Guanabenz Prevents d-Galactosamine/Lipopolysaccharide-Induced Liver Damage and Mortality.

Jessica Perego,Lionel Spinelli,Philippe Pierre,Caroline Laprie,Evelina Gatti,Lionel Chasson,Voahirana Camosseto,Clarisse Bourbon

doi:10.3389/fimmu.2017.00679

Abstract

Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-α) expression. Consequently, drugs interfering with eIF2α phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2α phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti-inflammatory activity by increasing in vitro interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the d-galactosamine (d-galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF-α production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure.

Highlights

Endotoxemia is a complex syndrome defined by an uncontrolled activation of the innate immune system, with initiation of the complement pathway and high amounts of circulating proinflammatory tumor necrosis factor-alpha (TNF-α), which induces multiple organs failure [1]
While the DEGs with an expression reinforced by GBZ, belonged to pathways regulated by myeloid differentiation primary-response protein 88 (MyD88) and IFN γ, those with a reduced expression appeared to be controlled by IRF3 and SASH1 (Figure 1A). These results suggested that GBZ skews TLR4 activation by reducing the intensity of the IRF3 signaling pathway [22], while promoting instead the MyD88dependent pathway leading to increased transcription of IL-12 and potentially of IL-10 [23]
Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by massive pro-inflammatory cytokines release and liver damage [28]

Summary

Introduction

Endotoxemia is a complex syndrome defined by an uncontrolled activation of the innate immune system, with initiation of the complement pathway and high amounts of circulating proinflammatory tumor necrosis factor-alpha (TNF-α), which induces multiple organs failure [1]. Systemic TLR4 triggering is GBZ Protects from Endotoxemia often the result of microbe translocation from the gut lumen into the blood stream, which is normally reduced by a collaboration between the intestinal tract cells and associated immunocytes In this situation, the liver constitutes the second line of defense by eliminating the remaining invading bacteria and bacterial products (e.g., LPS), and preventing systemic dispersion. Liver dysfunction often occurs in early sepsis, and one of the classical experimental mouse model of endotoxemia is based on liver sensitization by d-galactosamine (d-galN) prior to LPS injection [5] In this model, LPS-induced lethality has been shown to be triggered by a caspase-dependent fulminant apoptotic hepatitis induced by TNF-α overproduction and not directly from the systemic inflammatory response [6]

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Results

Conclusion