Markedly Increased Nasal Blockage by Intranasal Leukotriene D4 in an Experimental Allergic Rhinitis Model: Contribution of Dilated Mucosal Blood Vessels

Abstract

ABSTRACT-We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized -challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD 4 (10 m l /nostril) at 10 -10 to 10 -6 M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dosedependently suppressed by N M -nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized -challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized -non-challenged group. The amount of NO2-and NO3 -in nasal cavity lavage fluid after LTD4 instillation in the sensitized -challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.Keywords: Hyperresponsiveness, Allergic rhinitis, Leukotriene D4, Nasal blockage, Nitric oxide Cysteinyl leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. It has been reported that CysLTs were detected in the nasal washings following antigen challenge of subjects with allergic rhinitis (1, 2) and that treatment with a 5-lipoxygenase inhibitor and a CysLT1-receptor antagonist modified allergen-induced nasal mucosa swelling via dilatation of nasal capacitance blood vessel and increases in nasal capillary permeability (3 -5), suggesting that CysLTs act as significant inflammatory mediators in allergic rhinitis and that allergen-induced vascular changes are predominantly induced by CysLTs.To date, clinical examinations revealed that allergic rhinitis patients show obviously increased nasal blockage in response to topical LTD4, a phenomenon known as nasal hyperresponsiveness (6 -8). On the other hand, although very high doses of topical LTD 4 have been reported to increase either nasal blockage or nasal vascular permeability in non-sensitized animals (9, 10), it has not been determined whether a higher response to the agonist occurs in the allergic rhinitis model. Due to the limitation of clinical research and insufficient information obtained from normal animals, the mechanism of nasal hyperresponsiveness to LTD4 in allergic rhinitis patients remains unclear. The use of an experimental allergic rhinitis model that closely resembles the human case indispensably resolv...

Effect of Oral Immunotherapy on Nasal Blockage in Experimental Allergic Rhinitis

“…Two days after the pollen inhalation challenges, nasal responsiveness to intranasally instilled LTD 4 was measured as previously described (15). At 20-min intervals, increasing doses (10 µl / each nostril) of the LTD 4 solution (10 −8 and 10 −6 M) were bilaterally applied.…”

Comparison of Cedar Pollen-Induced Allergic Rhinitis in Passively and Actively Sensitized Guinea Pigs

“…When non-sensitized guinea pigs were forced to inhale the cedar pollen repeatedly, their nasal responsiveness to LTD4 was slightly increased (9). In addition, nasal responsiveness to LTD4 in guinea pigs that had been treated only with the present active sensitization procedure (intranasal instillation with pollen extract + Al(OH)3 twice a day for 7 days) without repeated pollen inhalation was also only slightly potentiated (9). However, these increases in responsiveness to LTD 4 were considerably less marked than the hyperresponsiveness observed in the actively sensitized, repeatedly challenged guinea pigs.…”

Comparison of the efficacy of prednisolone, montelukast, and omalizumab in an experimental allergic rhinitis model

“…Previously, CysLTs were recovered in the nasal washings of patients with allergic rhinitis following nasal challenges with specific allergens, and their concentrations were shown to be directly related to the dose of the allergen (22). Intranasal instillation of LTD4 was shown to induce nasal blockage (an increase of specific airway resistance) by dilatation of nasal blood vessels in S/C guinea pigs, which was largely blocked with pranlukast, a CysLT antagonist and naphazoline (23). In this study, IgE, IL-4, and CysLT increased significantly in sensitized groups.…”

“…CysLTs levels decreased after treatment with montelukast, omalizumab, and prednisolone; the most remarkable efficacy was with montelukast treatment. Previous clinical and experimental studies evaluated the efficacy of antiinflammatory medications in controlling the nasal allergic symptoms and mucosa inflammation at the tissue level (16,23,(25)(26)(27). Roa et al (16) showed that montelukast decreased nasal symptoms in a dosedependent manner and significantly lowered the number of eosinophils in both bone marrow and nasal tissue in mice.…”