Molecular mechanisms of organ damage in sepsis: an overview

Abstract

Sepsis is one of the most common reasons for hospitalization. This condition is characterized by systemic inflammatory response to infection. International definition of sepsis mainly points out a multi-organ dysfunction caused by a deregulated host response to infection. An uncontrolled inflammatory response, often referred to as "cytokine storm", leads to an increase in oxidative stress as a result of the inhibition of cellular antioxidant systems. Oxidative stress, as well as pro-inflammatory cytokines, initiate vascular endothelial dysfunction and, in consequence, impair microcirculation. Microcirculation damage leads to adaptive modifications of cell metabolism. Moreover, mitochondrial dysfunction takes place which results in increased apoptosis and organ damage. Non-coding RNA fragments, especially miRNA molecules, may play an important role in the pathomechanism of sepsis. Numerous studies have indicated altered expression of various miRNAs in sepsis. miRNAs can be used as markers in the diagnosis and prognosis of disease development. In turn, intracellular miRNAs regulate the TLR4/NFκB pathway responsible for the expression of pro-inflammatory cytokine genes involved in the inflammatory response in sepsis. The understanding of detailed molecular mechanisms leading to organ damage can contribute to the development of specific therapy methods thereby improving the prognosis of patients with sepsis.

Keywords: Cytokine storm; Mitochondria; Oxidative stress; Sepsis; miRNA.

Fig. 1

Microcirculation dysfunction and organ damage in sepsis.

Fig. 2

NFκB activation pathway.

Fig. 3

The generation of intra-mitochondrial ROS and its consequences for the functioning of mitochondria. ROS formed in mitochondria promote oxidative damage to mitochondrial proteins, membranes and mtDNA. These damages result in the outflow of cytochrome C into the cytosol and consequent increase in apoptosis. Increased permeability of inner mitochondrial membrane enables the transport of many different small molecules. Mitochondrial ROS affect signal transmission processes, which may alter some cell functions. mtDNA - mitochondrial DNA.

Fig. 4

Generation and significance of reactive nitrogen species (RNS).

Fig. 5

Mitochondrial fusion and disintegration. Damaged elements present in different organelles are gathered as a result of fusion into one mitochondrion. Asymmetric decay leads to the formation of functional organelles and mitochondria in which all damages are accumulated. These dysfunctional mitochondria are removed by autophagy.

Fig. 6

Apoptosis of various cells in sepsis and its consequences for organ functioning.