Work

Measurement of hepatic lipid content and composition in humans with proton ultra-short TE MR spectroscopy at 7T

Year: 2015

Type: conference-paper

Abstract: BACKGROUND: Acute lung injury (ALI) is a life threatening disease characterized by a damaged alveolar endothelium and epithelium, loss of the capillary-alveolar barrier, edema formation and infiltration of inflammatory cells, such as neutrophils.Neutrophil extravasation is mainly mediated by inflammatory cytokines, but recently it was shown that also platelets conduct neutrophil migration to sites of injury.One important kinase transmitting platelet activation is the phosphoinositide 3-kinase (PI3K).The aim of this project is to elucidate the influence of platelet PI3K on ALI.METHODS: To study this task we bred mice with a megakaryocyte/platelet specific gene deletion of p85α one of the regulatory subunits of the PI3K.First, we examined the effects of p85α deficiency on platelet activation in vitro by measuring surface activation markers via flow cytometry and their potential to aggregate via light transmission aggregometry.Further, we treated mice intra-tracheally with hydrochloric acid (HCl) and analyzed leukocyte influx into the lung using flow cytometry and cytokine release by ELISA.RESULTS: We found that platelets lacking p85α have a reduced surface expression of CD62P and CD40L compared to wildtype platelets in response to ADP (P2Y 12 agonist) and AY-NH2 (PAR4 agonist).Additionally, the p85α knockout provokes a diminished aggregation after thrombin activation.Challenging knockout mice and wild-type littermates with HCl intra-tracheally, we observed attenuated leukocyte accumulation in the bronchoalveolar space and decreased cytokine release of interleukin-12 (IL-12) in the platelet p85α deficient mice.CONCLUSIONS: These results indicate that PI3K is important to conduct platelet activation upon stimulation with various agonists.Lack of platelet PI3K reduces platelet activation and therefore likely diminishes leukocyte extravasation, leading to ameliorated symptoms in the murine model of ALI.

Source: MPG.PuRe (Max Planck Society)