Low Dose of Esmolol Attenuates Sepsis-Induced Immunosuppression via Modulating T-Lymphocyte Apoptosis and Differentiation

Abstract

Background: Immunosuppression caused by immune cell apoptosis and an imbalance of T helper 2 cells (T H 2) and T helper 1 cells (T H 1), is associated with poor outcomes in septic patients. Esmolol was reported to improve survival by modulating immune responses in septic shock. Whether esmolol could alleviate sepsis-induced immunosuppression and the optimal dose are unclear. Methods: Four hours after cecal ligation and puncture (CLP), Wistar rats were randomized into CLP, CLP + E-5 (esmolol: 5 mg·kg −1 ·h −1 ) and CLP + E-18 (esmolol: 18 mg·kg −1 ·h −1 ) groups. Eight rats were underwent sham operation. Eighteen hours after CLP, hemodynamics and organ histological injuries were evaluated, peripheral blood mononuclear cells apoptosis and T-lymphocyte subsets counts were determined by flow cytometry, and the expression of p-Akt, Bcl-2, cleaved Caspase-3, and p-Erk1/2 in splenic CD4 + T-lymphocytes was determined by western blot and immunohistochemistry. β 1 -Adrenoreceptor expressions were evaluated using real-time polymerase chain reaction and immunohistochemistry. Results: Cecal ligation and puncture induced tachycardia, hypotension, hyperlactatemia, and multiple organ injury. Heart rate was unchanged in the CLP + E-5 group but decreased in the CLP + E-18 group. Hypotension, lactatemia, and multiple organ injuries were improved only in the CLP + E-5 group. T-lymphocyte apoptosis and T H 2/T H 1 ratio was decreased in CLP + E-5 but not in CLP + E-18. p-Akt and Bcl-2 expressions were increased, while cleaved Caspase-3 and p-Erk1/2 expressions were decreased in CLP + E-5. β 1 -Adrenoreceptor expressions were unchanged in both CLP + E-5 and CLP + E-18 groups. Conclusions: Low dose of esmolol reduced T-lymphocyte apoptosis and restored T H 2/T H 1 ratio in septic shock. Esmolol might modulate Akt/Bcl-2/Caspase-3 pathway to relieve T-lymphocyte apoptosis and inhibit Erk1/2 activity to decrease T H 0 differentiation to T H 2. Esmolol may be a potential immunoregulator of septic shock.

Identification of Key Molecular Signaling Pathways and Therapeutic Targets in Sepsis Shock

“…PPI network analyzed for the intersection genes and showed that adaptive immunity genes formed a prominent cluster, mainly composing to sepsis [2,8] . Our study was quite in consensus with the suggestions as demonstrated by the fact that the MEblue module significantly associated with sepsis shock and was enriched with downregulated genes for antigen processing and presentation, and type 1 and type 2 helper T cell differentiation [9][10][11] , which exhibited inhibition of T cell activation and differentiation. Besides, the MEblue module was enriched with decreased hematopoietic cell lineage genes including CD2, CD5 and CD7 markers for T-cell progenitors, which meant competence of primitive Hematopoietic Stem Cell (HSC) to produce T lymphocytes might be severely compromised in sepsis shock patients.…”

“…In steady-state, HSC was kept in a cell and Th17 differentiation. Our study suggested that HSCs defective derived T-cells might be the predominant reason for T-cell number reduction, despite sepsis shock it also induces apoptosis or any other unfavourable conditions as reported [10,32] . A clinical study had documented that lymphopenia and T-cell depletion were critically associated with increased mortality.…”

Prediction of Prognosis in Patients with Sepsis Based on Platelet-Related Genes

“…Abnormal differentiation of T lymphocytes may lead to the pathogenesis of sepsis [21]. Ma et al [22] found that low-dose esmolol alleviates sepsis-induced immune suppression by regulating T lymphocyte apoptosis and differentiation. The process of white blood cells extravasating from the bloodstream to inflamed tissues requires adhesion between white blood cells and endothelial cells, allowing white blood cells to locate infected or damaged tissues and participate in pathogen clearance, repair, and regeneration processes [23].…”

Combination of NK and Other Immune Markers at Early Phase Stratify the Risk of Sepsis Patients: A Retrospective Study

“…The apoptosis rate of T cells shows an obvious increase in sepsis, and inhibition of apoptosis alleviates the severity of sepsis. 19 , 20 The exhaustion of T cells is also closely related to the mortality of sepsis patients. 10 , 21 , 22 HLA-DR is a class II major histocompatibility complex (MHC) protein that mediates antigen-specific recognition by CD4+ helper T lymphocytes.…”