Abstract
Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo–metabolic state. NaHS infusion reduced sepsis–related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α–tubulin and protein kinase C–ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor–γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.
Highlights
Streptococcus pneumoniae is the leading cause of community acquired pneumonia in patients that require admission to the intensive care unit [1]
S. pneumoniae Resulted in Severe Pneumosepsis, Characterized by Lung Injury, Systemic Inflammation, Organ Injury and Low Bio-energetic Status
Preservation of the endothelial barrier may have been a mechanism of the observed decrease in distant organ injury in this study, as biomarkers of endothelial damage have been found in blood of patients with pneumonia, contributing to multiple organ failure [23]
Summary
Streptococcus pneumoniae is the leading cause of community acquired pneumonia in patients that require admission to the intensive care unit [1]. Infection with S. pneumoniae triggers an intense inflammatory reaction, which can lead to sepsis and multiple organ failure, including acute lung injury and acute kidney injury. Supportive treatment aims to enhance substrate and oxygen delivery to tissues to produce adenosine triphosphate (ATP), thereby preserving the bio–energetic status of organs [2]. The inflammatory response can directly damage mitochondrial DNA, lipids and respiratory complexes, thereby inhibiting oxidative phosphorylation [4] and diminishing ATP availability [2]. Mitochondrial dysfunction is associated with adverse outcome [5]. Influencing mitochondrial substrate utilization was shown to improve outcome in sepsis [6,7,8], which may be due to preserved mitochondrial structure and function [9], thereby preserving local ATP levels
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