Relationship between COX-1 and proinflammatory cytokines in systemic inflammation

• Grant number: 22/13467-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2022
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre Alarcon Steiner
• Grantee: Manoela Osorio Reis Sales
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/03418-0 - Hypothermia in Sepsis: causes and consequences, AP.TEM

Abstract

Cyclooxygenases (COX) are key enzymes in the biosynthesis of lipid mediators that play key roles in inflammation, especially the inducible isoform, called COX-2. The "constitutive" isoform, called COX-1, is seen asan enzyme of importance for "housekeeping" functions, with no role in inflammation.Recent evidence challenges this paradigm by revealing that COX-1 can also beimportant in inflammation when it is severe and systemic, as in the case of sepsis. It is knownthat pharmacological inhibition of COX-1 in rats attenuates several physiological manifestationsof severe systemic inflammation induced by bacterial lipopolysaccharide (LPS), such ashypotension, acidosis and hypothermia. However, the cellular and molecular mechanisms involvedstill need to be clarified. This project aims toassess whether COX-1 inhibition affects the balance between pro- and anti-inflammatory cytokinesin this model. A selective COX-1 inhibitor (SC-560) or its vehicle will be administered i.p.90 min before challenge with a relatively high dose of LPS (1 mg/kg i.v.), and samplesof blood (plasma) and organs will be collected at 90 and 180 min post-LPS. The plasma levels ofcytokines will be determined by ELISA, while their gene expressionswill be evaluated in the organs by real time RT-PCR. Those cytokines thatare involved in the acute phase of the inflammatory response will be evaluated: TNF, IL-1b, IL-6 and IFN-gamma, IL-10, sTNFR and IL1ra.