Tachykinins via Tachykinin NK(2) receptor activation mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs

Abstract

1. Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. The aim of this study was to determine whether tachykinins mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. 2. Anaesthetized guinea-pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood. 3. A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK(3) receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK(2) receptor antagonist, SR-48,968. A high dose of SP increased the permeability in a manner reversible by the NK(1) receptor antagonist, CP-96,345. 4. Pretreatment with SR-48,968 completely inhibited the ozone-induced increase in the permeability, whereas CP-96,345 had no effect. 5. It is thus concluded that endogenous tachykinins mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs mainly via NK(2) receptor activation.

Figure 1

Effects of substance P (SP) on the permeability of the tracheal mucosa. Shown are plasma levels of horseradish peroxidase (HRP) in guinea-pigs administered 10 nmol kg⁻¹ i.v. of SP (n=5, closed circles) and 1 nmol kg⁻¹ i.v. of SP (n=5, closed squares), in guinea-pigs pretreated with CP-96,345 and then administered 10 nmol kg⁻¹ i.v. of SP (n=5, closed triangles), and in controls (n=5, open circles). The time point 0 indicates the point of instillation of the HRP solution into the tracheal segment. **P<0.01, as compared with the control group. ^§P<0.01, as compared with the group administered 10 nmol kg⁻¹ i.v. of SP.

Figure 2

Effect of neurokinin A (NKA) on the permeability of the tracheal mucosa. Shown are plasma levels of horseradish peroxidase (HRP) in guinea-pigs administered 1 nmol kg⁻¹ i.v. of NKA (n=5, closed circles) and 0.1 nmol kg⁻¹ i.v. of NKA (n=5, closed squares), in guinea-pigs pretreated with SR-48,968 and then administered 1 nmol kg⁻¹ i.v. of NKA (n=5, closed triangles), and in controls (n=5, open circles). The time point 0 indicates the point of instillation of the HRP solution into the tracheal segment. **P<0.01, as compared with the control group. ^§P<0.01, as compared with the group administered 1 nmol kg⁻¹ i.v. of NKA.

Figure 3

Effects of senktide on the permeability of the tracheal mucosa. Shown are plasma levels of horseradish peroxidase (HRP) in guinea-pigs administered 10 nmol kg⁻¹ i.v. of senktide (n=5, closed circles) and 1 nmol kg⁻¹ i.v. of senktide (n=5, closed squares), and in controls (n=5, open circles). The time point 0 indicates the point of instillation of the HRP solution into the tracheal segment.

Figure 4

Effect of the NK₁ receptor antagonist, CP-96,345, on the ozone-induced increase in the permeability of the tracheal mucosa. Plasma levels of horseradish peroxidase (HRP) during a 40-min sampling period in guinea-pigs pretreated with CP-96,345 and then exposed for 30 min to 3 p.p.m. of ozone (n=5, closed squares), and in those pretreated with the vehicle and then exposed to either ozone (n=5, closed circles) or filtered air (n=5, open circles), are shown. The time point 0 indicates the point of instillation of the HRP solution into the tracheal segment. **P<0.01, as compared with the vehicle-treated, air-exposed group.

Figure 5

Effect of the NK₂ receptor antagonist, SR-48,968, on the ozone-induced increase in the permeability of the tracheal mucosa. Plasma levels of horseradish peroxidase (HRP) during a 40-min sampling period in guinea-pigs pretreated with SR-48,968 and then exposed for 30 min to 3 p.p.m. of ozone (n=5, closed triangles), and in those pretreated with the vehicle and then exposed to either ozone (n=5, closed circles) or filtered air (n=5, open circles), are shown. The time point 0 indicates the point of instillation of the HRP solution into the tracheal segment. **P<0.01, as compared with the vehicle-treated, air-exposed group. ^§P<0.01, as compared with the vehicle-treated, ozone-exposed group.