Role of platelet-activating factor in pneumolysin-induced acute lung injury

Abstract

PAF significantly contributed to PLY-induced acute injury in murine lungs. The PAF-mediated pressor response to PLY depends on thromboxane and on the downstream effectors phosphatidylcholine-specific phospholipase C, protein kinase C, and Rho-kinase.

Pneumolysin Mediates Platelet Activation In Vitro

“…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.…”

“…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].…”

“…Importantly, platelets are now recognized to be key players in orchestrating inflammatory responses [15], with platelet activation seemingly associated with acute lung injury in the experimental setting [9] and with myocardial infarction, worsening heart failure or arrhythmias in the clinical setting of invasive pneumococcal disease [16]. To our knowledge, however, only one previous study has addressed the direct involvement of Ply in mediating platelet activation, documenting aggregation of these cells following exposure to very high concentrations of the toxin, but without characterizing the mediators and mechanisms involved [17].…”

PKC-Dependent Phosphorylation of eNOS at T495 Regulates eNOS Coupling and Endothelial Barrier Function in Response to G+ -Toxins

“…Bactericidal antibiotics can promote significant release of G + -toxins and cause extensive and enduring injury even in a sterile lung. These thiol-sensitive gram positive (G + ) virulence factors oligomerize in the presence of cholesterol to form plasma membrane pores that not only stimulate calcium entry in various cell types but also stimulate phospholipase C and protein kinase C alpha (PKCα) as we and others have recently shown [5]–[7]. Listeria infections are most commonly associated with food-borne diseases but can result in severe and often fatal pulmonary diseases that are also characterized by permeability edema [8].…”

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

“…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.…”