Investigatoin of urate oxidation and urate-derived adducts in plasma albumin in cystic fibrosis and sepsis

Abstract

During the development of the PhD thesis which this research plan is related to (FAPESP, 2015/21563-9) we demonstrated the oxidation of uric acid and formation of urate hydroperoxide by activated blood neutrophils. Urate hydroperoxide and other electrophile intermediates from urate oxidation can react with plasma albumin to form covalent adducts and these adducts can be used as biomarkers for urate oxidation and inflammatory progression in the vascular sheet. Beside to that, the oxidation of uric acid by neutrophils decreased the production of hypochlorous acid due to the competition between uric acid and chloride by myeloperoxidase and this disturbed the killing activity of these cells against Pseudomonas aeruginosa. Therefore, uric acid oxidation in inflammation clearly affects the ability of the immune cells to deal with invading pathogens. In agreement to that, higher levels of plasma uric acid and its oxidation product, allantoin, were correlated with a worst outcome in patients with cystic fibrosis infected with Pseudomonas aeruginosa. In this BEPE project, we will further reinforce the correlation between uric acid oxidation and infection in cystic fibrosis by evaluating adducts between albumin and urate-derivated electrophiles in plasma of patients presenting this disease. Plasma albumin adducts constitute a better biomarker than allantoin and other urate oxidation products because they are more stable. In addition, this will be additional evidence to confirm a role for urate oxidation in the progression of infectious disease. Clinical analyses will be also performed in septic patients from the Christchurch Hospital - Medical School, Unviversity of Otago. This will give the student the opportunity to learn the analytical method of proteome from plasma patients and also to perform statistical analyses in clinical studies. This clinical study will be continued here in Brazil, in collaboration with Hospital das Clinicas, Universidade de São Paulo. Plasma from septic patients that were admitted in the intensive unit care will be analysed and correlated with disease outcome. Thus, a bilateral Brazil-New Zealand clinical study will be carried out, supporting the relevance and impact of the study. (AU)