HIF-1 alpha and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes From Survivors and Non-Survivors Patients During Clinical Sepsis

Author(s)

Ferreira, Bianca Lima ^[1] ; Figueiredo Leite, Giuseppe Gianini ^[1] ; Colo Brunialti, Milena Karina ^[1] ; Assuncao, Murillo ^[2] ; Pontes Azevedo, Luciano Cesar ^[3] ; Freitas, Flavio ^[4] ; Salomao, Reinaldo ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Div Infect Dis, Escola Paulista Med, Sao Paulo - Brazil

^[2] Hosp Israelita Albert Einstein, Intens Care Unit, Sao Paulo - Brazil

^[3] Hosp Sirio Libanes, Intens Care Unit, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Hosp Sao Paulo, Intens Care Unit, Escola Paulista Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: Shock; v. 56, n. 1, p. 80-91, JUL 2021.
• Web of Science Citations: 1

Abstract

Hypoxia inducible factor 1 alpha (HIF-1 alpha) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1 alpha by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation, and apoptosis. Here, we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1 alpha and other hypoxia responsive genes in peripheral blood mononuclear cells from patients with sepsis secondary to community acquired infections. Samples were collected at intensive care unit admission (D0, n=29) and after 7 days follow-up (D7, n = 18); healthy volunteers (n = 10) were included as controls. Hypoxia and glycolysis were among the top scored molecular signatures in the transcriptome datasets. PCR array showed that 24 out of 78 analyzed genes were modulated in septic patients compared with healthy volunteers; most of them (23/24) were downregulated at admission. This same pattern was observed in surviving patients, while non-survivors presented more upregulated genes. EGLN1, EGLN2, and HIF1AN, inhibitors of HIF-1 alpha activation were downregulated in patients, regardless of the outcome, while HIF-1 alpha and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO(2) ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis. (AU)

• FAPESP's process: 17/21052-0 - Sepsis: mechanisms, therapeutic targets and epidemiology
• Grantee: Reinaldo Salomão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/13855-2 - Evaluation of energy and oxidative metabolism in peripheral blood mononuclear cells (PBMC) from septic patients
• Grantee: Bianca Rodrigues Lima Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate