Shinichiro Narita

Effects of thromboxane A2 receptor antagonist (Bay u 3405) on nasal symptoms after antigen challenge in sensitized guinea pigs.

To define the role of thromboxane A2 (TxA2) in allergic rhinitis, we examined the effects of the TxA2 receptor antagonist Bay u 3405 (1, 3 and 10 mg/kg, orally) on nasal symptoms, changes in total airway resistance (TAR), histamine hypersensitivity and eosinophil infiltration into the nasal mucosa induced by topical antigen challenge in actively sensitized guinea pigs. Nasal symptoms (number of sneezes and scratches) were significantly inhibited by pretreatment with Bay u 3405, in a dose-dependent manner. We noted a biphasic increase in TAR after antigen challenge. The first peak response of TAR (177.5 +/- 6.1%, mean +/- SE) was partially but significantly inhibited by Bay u 3405 at 10 mg/kg (142.8 +/- 4.3%, p < 0.01). The second peak response of TAR (181.0 +/- 13.4%) was also inhibited by Bay u 3405 at 3 mg/kg (120.3 +/- 3.1%) and 10 mg/kg (125.2 +/- 9.4%) (both, p < 0.01). The histamine hypersensitivity induced by antigen was inhibited by Bay u 3405 at 15 mg/kg (p < 0.05). Moreover, the mean eosinophil infiltration into the nasal mucosa induced by antigen (644.1 +/- 202.6/both sides of the nasal septum) was inhibited to 137.8 +/- 69.0 by Bay u 3405 at 10 mg/kg (p < 0.05). In conclusion, our results suggest that TxA2 may play an important role in allergic rhinitis in guinea pig models.

The Effects of Anti-PAF and Other Agents on the Nasal Symptoms in Sensitized Guinea Pigs

To define the role of platelet activating factor (PAF) in allergic rhinitis, we examined the effects of anti-PAF agents (WEB2086, SM10661) on the changes of nasal airway resistance (NAR) and nasal symptoms after topical antigen challenge in actively sensitized guinea pigs and compared these with the changes brought by anti-leukotriene (LT) agent (FPL 55712), 5-lipoxygenase inhibitor (E6080), anti-allergic agent (azelastine), and anti-histamine agent (mepyramine maleate). We noted biphasic increase in NAR after antigen challenge; the first peak, 146.3 +/- 4.3% at 10 min and the second peak, 163.3 +/- 7.8% at 240 min after antigen challenge. The first peak response of NAR was not affected by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, or azelastine; it was slightly but significantly inhibited by anti-histamine. The second NAR response was significantly inhibited by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, and azelastine, but was not affected by anti-histamine. The nasal symptoms which occurred within 30 min after antigen challenge were significantly inhibited by WEB2086, E6080, azelastine, and mepyramine, but were not affected by SM10661. Our results suggest that PAF activities and LTs may play an important role in the later phase increase of NAR after topical antigen challenge.

Study on the Dye Leakage Response of Nasal Mucosa Following Topical, Capsaicin Challenge in Guinea Pigs

We examined the serial changes of intravenously applied dye leakage and preliminary examined histamine release into nasal lavage fluid after topical stimulation with capsaicin in guinea pigs. A significant increase in the dye leakage response was detected for 30-40 min, with the maximum response occurring between 5 and 10 min after topical capsaicin stimulation. The dye leakage response to nasal capsaicin challenge was abolished by pretreatment with topical lidocaine, general substance P analogue, topical or general high dosage capsaicin. The dye leakage response to topical capsaicin challenge was significantly reduced following pretreatment with antihistamine, diphenhydramine or atropine sulfate, although it was not affected by pretreatment with an anti-leukotriene, FPL 55712. Topical methacholine challenge did not induce a dye leakage response. An increase in the concentration of histamine in the nasal lavage fluid was noted at 5 min after topical capsaicin challenge. The concentrations of released histamine tended to be positively correlated with those of leaked dye in the nasal lavage fluids. The histamine release induced by topical stimulation with capsaicin tended to be reduced following general and topical pretreatments with high dosage of capsaicin, and was almost completely abolished following atropine pretreatment. From this study it was concluded that nasal capsaicin stimulation can reflexively induce an intravenously applied dye leakage into the nasal cavity, and that C-fiber related cholinergic nerve reflex and histamine release might, at least partially, be related to this response.

Expression of substance P (NK1) receptor mRNA in human nose.

In airway tissues, it has been suggested that substance P is the transmitter of afferent sensory nerves which respond to various irritants and may be involved in airway allergic reactions. Three classes of tachykinin receptor are currently recognized, denoted as NK1, NK2 and NK3, which exhibit preferential affinity for substance P, neurokinin A and neurokinin B, respectively. We used molecular probes to study the gene expression and distribution of NK1 receptor in human nose. Total RNA was isolated from human nasal mucosa and NK1 receptor mRNA was detected in these tissues by using reverse transcription and polymerase chain reaction (RT-PCR). For in situ hybridization study of human nasal mucosa, we utilized the PCR directly to incorporate a T7 RNA polymerase promoter sequence onto the NK1 receptor cDNA, and these PCR products were used as the DNA templates for producing digoxigenin-labelled anti-sense and sense RNA probes. These studies revealed that NK1 receptor mRNA was expressed in submucosal glands and airway epithelium. The results may have an important clinical implication, and also promote further investigation of gene regulation of NK1 receptor in health and disease.

Role of Capsaicin-Sensitive Sensory Nerve Reflexes in Guinea Pig Model of Nasal Allergy

The aim of this study was to examine the pathophysiological role of capsaicin-sensitive sensory nerves in an animal model of nasal allergy. In ovalbumin (OA)-sensitized guinea pigs, a significant increase in nasal total airway resistance (TAR) was noted for at least 180 min after topical antigen challenge. The TAR response to antigen challenge was significantly inhibited for 120 min by general capsaicin pretreatment (167 +/- 12.1 vs. 113 +/- 5.0%, p < 0.001, and 186 +/- 14.9 vs. 119 +/- 6.6%, p < 0.001, control vs. capsaicin pretreatment group at 20 and 90 min after challenge, respectively). However, TAR was significantly though slightly affected even after general capsaicin pretreatment. Following nasal capsaicin challenge, TAR increased for 90 min, and nasal secretion for 30 min. Both the TAR and secretory responses to nasal capsaicin challenge were significantly greater in OA-sensitized guinea pigs than in nonsensitized animals (171 +/- 12.1 vs. 137 +/- 7.4% at 30 min, p < 0.05, and 82.3 +/- 8.6 vs. 13.4 +/- 1.7 mg/10 min, p < 0.05, TAR and secretory response to 300 microM nasal capsaicin challenge, respectively). These results suggest that capsaicin-sensitive sensory nerve reflexes play an important role in the occurrence of early-phase nasal symptoms following topical antigen exposure and are accelerated in OA-sensitized guinea pigs.

The Role of Platelet-Activating Factor on Histamine Hypersensitivity in Nasal Allergy in Guinea Pig Models

Using guinea pig models of nasal allergy, we investigated the role of PAF in mucosal hypersensitivity to topical histamine challenge. We found that the histamine sensitivity was significantly increased by nasal allergen challenge in actively sensitized guinea pigs, and the occurrence of histamine hypersensitivity was inhibited by pretreatment of anti-PAF agent (SM10661, 10 mg/kg, i.p.). Also, the histamine sensitivity was further increased by a single nasal challenge with PAF in actively sensitized guinea pigs. The histamine hypersensitivity was induced by repeated topical challenges with PAF in nonsensitized guinea pigs. Therefore, we believe that PAF plays an important role in hypersensitivity to histamine in nasal allergy.