Airway exposure of low-level dsRNA induces an allergen-specific Th17 cell response, which is mainly dependent on VEGF and IL-6.

These findings suggest that ASA changes Th17-type into Th2-type inflammation mainly via the adenosine and uric acid metabolic pathway in the lung.

Vascular endothelial growth factor (VEGF) is a key mediator in the development of airway immune dysfunction to inhaled allergens. However, the exact role of its receptors-mediated signaling is controversial. In this study, we evaluated the role of VEGF receptor (VEGFR)-1– and VEGFR-2–mediated signaling in T cell priming and polarization in the context of inhalation of LPS-containing allergens. A murine asthma model of mixed Th1 and Th17 cell responses was generated using intranasal sensitization with LPS-containing allergens. Pharmacologic intervention was performed during sensitization. In vivo production of VEGF and Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) were upregulated by airway exposure to LPS. Pharmacological intervention with a VEGFR-2–neutralizing Ab (anti-Flk1 mAb) abolished the production of IL-6 (but not IL-12p70) and the subsequent development of allergen-specific Th17 cell response. On the other hand, blocking VEGFR-1 signaling with a VEGFR-1 antagonist (anti-Flt1 hexapeptide) did not affect the production of IL-12p70 and IL-6. However, blocking VEGFR-1 signaling resulted in T cell tolerance rather than priming, mainly by inhibiting the maturation of lung dendritic cells, and their migration into lung-draining lymph nodes. These results suggest that T cell priming to LPS-containing allergens depends on VEGFR-1–mediated signaling, and the subsequent Th17 polarization depends on VEGFR-2 signaling.

Formyl peptide receptors (FPRs) are chemoattractant receptors that mediate inflammatory cell responses to infection. Recent evidence indicates that noneosinophilic asthma phenotypes can be developed by both Th1 and Th17 cell responses when exposed to LPS-containing allergens. In this study, we evaluated the effects of airway activation of FPRs by their synthetic agonist, Trp-Lys-Tyr-Met-Val-D-Met (W-peptide), on the development of Th1 and Th17 cell responses in a noneosinophilic asthma mouse model. A noneosinophilic asthma mouse model was generated by intranasal sensitization with 10 μg of LPS plus 75 μg of OVA on days 0, 1, 2, and 7. Mice were then challenged with 50 μg of OVA alone on days 14, 15, 21, and 22. W-peptide was administered during the sensitization period, and immune and inflammatory responses were evaluated after OVA challenge. Lung inflammation after OVA challenge was partly abolished by airway activation of FPRs during sensitization. Maturation of dendritic cells (DCs) and migration of DCs from the lung to lung-draining lymph nodes were inhibited by FPR activation. In addition, airway activation of FPRs inhibited allergen-specific T cell proliferation in the lymph nodes. Production of IL-12 and IL-6 (Th1- and Th17-polarizing cytokines) from lung DCs was decreased by airway activation of FPRs. This effect resulted in the inhibition of allergen-specific Th1 and Th17 cell responses. Airway activation of FPRs during sensitization effectively prevents the development of Th1 and Th17 cell responses induced by LPS-containing allergens via multiple mechanisms, such as inhibition of DC maturation and migration and the production of Th1- and Th7-polarizing cytokines.

15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation.

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BACKGROUND Lonicera japonica (LJ) has been applied to treatment of inflammatory diseases in Oriental medicine. We studied safety, tolerability, and pharmacokinetics of rising, single and multiple intravenous doses of aqueous extract from LJ, SKLJI in healthy volunteers. METHODS A randomized, placebo‐controlled, double blind, dose‐escalation study after single and multiple dosing was conducted. Total 80 subjects (56 for single, 24 for multiple; total 13 times for 4 days) were enrolled. Blood and urine samples were collected and subjects were monitored closely for adverse events throughout the study. RESULTS Seven and 14 cases of adverse events suspected to be related with SKLJI were reported in the single dose and multiple doses, respectively. They were mild, transient and relieved without an intervention. In single dose, Tmax were 30 min for 30 min‐duration infusion, 5 min for bolus injection, respectively. The elimination half‐life was 1.4–1.6 h. Linear pharmacokinetic profiles in a dose‐proportional manner were shown and interindividual variations were 15%‐30% in high dose group. Pharmacokinetics of multiple doses was similar to that of single dose group. The accumulation index ranged from 0.93 to 1.08, and renal clearance was 5–12 L/h. CONCLUSIONS SKLJI was safe and well tolerated as a single dose and multiple doses up to 100 mg. It showed linear pharmacokinetics proportional to dose‐escalation, short elimination half‐life, little accumulation, and relatively small interindividual variations. Clinical Pharmacology & Therapeutics (2005) 79, P58–P58; doi: