Nrf2-dependent and -independent cytoprotective actions of the electrophilic Cox-2-derived 17-oxo-DHA in human macrophages

17-oxo-DHA is an electrophilic derivative of the omega-3 fatty acid docosahexaenoic acid which is generated in activated macrophages by the action of ciclooxygenase-2. Herein we investigated whether 17-oxo-DHA (i) induced the anti-oxidant response, (ii) modulated cigarette smoke-induced ROS generation, and (iii) suppressed LPS- and cigarette smoke extract (CSE)-induced TNFa production in macrophage-differentiated THP-1 cells and in primary human alveolar macrophages. We also investigated whether the actions promoted by 17-oxo-DHA were dependent on the activation of the Nrf2 pathway. Results herein presented show that 17-oxo-DHA is a strong inducer of the Nrf2-dependent anti-oxidant response, and suppresses CSE-induced ROS generation and TNFa production. More interestingly, we demonstrated that while the anti-oxidant properties of 17-oxo-DHA depended on the induction of Nrf2, its anti-inflammatory effects were independent of Nrf2. Overall, the presented results show that 17-oxo-DHA displays strong anti-oxidant and anti-inflammatory properties by acting via multiple Nrf2-dependent and independent pathways. The clinical relevance of these data is further enhanced by their validation in primary human alveolar macrophages. Data herein presented strongly support the value of 17-oxo-DHA for the development of new therapeutic approaches for chronic diseases characterized by persistent inflammation and oxidative stress. In particular, the lack of effective therapeutic options for cigarette smoke-related airways chronic diseases urgently calls for the discovery of new drugs. In this respect, the endogenously generated 17-oxo-DHA stands as a promising lead compound.