The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction

Abstract

Background: Multiple organ injury and dysfunction often occurs in acute critical illness and adversely affects survival. However, in patients who survive, organ function usually recovers without permanent damage. It is, therefore, likely that there are reversible mechanisms, but this is poorly understood in the pathogenesis of multiple organ dysfunction syndrome (MODS). Aims: Based on our knowledge of extracellular histones and pneumolysin, as endogenous and exogenous pore-forming toxins, respectively, here we clarify if the extent of cell membrane disruption and recovery is important in MODS. Methods: This is a combination of retrospective clinical studies of a cohort of 98 patients from an intensive care unit (ICU) in a tertiary hospital, with interventional animal models and laboratory investigation. Results: In patients without septic shock and/or disseminate intravascular coagulation (DIC), circulating histones also strongly correlated with sequential organ failure assessment (SOFA) scores, suggesting their pore-forming property might play an important role. In vivo, histones or pneumolysin infusion similarly caused significant elevation of cell damage markers and multiple organ injury. In trauma and sepsis models, circulating histones strongly correlated with these markers, and anti-histone reagents significantly reduced their release. Comparison of pneumolysin deletion and its parental strain-induced sepsis mouse model showed that pneumolysin was not essential for sepsis development, but enhanced multiple organ damage and reduced survival time. In vitro, histones and pneumolysin treatment disrupt cell membrane integrity, resulting in changes in whole-cell currents and elevated intracellular Ca2+ to lead to Ca2+ overload. Cell-specific damage markers, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and cardiac troponin I (cTnI), were released from damaged cells. Once toxins were removed, cell membrane damage could be rapidly repaired and cellular function recovered. Conclusion: This work has confirmed the importance of pore-forming toxins in the development of MODS and proposed a potential mechanism to explain the reversibility of MODS. This may form the foundation for the development of effective therapies.