Severe
pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of
pneumonia is the G+ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing
antibiotic treatment due to the development of permeability
edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the
sodium transporters required for
edema reabsorption, including the apically expressed
epithelial sodium channel (ENaC) and the basolaterally expressed
sodium potassium pump (Na+-K+-
ATPase). The main agent inducing this
edema formation is the
virulence factor pneumolysin, a
cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by
antibiotic treatment or upon
autolysis. Sub-lytic concentrations of
pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated
sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability
edema, for which currently no standard
therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after
antibiotic treatment of patients with severe
pneumonia.