Expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and mitochondrial oxidative phosphorylation in septic patients.
OBJECTIVE
Sepsis is a complex disease that is characterized by activation and inhibition of different cell signaling pathways according to the disease stage. Here, we evaluated genes involved in the TLR signaling pathway, oxidative phosphorylation and oxidative metabolism, aiming to assess their interactions and resulting cell functions and pathways that are disturbed in septic patients.


METHODS
Blood samples were obtained from 16 patients with sepsis secondary to community acquired pneumonia at admission (D0), and after 7 days (D7, N = 10) of therapy. Samples were also collected from 8 healthy volunteers who were matched according to age and gender. Gene expression of 84 genes was performed by real-time polymerase chain reactions. Their expression was considered up- or down-regulated when the fold change was greater than 1.5 compared to the healthy volunteers. A p-value of ≤ 0.05 was considered significant.


RESULTS
Twenty-two genes were differently expressed in D0 samples; most of them were down-regulated. When gene expression was analyzed according to the outcomes, higher number of altered genes and a higher intensity in the disturbance was observed in non-survivor than in survivor patients. The canonical pathways altered in D0 samples included interferon and iNOS signaling; the role of JAK1, JAK2 and TYK2 in interferon signaling; mitochondrial dysfunction; and superoxide radical degradation pathways. When analyzed according to outcomes, different pathways were disturbed in surviving and non-surviving patients. Mitochondrial dysfunction, oxidative phosphorylation and superoxide radical degradation pathway were among the most altered in non-surviving patients.


CONCLUSIONS
Our data show changes in the expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and oxidative phosphorylation. Importantly, distinct patterns are clearly observed in surviving and non-surviving patients. Interferon signaling, marked by changes in JAK-STAT modulation, had prominent changes in both survivors and non-survivors, whereas the redox imbalance (iNOS signaling, oxidative phosphorylation and superoxide radical degradation) affecting mitochondrial functions was prominent in non-surviving patients.
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Laura A
LA
Nucci
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Sidnéia S
SS
Santos
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Milena K C
MK
Brunialti
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Narendra Kumar
NK
Sharma
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Flavia R
FR
Machado
Hospital Israelita Albert Einstein, São Paulo, Brazil.
Murillo
M
Assunção
Hospital Sírio Libanês, São Paulo, Brazil.
Luciano C P
LC
de Azevedo
Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de Sao Paulo, São Paulo, Brazil.
Reinaldo
http://orcid.org/0000-0003-1149-4598
R
Salomao
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018805:Sepsis / Q000175:diagnosis / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D051193:Toll-Like Receptors; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human