Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia

Witzenrath, Martin; Gutbier, Birgitt; Hocke, Andreas C.; Schmeck, Bernd; Hippenstiel, Stefan; Berger, Katharina; Mitchell, Tim; Toyos, Juan R. de los; Rosseau, Simone; Suttorp, Norbert; Schütte, Hartwig

doi:10.1097/01.ccm.0000220496.48295.a9

Cited by 127 publications

(141 citation statements)

References 46 publications

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“…Notwithstanding the previously documented direct, cytotoxic activities of Ply [8][9][10][11][12][13], the results of the current study are consistent with the existence of an additional potential mechanism of toxin-mediated acute adverse pulmonary and cardiac events, viz. platelet activation, which remains to be established in the clinical setting Nonetheless, these novel findings raise the important issue of the therapeutic potential of Ply-and platelet-directed therapies in the prevention or attenuation of pneumococcal CAP-related cardiac morbidity and mortality.…”

Section: As Shown Insupporting

confidence: 89%

“…Acute lung injury and multi-organ dysfunction syndrome, as well as acute cardiac events mostly occurring early in the course of CAP, have been identified as being significant contributors to mortality [1][2][3][4][5][6][7]. In the case of pneumococcal CAP, an increasing body of evidence, derived from both clinical and experimental studies, has implicated the major cytolytic, cholesterolbinding, pore-forming protein toxin, pneumolysin (Ply), in the pathogenesis of associated adverse pulmonary and cardiovascular events [8][9][10][11][12][13]. Although these harmful activities of Ply have been attributed to direct pulmonary and cardiac toxicity, it is noteworthy that Ply also possesses pro-inflammatory activities [14].…”

Section: Introductionmentioning

confidence: 99%

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Pneumolysin Mediates Platelet Activation In Vitro

Nel

Durandt

Mitchell

et al. 2016

Lung

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This study has explored the role of the pneumococcal toxin, pneumolysin (Ply), in activating human platelets. Following exposure to Ply [10-80 nanograms (ng)/ml], platelet activation and cytosolic Ca 2+ concentrations were measured flow cytometrically according to the level of expression of CD62P (P-selectin) and spectrofluorimetrically respectively. Exposure to Ply resulted in marked upregulation of expression of platelet CD62P, achieving statistical significance at concentrations of 40 ng/ml and higher (p<0.05), in the setting of increased influx of Ca 2+ . These potentially pro-thrombotic actions of Ply were attenuated by depletion of Ca 2+ from the extracellular medium, or by exposure of the cells to a pneumolysoid devoid of pore-forming activity. These findings are consistent with a mechanism of Plymediated platelet activation involving sub-lytic pore formation, Ca 2+ influx, and mobilization of CD62P-expressing α-granules, which, if operative in vivo, may contribute to the pathogenesis of associated acute lung and myocardial injury during invasive pneumococcal disease.

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Section: As Shown Insupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Pneumolysin Mediates Platelet Activation In Vitro

Nel

Durandt

Mitchell

et al. 2016

Lung

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“…Intriguingly, edema formation can occur days after the initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing and correlates with the presence of the bacterial virulence factor pneumolysin (PLY) (4,5). PLY is a 53-kDa cytoplasmic thiol-activated toxin released during pneumococcal lysis and is implicated in the pathogenesis of pneumococcal disease.…”

Section: Aggressive Treatment With Antibiotics In Patients Infected Withmentioning

confidence: 99%

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Lucas

Sridhar

Rick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na + transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na + /K + -ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na + uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.pneumonia | cyclic AMP

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“…Thereby, KLF2 may dampen the release of proinflammatory mediators in lung epithelium and endothelium; furthermore, it may act as a barrier-stabilizing molecule, as shown for vascular endothelial growth factor-mediated edema formation (45). It would be of interest to analyze how KLF2 expression contributes to the regulation of edema formation induced by pathogen-released agents, such as pneumolysin (24,46), as well as potent endogenous mediators, such as TNF-a, thrombin, or A, NF-kB activity seems to depend on PCAF acetylation. B and C, TLR2-and NOD2-related phosphorylation of PI3K results in pneumococcidependent expression of KLF2, which counterregulates NF-kB activity and IL-8 release.…”

Section: Discussionmentioning

confidence: 99%

“…Pneumonia in mice was induced by the encapsulated serotype 3 strain S. pneumoniae PN36 (National Collection of Type Cultures 7978), as described (24,25). S. pneumoniae R6x (and R6xDply; pneumolysin deficient) used for in vitro studies are the unencapsulated derivatives of serotype 2 strain D39 (10,26).…”

Section: Bacterial Strainsmentioning

confidence: 99%

TLR2- and Nucleotide-Binding Oligomerization Domain 2-Dependent Krüppel-Like Factor 2 Expression Downregulates NF-κB–Related Gene Expression

Zahlten

Steinicke

Opitz

et al. 2010

The Journal of Immunology

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The release of potent proinflammatory mediators is not only central for mounting an efficient host response, but also bears the risk for deleterious excessive tissue-damaging inflammation. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance between a robust inflammatory response to kill pneumococci and loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krüppel-like factor (KLF)2 counterregulates pneumococci- and pattern recognition receptor-related human lung cell activation. Pneumococci induced KLF2 expression in vitro and in a murine pneumonia model. Activation of TLR2- and nucleotide-binding oligomerization domain protein 2-related signaling induced KLF2 expression in a PI3K-dependent manner. Overexpression of KLF2 downregulated pneumococci-, TLR2-, and nucleotide-binding oligomerization domain protein 2-related NF-κB–dependent gene expression and IL-8 release, whereas small interfering RNA-based silencing of KLF2 provoked an enhanced inflammatory response. KLF2-dependent downregulation of NF-κB activity is partly reversible by overexpression of the histone acetylase p300/CREB-binding protein-associated factor. In conclusion, KLF2 may act as a counterregulatory transcription factor in pneumococci- and pattern recognition receptor-related proinflammatory activation of lung cells, thereby preventing lung hyperinflammation and subsequent organ failure.

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Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia

Abstract: Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension.

Cited by 127 publications

References 46 publications

Pneumolysin Mediates Platelet Activation In Vitro

Pneumolysin Mediates Platelet Activation In Vitro

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

TLR2- and Nucleotide-Binding Oligomerization Domain 2-Dependent Krüppel-Like Factor 2 Expression Downregulates NF-κB–Related Gene Expression

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