) (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1993

Regulation of human eosinophil degranulation and activation by endogenous phospholipase A2.

The unique granular proteins of eosinophils may have a pathogenetic role in asthma and in the defense against parasitic infestations. However, the mechanisms regulating eosinophil degranulation are largely unknown. We examined the hypothesis that release of these proteins is regulated by endogenous activation of phospholipase A2. Human eosinophils (HE) were isolated from the peripheral blood of 42 subjects either by Percoll density separation or by negative-selection immunomagnetic fractionation. Eosinophil activation was initiated in vitro with 10(-6) M FMLP and 5 micrograms/ml cytochalasin B and was assessed by measurement of eosinophil peroxidase (EPO), leukotriene C4 (LTC4) and superoxide radical (.O2-) secretion. Treatment of HE with 100 microM mepacrine before activation blocked EPO release (2.0 +/- 0.2 vs 10.2 +/- 2.1% cell content for activated HE, P < 0.004, n = 9), .O2- generation (2.6 +/- 0.9 vs 44.2 +/- 10.8 nmol/ml per 10(6) HE, P < 0.002, n = 5), and LTC4 secretion (68.2 +/- 32.2 vs 1,125.2 +/- 526.8 pg/ml per 10(6) HE, P < 0.04, n = 8). Pretreatment of HE with 100 microM 4-bromophenacyl bromide before activation similarly blocked EPO release, .O2- generation and LTC4 secretion. Addition of AA to HE after treatment with 100 microM mepacrine and before subsequent activation reversed the inhibition of both EPO (10.4 +/- 2.2% with 1 microM AA vs 2.0 +/- 0.2% for mepacrine, n = 5, P < 0.02) and LTC4 secretion (695.1 +/- 412.9 with 10 microM AA vs 68.2 +/- 32.2 pg/ml per 10(6) HE for mepacrine, n = 8, P < 0.04), but did not reverse inhibition of .O2- generation by mepacrine. We demonstrate that secretion of preformed cytotoxic proteins and .O2- by eosinophils is regulated endogenously by phospholipase A2.

Acetophenones↗

PubMed1992

Direct effects and augmentation of airway smooth muscle contraction caused by phospholipase A2.

We examined the effect of phospholipase A2 (PLA2; Naja naja) on isometric tracheal smooth muscle force generation in guinea pig trachealis in situ. Direct application of PLA2 to the surface of the trachea caused dose-related contraction of tracheal smooth muscle. In seven guinea pigs, a dose/density of 100 micrograms/cm2 PLA2 caused active tension (AT) that began immediately and was maximum (1.32 +/- 0.13 g/cm) at 5 min (p less than 0.01 versus baseline tension). PLA2 also augmented the contractile response to intravenously administered acetylcholine (ACh); AT caused by 3 x 10(-7) mol/kg ACh was 0.98 +/- 0.13 g/cm after PLA2 versus 0.64 +/- 0.09 g/cm in control animals (p = 0.003). PLA2 inactivated with bromophenacyl bromide (BPB) prior to topical application neither caused contraction (-0.18 +/- 0.18 g/cm AT, p = NS versus baseline tension) nor altered muscarinic responsiveness to 3 x 10(-7) mol/kg ACh. Contraction caused by 100 micrograms/cm2 PLA2 was greater after epithelium removal (2.73 +/- 0.40 g/cm AT versus 1.32 +/- 0.13 g/cm AT in epithelium-intact animals, p less than 0.005). However, epithelium removal (confirmed histologically) attenuated completely augmentation of muscarinic contraction caused by PLA2. Augmentation of muscarinic contraction also was blocked with 15 mg/kg 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline hydrochloride (BW 755c), an inhibitor of eicosanoid synthesis, administered intravenously 30 min prior to topical application of 100 micrograms/cm2 PLA2. In contrast, contraction of tracheal smooth muscle caused by PLA2 was not affected significantly by blockade of eicosanoid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1991

Effects of PAF on isolated rat airways perfused with blood-free solution.

We examined the mechanism of constriction and muscarinic augmentation of contraction of airway smooth muscle caused by platelet-activating factor (PAF) in airways from 55 Sprague-Dawley rats perfused through the isolated bronchial circulation (BC) and pulmonary circulation (PC) and isometrically in tissue perfusion chambers. Dose-response curves were generated cumulatively by infusing 10(-10) to 10(-7) mol PAF dissolved in Krebs-Henseleit solution buffer containing 4% bovine serum albumin into the BC or PC. The efficacy of PAF in central airways (BC) was approximately twofold greater in increasing lung resistance (RL) than for more peripheral airways perfused by the PC (P less than 0.05). Tachyphylaxis was demonstrated in both BC and PC for preparations in which a second PAF dose-response curve was generated. Bolus injection of 10(-6) mol of the PAF antagonist, CV-6209, plus 10(-7) mol PAF caused 81% reversal of the maximal BC response. The same dose of CV-6209 reversed the response to PAF in the PC by 99.2%. Initial administration of 10(-6) mol CV-6209 with PAF prevented completely contraction elicited by PAF in the BC and PC. Concentration-response studies also were generated isometrically in tissue perfusion chambers from 64 tracheal smooth muscle strips. Maximal contraction elicited by 10(-6) M PAF was blocked completely with 10(-6) M CV-6209. In separate studies, addition of 10(-6) mol CV-6209 to the BC perfusate caused 93% blockade of the RL response to PAF and 100% inhibition when administered in the PC. Prior administration of PAF caused two- to fourfold augmentation of the contractile response to acetylcholine (ACh) within the same preparation; in the presence of CV-6209, the response to ACh was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗