Mini-review: Novel therapeutic strategies to blunt actions of pneumolysin in the lungs

Rudolf Lucas, Istvan Czikora, Supriya Sridhar, Evgeny Alexandrovich Zemskov, Boris A Gorshkov, Umapathy N Siddaramappa, Aluya Oseghale, Jonathan Lawson, Alexander Dmitriyevich Verin, Ferenc G. Rick, Norman L. Block, Helena Pillich, Maritza Josefina Romero Lucas, Martin Leustik, Andrew V. Schally, Trinad Chakraborty

Research output: Contribution to journalReview article

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1244-1260
Number of pages17
JournalToxins
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2013

Fingerprint

Anti-Bacterial Agents
Lung
Edema
Sodium
Epithelial Sodium Channels
Sodium-Potassium-Exchanging ATPase
Pneumonia
Virulence Factors
Pathogens
Streptococcus pneumoniae
Adenosine Triphosphatases
Permeability
Bacteria
Therapeutics
Cholesterol
Alveolar Epithelial Cells
Autolysis
Streptococcus pneumoniae plY protein
Cause of Death
Epithelial Cells

Keywords

  • Growth hormone-releasing hormone
  • Permeability edema
  • Pneumolysin
  • TNF

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Mini-review : Novel therapeutic strategies to blunt actions of pneumolysin in the lungs. / Lucas, Rudolf; Czikora, Istvan; Sridhar, Supriya; Zemskov, Evgeny Alexandrovich; Gorshkov, Boris A; Siddaramappa, Umapathy N; Oseghale, Aluya; Lawson, Jonathan; Verin, Alexander Dmitriyevich; Rick, Ferenc G.; Block, Norman L.; Pillich, Helena; Romero Lucas, Maritza Josefina; Leustik, Martin; Schally, Andrew V.; Chakraborty, Trinad.

In: Toxins, Vol. 5, No. 7, 01.07.2013, p. 1244-1260.

Research output: Contribution to journalReview article

Lucas, R, Czikora, I, Sridhar, S, Zemskov, EA, Gorshkov, BA, Siddaramappa, UN, Oseghale, A, Lawson, J, Verin, AD, Rick, FG, Block, NL, Pillich, H, Romero Lucas, MJ, Leustik, M, Schally, AV & Chakraborty, T 2013, 'Mini-review: Novel therapeutic strategies to blunt actions of pneumolysin in the lungs', Toxins, vol. 5, no. 7, pp. 1244-1260. https://doi.org/10.3390/toxins5071244
Lucas, Rudolf ; Czikora, Istvan ; Sridhar, Supriya ; Zemskov, Evgeny Alexandrovich ; Gorshkov, Boris A ; Siddaramappa, Umapathy N ; Oseghale, Aluya ; Lawson, Jonathan ; Verin, Alexander Dmitriyevich ; Rick, Ferenc G. ; Block, Norman L. ; Pillich, Helena ; Romero Lucas, Maritza Josefina ; Leustik, Martin ; Schally, Andrew V. ; Chakraborty, Trinad. / Mini-review : Novel therapeutic strategies to blunt actions of pneumolysin in the lungs. In: Toxins. 2013 ; Vol. 5, No. 7. pp. 1244-1260.
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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.",
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