Organ Damage in Sepsis: Molecular Mechanisms

*Grażyna Sygitowicz and Dariusz Sitkiewicz*

### **Abstract**

Sepsis is one of the most common reasons for hospitalisation. This condition is characterised 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 impaired autophagy. Non-coding RNA, especially miRNA and lncRNA molecules, may play an important role in the pathomechanism of sepsis. Altered expression of various ncRNAs in sepsis suggest, that these molecules can be used not only as diagnostics and prognostic markers but also as the target points in the pharmacotherapy of 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:** sepsis, cytokine storm, microcirculation, oxidative stress, RAS, ncRNA

### **1. Introduction**

Sepsis was already known to ancient Greeks since the times of Hippocrates (460–370 BC) as a condition causing "rotting" of the body. Later, the Persian philosopher and physician Ibn Sina, or Avicenna (980–1037 AD) described for the first time sepsis as a "decay" of blood and tissues accompanied by fever. Sepsis is one of the most frequent causes of hospitalisation in Intensive Care Units. It constitutes a significant clinical problem, in many cases with a fatal outcome. Significant advances in critical care medicine have defined sepsis as an organ dysfunction syndrome. The incidence of this type of disorder is still constantly rising. Morbidity significantly correlates with the ageing of societies and presence of other comorbidities. The prognosis is worse when the mentioned correlations are strong and the patient is diagnosed too late. Although sepsis can occur in any age group, its risk is definitely greater in patients over 60 years of age. Moreover, sepsis is growing rapidly as a result of a poorly controlled, multidirectional response of the organism to an external factor, i.e. pathogen, and its further increase may be due to endogenous factors or coexisting diseases [1].

Sepsis starts with a period of hyperinflammation, in which the macrophages, monocytes, T-cells and neutrophils are activated and recruited to various organs. The uncontrolled inflammatory response, so-called cytokine storm leads to many metabolic disorders associated with oxidative stress. The oxidative stress, but also proinflammatory cytokines, promote endothelial function disorders and, consequently, microcirculatory damages. At the final stage of cytokine storm a hypoinflammatory reaction develops, leading to multiple organ damages. These changes are underlined by mitochondrial function disorders, intensified oxidative stress and deregulation of apoptosis and autophagy processes. A neurohormonal activation, in the first place of the renin-angiotensin system (RAS), is an important element of the mechanisms leading to organ damage. Many studies have suggested that in sepsis, changes occur of the expression of various RNA molecules: long non-coding RNA (lncRNA) and microRNA (miRNA). The non-coding RNA fragments can thus play the role of molecular markers, both diagnostic, and prognostic, in the development of sepsis. The knowledge of the molecular mechanisms responsible for organ damages would enable a development of adequate and effective therapeutic methods, improving the prognosis for patients.
