Modulation of airway smooth muscle tone by protease activated receptor-1,-2,-3 and -4 in trachea isolated from influenza A virus-infected mice - PubMed (original) (raw)

Modulation of airway smooth muscle tone by protease activated receptor-1,-2,-3 and -4 in trachea isolated from influenza A virus-infected mice

R S Lan et al. Br J Pharmacol. 2000 Jan.

Abstract

Relaxant and contractile effects of the tethered ligand domain sequences of murine PAR-1, PAR-2, PAR-3 and PAR-4, and of the proteases thrombin and trypsin were examined in mouse isolated tracheal preparations. The epithelium- and cyclo-oxygenase-dependence of these effects and the potential modulatory effects of respiratory tract viral infection were also investigated. In carbachol-contracted preparations, trypsin, thrombin, and the tethered ligand domain sequences of murine PAR-1 (SFFLRN-NH(2)), PAR-2 (SLIGRL-NH(2)) and PAR-4 (GYPGKF-NH(2)), but not PAR-3 (SFNGGP-NH(2)), induced transient, relaxant responses that were abolished by the cyclo-oxygenase inhibitor indomethacin. Repeated administration of SFFLRN-NH(2), SLIGRL-NH(2) or GYPGKF-NH(2) (30 microM) was associated with markedly diminished relaxation responses (homologous desensitization), although there was no evidence of cross-desensitization between these peptides. The tethered ligand domain sequences for PAR-1 and PAR-4 induced a rapid, transient contractile response that preceded the relaxant response. Contractions were not inhibited by indomethacin and were not induced by either thrombin or trypsin. Influenza A virus infection did not significantly affect the responses induced by either the proteases or peptides. Furthermore, epithelial disruption caused by mechanical rubbing had no significant effect on responses to these PAR activators in preparations from either virus- or sham-infected mice. In summary, the proteases trypsin and thrombin, and peptide activators of PAR-1, PAR-2 and PAR-4 induced relaxant responses of mouse isolated tracheal smooth muscle preparations, which were mediated by a prostanoid, probably PGE(2). Interestingly, PAR-mediated relaxations were not significantly diminished following acute damage to the epithelium caused by mechanical rubbing and/or the respiratory tract viral pathogen, influenza A. British Journal of Pharmacology (2000) 129, 63 - 70.

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Figures

Figure 1

(a) Representative isometric tension recording traces of responses induced by peptide (SFFLRN-NH2, SLIGRL-NH2, SFNGGP-NH2, GYPGKF-NH2,

PFKF-NH2) and enzyme (trypsin, thrombin) activators of PARs in mouse isolated tracheal smooth muscle preparations pre-contracted with 1 μ

carbachol. (b) Peak relaxant responses induced by the PAR peptides SFFLRN-NH2, SLIGRL-NH2, SFNGGP-NH2, GYPGKF-NH2 and

PGKF-NH2 in mouse isolated tracheal smooth muscle preparations pre-contracted with 1 μ

carbachol. Data is presented as mean±s.e.mean (_n_=9–13). (c) Peak contractile responses induced by the PAR peptides SFFLRN-NH2, SLIGRL-NH2, SFNGGP-NH2, GYPGKF-NH2 and

PFKF-NH2 in mouse isolated tracheal smooth muscle preparations pre-contracted with 1 μ

carbachol. Data is presented as mean±s.e.mean (_n_=9–13).

Figure 2

Cross-desensitization studies. Peak relaxant responses induced by 100 μ

(a) SFFLRN-NH2, (b) SLIGRL-NH2 and (c) GYPGKF-NH2 in carbachol-contracted preparations following repeated exposure to SFFLRN-NH2, SLIGRL-NH2 or GYPGKF-NH2 to induce desensitization. Data are presented as mean±s.e.mean. *P<0.05, two-way ANOVA followed by modified _t_-statistic, using the Bonferroni correction for multiple comparisons.

Figure 3

Influence of indomethacin (+Indo) and mechanical disruption of the epithelium (−Epi) on peak relaxant and contractile responses induced by (a,b) SFFLRN-NH2, (c) SLIGRL-NH2 and (d, e) GYPGKF-NH2 in sham-infected mouse tracheal preparations. Data are presented as mean±s.e.mean (_n_=9–13). Also shown are responses to the respective control peptides,

FLRN-NH2 (a,b),

IGRL-NH2 (c) and GYPG

-NH2 (d,e).

Figure 4

Histological examination of the influence of viral infection and of mechanical rubbing on mouse tracheal epithelium. Lightfield photomicrographs of hematoxylin-stained sections of mouse trachea following (a) sham-infection only, (b) virus-infection only, (c) sham-infection with rubbing, and (d) virus-infection with rubbing. Bar=20 μm.

Figure 5

Peak relaxant and contractile responses induced by (a,b) SFFLRN-NH2, (c) SLIGRL-NH2 and (d,e) GYPGKF-NH2 (_n_=9–13) in carbachol-contracted tracheal preparations from sham- and virus-infected mice. Data are presented as mean±s.e.mean.

Figure 6

Influence of indomethacin (+Indo) and mechanical disruption of the epithelium (−Epi) on peak relaxant and contractile responses induced by (a,b) SFFLRN-NH2, (c) SLIGRL-NH2 and (d, e) GYPGKF-NH2 (_n_=9–13) in virus-infected mouse tracheal preparations. Data are presented as mean±s.e.mean. Also shown are responses to the respective control peptides,

FLRN-NH2 (a, b),

IGRL-NH2 (c) and GYPG

-NH2 (d,e).

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Modulation of airway smooth muscle tone by protease activated receptor-1,-2,-3 and -4 in trachea isolated from influenza A virus-infected mice - PubMed (original) (raw)