Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis.

Flora Magno De Jesus Oliveira,Patrícia Alves Reis,Adriana Ribeiro Silva,Hugo Caire De Castro Faria Neto,Cassiano Felippe Gonçalves-De-Albuquerque,Isabel Matos Medeiros De Moraes,Vinicius Novaes Rocha,Patrícia Torres Bozza,Ronald Gladue

doi:10.1155/2020/1839762

Abstract

Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1β. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis.

Highlights

According to the Third International Consensus, sepsis is defined as life-threatening organ dysfunction caused by a deregulated host response to infection [1]
Sepsis was induced through cecal ligation and puncture (CLP), and sham-operated animals were used as controls
We demonstrated that a single dose treatment with simvastatin (2 mg/kg b.w., intravenously) was able to improve renal function (Figure 1(b)) and to reduce hepatic dysfunction (Figure 1(a))

Summary

Introduction

According to the Third International Consensus, sepsis is defined as life-threatening organ dysfunction caused by a deregulated host response to infection [1]. Sepsis is one of the most common causes of death and critical illness in the world and is increasingly prevalent in the developed world with high financial cost. Systemic infection is often revealed by or associated with brain dysfunction, which is characterized by alteration of consciousness, ranging from delirium to coma, seizure or focal neurological signs, and long-term cognitive disability [2]. Sepsis evolves when the host cannot limit primary infection, leading to a severe inflammatory response syndrome (SIRS) [3] that can be followed by immunosuppression [4]. Statins are lipid lowering drugs, indicated for the prevention of cardiovascular diseases [5]. Statins compete with and inhibit the enzyme HMG-CoA reductase, hindering

Methods

Results

Conclusion