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LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals with Diabetes

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posted on 15.06.2021, 18:49 by Icaro Bonyek-Silva, Antônio Fernando Araújo Machado, Thiago Cerqueira-Silva, Sara Nunes, Márcio Rivison Silva Cruz, Jéssica Silva, Reinan Lima Santos, Aldina Barral, Pablo Rafael Silveira Oliveira, Ricardo Khouri, Henrique C. Serezani, Cláudia Brodskyn, Juliana Ribeiro Caldas, Manoel Barral-Netto, Viviane Boaventura, Natalia Machado Tavares
Diabetes is a known risk factor for severe COVID-19, the disease caused by the new coronavirus SARS-CoV-2. However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. Therefore, we aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of hospitalized patients for COVID-19, with diabetes and without diabetes. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of SARS-CoV-2 main receptor system (ACE2/TMPRSS2) and main molecule of LTB4 pathway (ALOX5). We found that diabetes activates LTB4 pathway, and during COVID-19, it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19-related disorders, such as reduced SpO2/FiO2 and PaO2/FiO2 levels, and increased disease duration. In addition, the expression of ACE2 and ALOX5 are positively correlated, with increased expression in COVID-19 patients with diabetes requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB4 is significantly increased in individuals with diabetes. Besides, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB4 and IL-6 systemic levels, as well as, ACE2/ALOX5 blood expression could be early markers of severe COVID-19 in individuals with diabetes.

Funding

This work was supported by Foundation for Scientific and Technological Development in Health (FIOTEC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) under Finance Code 001 and Conselho Nacional de Desenvolvimento Científico e Tecnológico – BRAZIL (CNPq).

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