Gene Expression of Protein Tyrosine Phosphatase 1B and Endoplasmic Reticulum Stress During Septic Shock

Abstract

Introduction: Protein Tyrosine Phosphatase 1B (PTP1B) and endoplasmic reticulum stress (ERS) are involved in the septic inflammatory response. Their inhibition is associated with improved survival in murine models of sepsis. The objective was to describe PTP1B and ERS expression during septic shock in human.Material and Methods: Prospective study including patients admitted to intensive care unit (ICU) for septic shock. Blood samples were collected on days 1 (D1), 3 and 5 (D5). Quantitative PCR (performed from whole blood) evaluated the expression of genes coding for PTP1B (PTPN1) and key elements of ERS (GRP78, ATF6, CHOP) or for endothelial dysfunction-related markers (ICAM1 and ET1). We analyzed gene variation between D5 and D1, collected glycemic parameters, insulin resistance and organ failure was evaluated by Sequential Organ Failure Assessment (SOFA) score.Results: We included 44 patients with a mean SAPS II 50 ± 16 and a mortality rate of 13.6%. Between D1 and D5, there was a significant decrease of PTPN1 (p < 0.001) and ATF6 (p < 0.001) expressions. Their variations of expression were correlated with SOFA variation (PTPN1, r = 0.35, CI 95% [0.05; 0.54], p = 0.03 and ATF6, r = 0.45 CI 95% [0.20; 0.65], p < 0.001). We did not find any correlation between PTPN1 expression and insulin resistance or glycemic parameters. Between D1 and D5, ATF6 and PTPN1 expressions were correlated with that of ET1.Conclusions: Our study has evaluated for the first time the expression of PTP1B and ERS in patients with septic shock, revealing that gene expression variation of PTPN1 and ATF6 are partly correlated with the evolution of septic organ failure and with endothelial dysfunction markers expression.

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

“…ATF6 upregulates many protective genes and downregulates many potentially damaging genes, and previous studies have shown that ATF6 activation in cardiac myocytes protects the heart from ischemic damage, while inhibiting ATF6 has the opposite effect ( 30 – 32 ). Given our results and as previously suggested, it is possible that among UPR pathways, ATF6 is the most intensely involved pathway during acute SIRS (which could explain why its activation continued to increase 24 h after CPB) ( 10 ). The three UPR pathways have, in part, common effects to resolve ERS: chaperone synthesis, activation of ER associated degradation, activation of Nuclear Factor-Kappa B, etc.…”

“…It has been shown that ERS is implicated in endothelial dysfunction and that its inhibition in humans improves endothelial dysfunction induced by glucose ingestion ( 13 , 35 ). Moreover, in a previous study conducted in septic patients, we have shown an association between expressions of ATF6 and ET1 (coding for endothelin-1 which is associated with endothelial dysfunction) ( 10 ). However, we did not find a link between VCAM-1, Syndecan-1 or IL-6 and GRP78 variations.…”

“…In view of a previous work studying UPR expression during septic SIRS, we considered that it was necessary to include at least 45 patients to highlight a significant UPR after CPB ( 10 ). Since each subject was taken as its own control, the non-parametric Wilcoxon matched pairs signed rank test was used to assess significant variations in quantitative parameters.…”

“…Cytokine synthesis induces a massive increase in protein synthesis and, thus, an ERS which in turn activates NF-kB and thus maintains this synthesis ( 9 ). Cellular dysfunction, hallmarked by ERS, is increasingly recognized as an important contributor to the development of organ failure in critical illness, and in particular during systemic inflammation ( 6 , 10 , 11 ). ERS induces dysfunction and apoptosis of cardiomyocytes that can lead to heart failure and UPR have a protective effect on acute or chronic heart failure ( 12 ).…”

“…In experimental sepsis, a treatment with 4-phenylbutyric acid (4BPA; a chemical chaperone which inhibits ERS) decreases the tissue expression level of inflammatory cytokines, reduces organ dysfunction and improves survival ( 14 , 15 ). In human, ERS is activated in the mononuclear cells of patients with septic acute lung injury, is involved in AKI and its expression is partly correlated with organ failure in patients with septic shock ( 10 , 14 , 16 ). A recent work has shown the feasibility of the non-invasive detection of the ERS in urine in patients undergoing cardiac surgery with CPB and indicates that an early and robust adaptive UPR is critical for endogenous protection to acute renal failure ( 17 ).…”