Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-alpha, IL-1beta, and LPS resulted in significant ROS production and NF-kappaB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-alpha levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b+ macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.
Animals ; Antioxidants/metabolism ; Asthma/complications/metabolism/pathology/physiopathology ; Bronchial Hyperreactivity/drug therapy/pathology ; Bronchial Provocation Tests ; Bronchoalveolar Lavage Fluid/cytology ; Cells, Cultured ; Drug Evaluation, Preclinical ; Humans ; Inflammation/*etiology/metabolism ; Jurkat Cells ; Lipoxygenase/*physiology ; Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Lymphocytes/drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Nordihydroguaiaretic Acid/pharmacology/therapeutic use ; Reactive Oxygen Species/*adverse effects/*metabolism