title: Mini-review: novel therapeutic strategies to blunt actions of pneumolysin in the lungs.
abstract: 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.
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, USA. rlucas@gru.edu
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.forename: Istvan
authors.initials: I
authors.lastname: Czikora
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.forename: Evgeny
authors.initials: E
authors.lastname: Zemskov
authors.forename: Boris
authors.initials: B
authors.lastname: Gorshkov
authors.forename: Umapathy
authors.initials: U
authors.lastname: Siddaramappa
authors.forename: Aluya
authors.initials: A
authors.lastname: Oseghale
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lawson
authors.forename: Alexander
authors.initials: A
authors.lastname: Verin
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Helena
authors.initials: H
authors.lastname: Pillich
authors.forename: Maritza
authors.initials: M
authors.lastname: Romero
authors.forename: Martin
authors.initials: M
authors.lastname: Leustik
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Trinad
authors.initials: T
authors.lastname: Chakraborty
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000633:toxicity; D002675:Child, Preschool; D004195:Disease Models, Animal; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000382:microbiology; D037102:Lectins / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology* / Q000473:pathology; D011014:Pneumonia / Q000382:microbiology / Q000628:therapy*; D011654:Pulmonary Edema / Q000382:microbiology / Q000628:therapy; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D013301:Streptolysins / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D037521:Virulence Factors
chemical_list: D001426:Bacterial Proteins; D037102:Lectins; D013301:Streptolysins; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; C032290:plY protein, Streptococcus pneumoniae; D013006:Growth Hormone