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See detailAn epithelial-dependent contracting factor induced by calcium influx in guinea-pig trachea
Bertrand, C.; Da Silva, A.; Landry, Y. et al

in Pulmonary Pharmacology (1993), 6(1), 69-76

The effects of epithelium removal were studied on the contraction induced by Ca2+ in K(+)-depolarizing solution, and by the calcium ionophore A 23187 in guinea-pig isolated tracheal strips. Epithelium ... [more ▼]

The effects of epithelium removal were studied on the contraction induced by Ca2+ in K(+)-depolarizing solution, and by the calcium ionophore A 23187 in guinea-pig isolated tracheal strips. Epithelium removal reduced the maximal response to Ca2+ in K(+)-depolarizing solution and caused a significant shift to the right of the Ca2+ concentration-response curves. The contraction induced by the calcium ionophore A 23187 (10(-6) M) was also markedly reduced by epithelium removal. These results suggest the occurrence of an epithelium-derived contracting factor. The effects of hexamethonium, atropine, spantide and thiorphan showed that acetylcholine and neurokinins play a minor role in the Ca(2+)-induced contraction. The epithelium-dependent potentiation of the calcium- and of the A 23187-induced contractions was inhibited by an antibody selective for rat calcitonin gene-related peptide (rCGRP alpha). Therefore, CGRP-like immunoreactive material may be part of the epithelium-dependent contracting factor of guinea-pig trachea. Comparison of concentration-response curves for rCGRP alpha in epithelium-free and in intact guinea-pig tracheal strips suggests that an epithelium-dependent contracting factor may be mobilized by CGRP. [less ▲]

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See detailEpithelial factors: modulation of the airway smooth muscle tone
Bertrand, C.; Tschirhart, Eric UL

in Fundamental & Clinical Pharmacology (1993), 7(6), 261-73

The airway epithelium is composed of a heterogeneous population of cells. This epithelial layer is not only a physical barrier but also a target responding to a variety of inflammatory mediators. These ... [more ▼]

The airway epithelium is composed of a heterogeneous population of cells. This epithelial layer is not only a physical barrier but also a target responding to a variety of inflammatory mediators. These cells can respond by releasing contracting and relaxing factors to modulate airway responsiveness. They can also metabolize some of the inflammatory mediators. Epithelial damage is a consistent feature of some respiratory conditions, but whether or not such damage contributes to airway disease is for the moment unknown. This review summarizes the literature on the known and proposed roles of the epithelium in the modulation of the airway smooth muscle tone. [less ▲]

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See detailEpithelial modulation of thromboxane A2 and PAF involvement in IgE- and IgG-mediated guinea pig anaphylaxis
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in Immunopharmacology (1992), 22(2), 115-25

The role of prostanoids and platelet-activating factor (PAF) was studied in the in vitro response of guinea pig trachea to immunochallenge according to the presence or the absence of the epithelial layer ... [more ▼]

The role of prostanoids and platelet-activating factor (PAF) was studied in the in vitro response of guinea pig trachea to immunochallenge according to the presence or the absence of the epithelial layer and to the sensitization procedure leading to the preferential synthesis of immunoglobulin E (IgE) or immunoglobulin G (IgG) antibodies. Indomethacin, a cyclooxygenase inhibitor, potentiated the antigen-induced contractions both in IgE and IgG models, suggesting the involvement of relaxant prostaglandins (PGs), independently of the presence of the airway epithelium. UK-38485, a thromboxane synthetase inhibitor, did not modify the tracheal response to antigen in the IgE model. However, this compound enhanced the maximum contractile response to antigen of the intact tracheal strips of IgG-sensitized guinea pig, but reduced the contractile response of the epithelium-free tracheal strips. Two potent non-structurally related PAF antagonists, Ro 19-3704 and BN 52021, reduced antigen-induced contraction of the epithelium-free tracheal strips in the IgE model. In contrast, these compounds did not affect the contractile responses of the preparations in the IgG model. These results suggest the selective implication of thromboxane A2 and PAF, in IgG- and IgE-mediated guinea pig anaphylaxis respectively. Finally, these results indicate that thromboxane A2 (TXA2) and PAF are potent inducers of epithelium-derived mediators. [less ▲]

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See detailSelective implication of thromboxane A2 and PAF-acether in two guinea pig anaphylactic models
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in Agents and Actions. Supplements (1991), 31

In an IgE and an IgG model of anaphylaxis in the guinea pig, we investigated the role of prostanoids and PAF-acether in the tracheal response in vitro to immunochallenge. Indomethacin (10(-6) M ... [more ▼]

In an IgE and an IgG model of anaphylaxis in the guinea pig, we investigated the role of prostanoids and PAF-acether in the tracheal response in vitro to immunochallenge. Indomethacin (10(-6) M) potentiated the antigen-induced contraction in both models suggesting the synthesis of relaxant prostaglandins during the anaphylactic phenomenon. UK-38,485 (10(-5) M), a thromboxane (TxA2) synthetase inhibitor, did not modify the tracheal response in the IgE model. In the IgG model, this drug reduced the response of the tracheal strips to antigen. Ro 19-3704 (10(-6) M) and BN 52021 (10(-5) M), two potent PAF antagonists, reduced antigen-induced contraction of the tracheal strips in the IgE model. These two drugs did not modify the contractile response in the IgG model. These results indicate that PAF-acether and TxA2 play a role in the IgE and IgG model of anaphylaxis, respectively. [less ▲]

Detailed reference viewed: 67 (0 UL)
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See detailEvidence for the involvement of calcitonin gene-related peptide in the epithelium-dependent contraction of guinea-pig trachea in response to capsaicin
Tschirhart, Eric UL; Bertrand, C.; Theodorsson, E. et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1990), 342(2), 177-81

Capsaicin (10(-9) to 10(-5) M) contracted guinea-pig tracheal strips. Epithelium-containing tracheal strips developed a maximum active tension which was significantly higher than that observed in ... [more ▼]

Capsaicin (10(-9) to 10(-5) M) contracted guinea-pig tracheal strips. Epithelium-containing tracheal strips developed a maximum active tension which was significantly higher than that observed in epithelium-free strips. Anti-CGRP (calcitonin gene-related peptide) serum blocked the epithelium-dependent potentiation of the capsaicin-induced contraction in the intact tracheal strips, without affecting the response of the epithelium-free strips. This result suggests the occurrence of an epithelium-dependent release of CGRP. This same serum markedly reduced the contraction induced by exogenous rat CGRP in both intact and epithelium-free tracheal strips. In epithelium-free tracheal strips, capsaicin-induced contraction was abolished by spantide (10(-6) and 10(-5) M), a substance P antagonist, but, in intact tracheal strips, spantide did not abolish the capsaicin-induced contraction, showing that both CGRP and substance P release are directly induced by capsaicin. Moreover, the contractile responses to rat CGRP of intact tracheal strips from guinea pig suggest that CGRP itself might be able to release a contracting factor from the airway epithelium. Therefore, CGRP originating from the airway epithelium may play a major role in the control of airway smooth muscle tone. [less ▲]

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See detailContractile activity of the N-acylated C-terminal part of substance P7-11 in guinea pig trachea. Effect of epithelium removal
Tschirhart, Eric UL; Schmitt, P.; Bertrand, C. et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1989), 340(1), 107-10

Substance P, neurokinin A, neurokinin B, and N-acylated pentapeptide X-Phe-Phe-Gly-Leu-Met-NH2 analogs of substance P7-11 were tested for their spasmogenic activities in intact or in epithelium-denuded ... [more ▼]

Substance P, neurokinin A, neurokinin B, and N-acylated pentapeptide X-Phe-Phe-Gly-Leu-Met-NH2 analogs of substance P7-11 were tested for their spasmogenic activities in intact or in epithelium-denuded tracheal strips from guinea pig. Epithelium removal enhanced the efficacies and potencies relative to substance P of all the peptides tested in guinea pig trachea. In epithelium-containing preparations, the presence of a cyclic substituent (o-hydroxyphenyl-acetyl, p-hydroxyphenyl-acetyl, pyroglutamyl) in Phe7 greatly enhanced the potency and efficacy compared to substance P. These substitutions were twice as active as neurokinin A itself. The presence of an aliphatic chain (non-protected and t-butyloxycarbonyl-protected aminopropyl and aminocaproyl) in Phe7 also improved the potency and the efficacy of the synthetic peptides. The aliphatic substituents could favour an increase in local concentration of the peptides in the vicinity of the receptor(s) allowing a more effective ligand-receptor interaction. Thus, lipophilicity could be determinant in the potency of the peptides in intact guinea pig trachea. In epithelium-denuded tracheal strips from guinea pig, all the synthetic peptides were more effective than substance P but less active than neurokinin A which probably reflects the presence of the NK2 receptor subtype, which may be predominant in this type of epithelium-denuded preparation. Our results suggest that hydrophobicity plays a strong role in the interaction of the peptides, namely substance P and its analogues with the membrane and possibly the receptors themselves. [less ▲]

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See detailNedocromil sodium inhibits IgE- and IgG-related antigen-induced contraction in guinea-pig trachea
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in International Archives of Allergy and Applied Immunology (1989), 88(4), 439-46

The effects of nedrocromil sodium and disodium cromoglycate were studied on the anaphylactic contraction of guinea-pig trachea in two models of active sensitization (IgE and IgG models). The influence of ... [more ▼]

The effects of nedrocromil sodium and disodium cromoglycate were studied on the anaphylactic contraction of guinea-pig trachea in two models of active sensitization (IgE and IgG models). The influence of epithelial removal on the effects of nedocromil sodium and disodium cromoglycate was examined because several studies have shown that the epithelial layer can modulate agonist- or antigen-induced contractile responses. Disodium cromoglycate (10(-4) M) and nedocromil sodium (10(-4) M) provided significant protection against antigen-induced contractions of guinea-pig tracheal smooth muscle in the IgG model. But only nedocromil sodium had an effect at this concentration in the IgG model and was also effective at 10(-5) M in the epithelium-denuded tracheal strips. At this concentration, disodium cromoglycate lost its protective effect. Comparison with the results obtained with FPL-55712, AA-861 and mepyramine suggested that these drugs affect histamine and particularly leukotriene synthesis and/or release by mast cells or other immunocompetent cells. These findings indicate that nedocromil sodium inhibits the IgE- and IgG-related antigen-induced contraction in guinea-pig airways, whereas disodium cromoglycate inhibits only the IgG-related processes. This study supports the hypothesis that these drugs modulate antigen-induced mediator synthesis and/or release from immunocompetent cells. [less ▲]

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See detailArachidonic acid metabolites and airway epithelium-dependent relaxant factor
Tschirhart, Eric UL; Frossard, N.; Bertrand, C. et al

in Journal of Pharmacology and Experimental Therapeutics (1987), 243(1), 310-6

Exogenous arachidonic acid (10(-8) to 10(-4) M) contracted epithelium-free guinea pig tracheal strips. Intact tracheal strips were contracted slightly by low concentrations of arachidonic acid (10(-8) to ... [more ▼]

Exogenous arachidonic acid (10(-8) to 10(-4) M) contracted epithelium-free guinea pig tracheal strips. Intact tracheal strips were contracted slightly by low concentrations of arachidonic acid (10(-8) to 10(-5) M), but higher concentrations relaxed them. In contrast, when tracheal strips were precontracted with histamine or carbachol, exogenous arachidonic acid had no effect on epithelium-free preparations but induced concentration-dependent (10(-8) to 10(-4) M) relaxation of intact tracheal strips. The effects of arachidonic acid both in epithelium-free and epithelium-containing trachea were blocked by either indomethacin (10(-6) M) or aspirin (10(-4) M). Studies on the effects of exogenous arachidonic acid, performed with a "sandwich protocol," demonstrated that the postulated airway epithelium-dependent relaxant factor released by an intact tracheal strip relaxes an adjacent epithelium-free strip in the same organ bath. This relaxation is antagonized by indomethacin suggesting the involvement of a cyclooxygenase product in this phenomenon. Comparison of concentration-response curves for contractile agonists in epithelium-free preparations and in one containing epithelium suggests the mobilization of airway epithelium-dependent relaxant factor by histamine but not by carbachol. The effects of cyclooxygenase and lipoxygenase inhibitors indicated that both relaxant and contractile arachidonic acid metabolites are generated by epithelial and nonepithelial cells alike in response to contractile agonists. [less ▲]

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