Abstract
Multiple organ failure (MOF) is the major cause of morbidity and mortality in intensive care patients, but the mechanisms causing this severe syndrome are still poorly understood. Inflammatory response, tissue hypoxia, immune and cellular metabolic dysregulations, and endothelial and microvascular dysfunction are the main features of MOF, but the exact mechanisms leading to MOF are still unclear. Recent progress in the membrane research suggests that cellular plasma membranes play an important role in key functions of diverse organs. Exploration of mechanisms contributing to plasma membrane damage and repair suggest that these processes can be the missing link in the development of MOF. Elevated levels of extracellular phospholipases, reactive oxygen and nitrogen species, pore-forming proteins (PFPs), and dysregulation of osmotic homeostasis occurring upon systemic inflammatory response are the major extracellular inducers of plasma membrane damage, which may simultaneously operate in different organs causing their profound dysfunction. Hypoxia activates similar processes, but they predominantly occur within the cells targeting intracellular membrane compartments and ultimately causing cell death. To combat the plasma membrane damage cells have developed several repair mechanisms, such as exocytosis, shedding, and protein-driven membrane remodeling. Analysis of knowledge on these mechanisms reveals that systemic damage to plasma membranes may be associated with potentially reversible MOF, which can be quickly recovered, if pathological stimuli are eliminated. Alternatively, it can be transformed in a non-resolving phase, if repair mechanisms are not sufficient to deal with a large damage or if the damage is extended to intracellular compartments essential for vital cellular functions.
Highlights
Considerable number of critically ill patients develop multiple organ failure (MOF) ( called multiple organ dysfunction syndrome (MODS), which is the leading cause of morbidity and mortality in intensive care patients [1–3]
We have considered two general pathological processes, systemic inflammatory response and hypoxia, which are associated with Multiple organ failure (MOF) and collected evidence that the release of substances causing damage to plasma membranes in diverse organs is a key process leading to MOF (Figure 4)
Inflammatory response causes damage to plasma membranes mediated by elevated levels of PLA2, reactive oxygen and nitrogen species (RONS), and pore-forming proteins (PFPs) in extracellular fluids
Summary
Considerable number of critically ill patients develop multiple organ failure (MOF) ( called multiple organ dysfunction syndrome (MODS), which is the leading cause of morbidity and mortality in intensive care patients [1–3]. The third mechanism of membrane damage accompanying the development of MOF is the interaction of membranes with so-called PFTs, termed as PFPs. These proteins disturb biological membranes and increase permeability by forming large pores [18] (Figure 1C) due to cytolytic transmembrane assemblies; this not necessarily kills the cells, but substantially changes cellular functions [54]. The mechanisms connecting damage of plasma and intracellular membranes and organ function/dysfunction will be considered below.
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