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J A Nadel

Publications and source records attributed to J A Nadel.

At least 55 records · Page 3Linked to original sources
PubMed1998

Goblet cell degranulation after antigen challenge in sensitized guinea pigs. Role of neutrophils.

Mucus hypersecretion is a common characteristic of asthma. Acute severe asthma is often associated with neutrophilic infiltration into airways. Neutrophils contain elastase, a potent secretagogue in airways. Therefore, we hypothesized that instillation of ovalbumin in sensitized guinea pigs causes goblet cell secretion by releasing elastase from recruited neutrophils. When we instilled ovalbumin into the trachea of ovalbumin-sensitized guinea pigs, early recruitment of neutrophils identified by 3,3'- diaminobenzidine staining, and goblet cell degranulation measured with a semiautomatic computer-based imaging system occurred. The Leumedin NPC 15669 (a drug that inhibits leukocyte recruitment) and an antibody to intercellular adhesion molecule-1 (ICAM-1) both prevented neutrophil recruitment and goblet cell degranulation, implicating leukocytes in the response. Using immunofluorescence we showed that the leukocytes recruited early after antigen challenge were CD-16-positive, implicating neutrophils. Pretreatment with the selective neutrophil elastase inhibitor ICI 200,355 also prevented ovalbumin-induced goblet cell degranulation, implicating elastase. We conclude that ovalbumin-induced goblet cell degranulation is due to neutrophil recruitment and elastase release.

3,3'-Diaminobenzidine↗
PubMed1997

PACAP-induced plasma extravasation in rat skin.

The effects of pituitary adenylate cyclase activating peptide (PACAP) 38, PACAP 27 and vasoactive intestinal peptide (VIP) on plasma extravasation were investigated in vivo in rat skin. PACAP 38, PACAP 27 and VIP, caused concentration-dependent extravasation in rat skin. The order of potency was PACAP 38 > PACAP 27 = VIP, whereas the order of maximal induced extravasation was PACAP 38 = PACAP 27 > VIP, suggesting that PACAP 38 might be the most powerful inducer of plasma extravasation of the three tested members of the secretin-glucagon-VIP family. Substance P (SP) was about 5 times more potent than PACAP 38 and 15 times more potent than PACAP 27. These data indicate that PACAP 38 induced plasma extravasation in concentrations roughly equimolar to SP. Pyrilamine (H1 receptor antagonist) reduced the PACAP 38-induced plasma extravasation more than 50%; cimetidine (H2 receptor antagonist) was without effect. To investigate whether a cAMP-mediated process is involved in the induction of plasma extravasation, the synthetic adenosine 3',5'-cyclic monophosphate (cAMP), dibutyryl adenosine cyclic monophosphate (DBcAMP) and the cAMP-inducing drug, salbutamol, were each injected in the skin; neither of these drugs caused extravasation. We conclude that PACAP 38 and PACAP 27 cause potent plasma extravasation which, at least in part, involves histamine release.

Albuterol↗
PubMed1997

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease.

An unresolved question in cystic fibrosis (CF) research is how mutations of the CF transmembrane conductance regulator, a Cl ion channel, cause airway mucus obstruction leading to fatal lung disease. Recent evidence has linked the CF transmembrane conductance regulator mutation to the onset and persistence of Pseudomonas aeruginosa infection in the airways, and here we provide evidence directly linking P. aeruginosa infection to mucus overproduction. We show that P. aeruginosa lipopolysaccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this effect is blocked by the tyrosine kinase inhibitors genistein and tyr-phostin AG 126. These findings improve our understanding of CF pathogenesis and suggest that the attenuation of mucin production by lipopolysaccharide antagonists and tyrosine kinase inhibitors could reduce morbidity and mortality in this disease.

Benzylidene Compounds↗
PubMed1997

Functional type II VIP-PACAP receptors in human airway epithelial-like cells.

VIP-PACAP receptors were characterized in a human airway epithelial-like cell line (Calu-3), Pituitary adenylate cyclase activating polypeptide (PACAP) 1-27, PACAP 1-38, vasoactive intestinal polypeptide (VIP) and the beta 1- and beta 2-adrenoceptor agonist isoproterenol (3 nM-1 microM) increased cAMP concentration dependently. The peptides and isoproterenol displayed similar potencies (range of means pEC50[M]: 6.5-7.1). The maximum increase in cAMP (Emax in % of basal cAMP level) was similar for the peptides (range of means Emax: 2500-5100%). Pretreatment with the peptidase inhibitors captopril (10 microM) and phosphoramidon (1 microM) significantly increased the cAMP response to PACAP 1-38 (to 480% of control) only.

Captopril↗
PubMed1997

Long lasting smooth muscle relaxation by a novel PACAP analogue in guinea-pig and primate airways in vitro.

1. We compared the relaxant effect of pituitary adenylate cyclase activating peptide (PACAP) 1-27 with that of a newly developed PACAP 1-27 analogue, [Arg15,20,21Leu17]-PACAP-Gly-Lys-Arg-NH2, in the guinea-pig trachea and primate bronchi in vitro (n = 4-5). 2. In the guinea-pig trachea precontracted by a submaximally effective carbachol concentration (0.1 microM), cumulative administration of PACAP 1-27 and the beta 2-adrenoceptor agonist salbutamol (3 nM-3 microM) caused significant and concentration-dependent smooth muscle relaxation, with salbutamol being approximately one log-step more potent in this model. However, in primate bronchi precontracted by carbachol (0.1 microM), cumulative administration of PACAP 1-27 and salbutamol caused concentration-dependent smooth muscle relaxation with very similar potencies and maximum relaxant effects. 3. In the guinea-pig trachea, non-cumulative administration of the PACAP 1-27 analogue and the original PACAP 1-27 (0.3-3 microM) caused concentration-dependent relaxation with a very similar maximum relaxant effect and potency. However, the onset and offset of action was markedly slower for the PACAP 1-27 analogue than for the original PACAP 1-27 (< 90% versus < 10% of peak relaxation remaining 6 h after administration). Separate experiments confirmed that the PACAP 1-27 analogue also caused significant relaxation with slower onset and offset of action than did the original PACAP 1-27 in primate bronchi. 4. Peptidase inhibition by captopril (10 microM) and phosphoramidon (1 microM) significantly increased the maximum relaxant effect and duration of action of PACAP 1-27 but not of the PACAP 1-27 analogue, during the 3 h of observation in the guinea-pig trachea. 5. We conclude that [Arg15,20,21Leu17]-PACAP-Gly-Lys-Arg-NH2 produces significant, concentration-dependent and sustained airway smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the PACAP 1-27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP 1-27.

Albuterol↗
PubMed1997

A method for canine nasal mucosa superfusion, in vivo; evidence that pseudomonas-induced neutrophil migration is inhibited by alpha2-adrenoceptor agonist.

METHODS AND RESULTS: A method for isolating and superfusing a segment of the nasal cavity in the anaesthetized dog was developed. Introduction of Pseudomonas aeruginosa supernatant (PA), which is known to induce IL-8 release, resulted in a marked time-dependent exponential increase in neutrophil recruitment to the nasal chamber. When oxymetazoline (final concentration, 10(-5) M), was added to the superfusate, the PA induced-neutrophil migration was inhibited; the addition of benzalchoniul chloride to the superfusate had no effect on the PA induced-neutrophil migration. CONCLUSION: We conclude that a alpha2 adrenoceptor agonist profoundly inhibits neutrophil migration in response to bacterial products. Our novel method allows continuous introduction of stimuli and monitoring of responses in the nasal mucosa.

Adrenergic alpha-Agonists↗
PubMed1996

Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma.

BACKGROUND: Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma. METHODS: The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants. FINDINGS: The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine. INTERPRETATION: The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.

Adult↗
PubMed1996

Increased liposome extravasation in selected tissues: effect of substance P.

We have used a pharmacologic mediator to open intercellular connections in selected vessels to allow liposomes to escape from the blood stream and to extravasate into tissues that have appropriate receptors. We have examined the effects of substance P (SP), a peptide known to increase vascular permeability in selected tissues, such as trachea, esophagus, and urinary bladder in rats. We used quantitative fluorescence analysis of tissues to measure two fluorescent markers, one attached to the lipid (rhodamine-phosphatidylethanolamine) and another, doxorubicin (an anti-tumor drug), encapsulated within the aqueous interior. We have also examined the deposition of liposomes microscopically by the use of encapsulated colloidal gold and silver enhancement. Analysis of the biochemical and morphological observations indicate the following: (i) Injection of SP produces a striking increase in both liposome labels, but only in tissues that possess receptors for SP in postcapillary venules; (ii) liposome material in these tissues has extravasated and is found extracellularly near a variety of cells beyond the endothelial layer over the first few hours; (iii) 24 h following injection of liposomes and SP, liposome material is found in these tissues, localized intracellularly in both endothelial cells and macrophages. We propose that appropriate application of tissue-specific mediators can result in liposome extravasation deep within tissues that normally do not take up significant amounts of liposomes from the blood. Such liposomes are able to carry a variety of pharmacological agents that can be released locally within selected target tissues for therapeutic purposes.

Animals↗
PubMed1996

Cold air-induced bronchoconstriction is mediated by tachykinin and kinin release in guinea pigs.

In the present study, we investigated the role of acetylcholine, tachykinins and kinins in the bronchoconstriction induced by cold air inhalation. Cold air was delivered to anaesthetised, artificially ventilated guinea pigs through a tracheal cannula. Inhalation of cold air increased the maximum total pulmonary resistance (RL) in a time-dependent manner, reaching a maximum after 15 min of exposure. The increase in RL induced by exposure to cold air for 10 min was not affected by pretreatment with atropine (1.4 mu mol/kg, i.v.); it was abolished by the tachykinin NK2 receptor antagonist, SR 48968 (0.3 mu mol/kg, i.v.) and was reduced by 58% by the kinin B2 receptor antagonist, HOE 140 (0.1 mu mol/kg, i.v.). These findings suggest that cold air induces bronchoconstriction in guinea pigs via a cascade that involves the release of kinins and tachykinins.

Animals↗
PubMed1996

Tachykinins mediate the potentiation of antigen-induced bronchoconstriction by cold air in guinea pigs.

The role of tachykinins in the potentiation of antigen-evoked bronchoconstriction induced by inhalation of cold air was studied in guinea pigs. Cold air was delivered through a tracheal cannula to anesthetized, artificially ventilated guinea pigs sensitized with ovalbumin and pretreated with atropine (1.4 micromol/kg). Inhalation of cold air increased total pulmonary resistance (RL) in a time-dependent manner; inhalation of cold air for 10 or 15 minutes, but not for 5 minutes, produced a significant increase in RL. Aerosolized ovalbumin (5 breaths) increased RL in a dose-dependent manner (0.5% to 5%). Inhalation of cold air for 5 minutes significantly enhanced both the peak and the duration of the increase in RL induced by 0.5% ovalbumin. The tachykinin neurokinin 2-receptor antagonist, SR 48968 (0.3 micromol/kg intravenously) inhibited both the peak and the duration of the bronchoconstriction induced by 5-minute inhalation of cold air and ovalbumin (0.5%), whereas it did not affect the response to ovalbumin (0.5%) alone. These findings suggest that exposure to cold air potentiates the bronchoconstriction response to antigen and that this potentiation is mediated by tachykinin release from sensory nerves.

Airway Resistance↗
PubMed1996

Classical second messengers are not involved in proteinase-induced degranulation of airway gland cells.

Neutral serine proteinases such as mast cell chymase, cathepsin G, and neutrophil elastase are far more potent secretagogues for airway gland serous cells than all other agonists studied (e.g., histamine and bradykinin). To determine the mechanism of proteinase-induced secretion, we investigated the stimulation-secretion coupling in cultured bovine serous cells. Histamine stimulates degranulation of serous cells via adenosine 3', 5'-cyclic monophosphate-, protein kinase C-, and intracellular Ca2+ concentration ([Ca2+]i)-dependent pathways. Similarly, bradykinin-induced secretion involves inositol phosphates, protein kinase C, and [Ca2+]i. Degranulation caused by both agonists also depends on the activity of an endogenous metalloprotease, which is required in a late step of stimulation-secretion coupling, i.e., after Ca2+ entry. On the basis of the effect of different inhibitors, this metalloprotease is a Zn(2+)- and Ca(2+)-dependent enzyme similar to a gelatinase A synthesized by serous cells. In marked contrast to other secretagogues, degranulation induced by chymase, cathepsin G, and neutrophil elastase neither involves the classical second messengers nor the activity of the endogenous metalloprotease. These observations suggest that exogenous proteinases such as chymase, cathepsin G, and elastase may substitute for or mimic the action of an endogenous metalloprotease and directly activate degranulation, bypassing the signal transduction mechanisms necessary for secretion caused by other agonists.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Dimethyl sulfoxide decreases interleukin-8-mediated neutrophil recruitment in the airways.

In this study, we investigated the role of dimethyl sulfoxide (DMSO) in inhibiting interleukin-8 (IL-8)-mediated neutrophil recruitment induced by Pseudomonas aeruginosa (PA) bacterial supernatant. First, we tested whether DMSO could inhibit IL-8 production induced by PA in human bronchial epithelial (16-HBE) cells in vitro. In these cells, exposure to PA or H2O2 induced IL-8 production dose dependently, an effect that was inhibited by 1% DMSO at both the protein and RNA level. Second, we tested whether DMSO could block the recruitment of neutrophils induced by PA in a bypassed segment of dog trachea in vivo. PA supernatant was placed in the tracheal segment for 6 h in four dogs, and neutrophil recruitment and IL-8 concentrations were measured in the superfusate. DMSO prevented the recruitment of neutrophils and IL-8 production induced by PA time dependently. The results suggest that DMSO may play an anti-inflammatory role in the airway by inhibiting IL-8 production in epithelial cells.

Animals↗
PubMed1996

Ragweed antigen causes interleukin-8 production in sensitized dog trachea.

Antigen challenge in allergic subjects and in sensitized animals causes recruitment of neutrophils as well as eosinophils into the airways. In this study, we asked whether interleukin-8 (IL-8) is involved in the recruitment of neutrophils into the airways after antigen challenge. We administered ragweed antigen to an isolated, superfused tracheal segment of ragweed-sensitized dogs. Local tracheal instillation of the antigen caused an increase in IL-8 concentration and increases in both the number of recruited neutrophils and myeloperoxidase activity (one indicator of neutrophil activation in the recruited cells). The increase in IL-8 concentration was observed earlier than both the neutrophil recruitment and the increase in myeloperoxidase activity in the tracheal superfusate. Superfusate removed from the trachea 8 h after antigen challenge showed marked neutrophil chemotactic activity in a microchemotaxis chamber, and this activity was inhibited (mean, 75.6%) by a blocking antibody to dog IL-8. We conclude that ragweed antigen causes neutrophil recruitment into the airways at least in part because of IL-8 production.

Allergens↗
PubMed1995

Corticotropin-releasing factor inhibits antigen-induced plasma extravasation in airways.

We investigated the potential of corticotropin-releasing factor (CRF) to reduce neurogenic plasma extravasation in sensitised guinea pig airways evoked by antigen challenge. Inhalation of 5% ovalbumin for 2 min in the presence of phosphoramidon (2.5 mg/kg, i.v.) increased extravasation of Evans blue dye in the trachea and main bronchi. The increase in plasma extravasation induced by antigen challenge was significantly reduced by pretreatment with CRF (30 nmol/kg, i.v.) (73% in the trachea and 42% in the main bronchi). The inhibition of plasma extravasation by CRF (30 nmol/kg, i.v.) alone was not different from the inhibition induced by the combination of CRF and the tachykinin NK1 receptor antagonist, CP-99,994 (4 mg/kg, i.v.) (73% in the trachea and 38% in the main bronchi). CRF (30 nmol/kg, i.v.) inhibited by 32% in the trachea and by 43% in the main bronchi plasma extravasation induced by aerosolised bradykinin but did not reduce the plasma extravasation caused by aerosolised substance P in the presence of phosphoramidon. These findings suggest that CRF reduces ovalbumin-induced plasma extravasation in guinea pig airways by inhibiting the release of tachykinins from primary sensory nerves.

Animals↗