kp-496 and Inflammation

Cysteinyl-leukotrienes (cysLTs) and thromboxane A(2) (TXA(2)) are important mediators in inflammatory lung diseases such as bronchial asthma and idiopathic pulmonary fibrosis (IPF). We examined the effects of inhaled KP-496, a novel dual antagonist of the cysLTs and TXA(2) receptors, on bleomycin-induced IPF in mice. Mice were intravenously injected bleomycin on day 0, and 0.5% of KP-496 was inhaled twice a day (30 min/time) for the entire experimental period. The effects of KP-496 were evaluated by the number of infiltrated cells in bronchoalveolar lavage fluid (BALF), hydroxyl-L-proline content in the lung, and histopathology. Analyses of BALF on days 7 and 21 revealed that inhaled KP-496 significantly decreased total cell numbers, macrophages, neutrophils, and eosinophils on both days. KP-496 significantly decreased hydroxyl-L-proline content in the lung on day 21. Histopathological analyses of lungs on day 21 demonstrated that KP-496 significantly suppressed inflammatory and fibrotic changes. Our results suggested that the suppression of cysLTs and TXA(2) pathways by KP-496 could control airway inflammation and pulmonary fibrosis, and that KP-496 could be a new therapeutic agent for lung diseases with inflammation and fibrogenesis such as IPF and chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bleomycin; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Inflammation; Leukotriene Antagonists; Male; Mice; Mice, Inbred ICR; Pulmonary Fibrosis; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Thiazoles

Bronchial asthma is characterized by chronic airway inflammation. Eosinophils are involved in airway inflammation and play crucial roles in asthma. There is accumulating evidence to suggest contributions of cysteinyl leukotrienes (cysLTs) and thromboxane (TX) A(2) to the recruitment of eosinophils into lung in asthmatics. KP-496 is a novel dual antagonist for CysLT receptor type 1 and TXA(2) receptors. The aim of this study was to evaluate the anti-inflammatory effects of KP-496 on Sephadex-induced airway inflammation. Sephadex suspension was intratracheally injected into rats. Amounts of regulated on activation, normal T cell expressed and secreted (RANTES) and eotaxin, and numbers of infiltrating cells in bronchoalveolar lavage fluid were measured 24 and 48 h after Sephadex injection, respectively. KP-496 (30, 100 microg/head) was intratracheally administered to rats 1 h before and 7 h after Sephadex injection. KP-496 and prednisolone (10 mg/kg, per os) exhibited significant inhibitory effects on infiltration of total cells and eosinophils into lung. Production of RANTES was significantly inhibited by KP-496 and prednisolone. Production of eotaxin was significantly inhibited by prednisolone. KP-496 also inhibited the production of eotaxin, though this effect was not significant. These results demonstrate that KP-496 exhibited the anti-inflammatory effects by inhibiting infiltration of inflammatory cells and productions of RANTES and eotaxin.

Topics: Animals; Asthma; Benzoates; Bronchoalveolar Lavage Fluid; Chemokine CCL5; Dextrans; Eosinophils; Inflammation; Leukocyte Count; Leukotriene Antagonists; Male; Rats; Rats, Sprague-Dawley; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Thiazoles