Oncotarget

Research Papers:

Extracellular ATP is a danger signal activating P2X7 receptor in a LPS mediated inflammation (ARDS/ALI)

Sanja Cicko, Thomas Christian Köhler, Cemil Korcan Ayata, Tobias Müller, Nicolas Ehrat, Anja Meyer, Madelon Hossfeld, Andreas Zech, Francesco Di Virgilio and Marco Idzko _

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Oncotarget. 2018; 9:30635-30648. https://doi.org/10.18632/oncotarget.25761

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Abstract

Sanja Cicko1,*, Thomas Christian Köhler1,*, Cemil Korcan Ayata1, Tobias Müller1,2, Nicolas Ehrat1, Anja Meyer1, Madelon Hossfeld1, Andreas Zech1, Francesco Di Virgilio3 and Marco Idzko1

1University Hospital Freiburg, Department of Pneumology, Freiburg, Germany

2Division of Pneumology, University Hospital RWTH Aachen, Aachen, Germany

3Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy

*These authors contributed equally to this work

Correspondence to:

Marco Idzko, email: marco.idzko@uniklinik-freiburg.de

Keywords: acute respiratory distress syndrome; ATP; KN62; P2X7; celltype specific P2X7KO

Received: February 07, 2017     Accepted: June 19, 2018     Published: July 17, 2018

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a life-threating lung condition resulting from a direct and indirect injury to the lungs [1, 2]. Pathophysiologically it is characterized by an acute alveolar damage, an increased permeability of the microvascular-barrier, leading to protein-rich pulmonary edema and subsequent impairment of arterial oxygenation and respiratory failure [1]. This study examined the role of extracellular ATP in recruiting inflammatory cells to the lung after induction of acute lung injury with lipopolysaccharide (LPS). However, the precise mechanism is poorly understood. Our objective was to investigate the functional role of the P2X7 receptor in the pathogenesis of acute respiratory distress syndrome (ARDS/ acute lung injury (ALI)) in vitro and in vivo. We show that intratracheally applied LPS causes an acute accumulation of ATP in the BALF (bronchoalveolar lavage) and lungs of mice. Prophylactic and therapeutic inhibition of P2X7R signalling by a specific antagonist and knock-out experiments was able to ameliorate the inflammatory response demonstrated by reduced ATP-levels, number of neutrophils and concentration of pro-inflammatory cytokine levels in the BALF. Experiments with chimeric mice showed that P2X7R expression on immune cells was responsible for the observed effect. Consistently, the inflammatory response is diminished only by a cell-type specific knockdown of P2X7 receptor on non-stationary immune cells. Since the results of BALF from patients with acute ARDS or pneumonia simulated the in vivo data after LPS exposure, the P2X7 receptor may be a new therapeutic target for treatment in acute respiratory distress syndrome (ARDS/ALI).


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