Role of cyclooxygenase-1 in the generation of inflammatory mediators

Abstract

The cyclooxygenase enzymes (COX) play a key role in the pathogenesis of sepsis, in particular the COX-2 isoform, which is induced in immune cells during the inflammatory process. However, despite the fact that the role of COX-1 in inflammation has been historically neglected, recent evidences indicate that such isoform can participate in LPS-induced responses, especially in the most severe cases of systemic inflammation and in the initial phase of the inflammatory response. Such isoform would be, therefore, associated with the switch from fever to hypothermia at the onset of intensified systemic inflammation and also to hypotensive responses, typical of shock. It has been shown that the functional activity of COX-1 is increased in the spleen in hypothermic conditions induced by LPS. Our suggestion is that the COX-1 produced by the spleen plays a crucial role in the thermo metabolic responses observed in cases of sepsis by synthesizing prostanoids. In order to uncover how COX-1 interferes with the profile of inflammatory mediators produced during severe systemic inflammation, we will study the acting of such isoform by harvesting a rat's spleen to stimulate splenic macrophages in vitro, so that we can dose mediators produced after LPS stimulation. Furthermore, we will study the products derived from the COX-1 pathway in differentiated mast cells, originated from a rat's bone marrow, also to dose inflammatory mediators produced after stimulation. Thus, we aim to obtain results that indicate the role of COX-1 during the initial phase of the inflammatory response and which are the major lipid mediators produced by such route in said context. (AU)