The role of the P2Y6 purinergic receptor in human neutrophil peptides-mediated inflammatory response in a mouse model of ventilator-associated pneumonia
CCCF ePoster library. Zheng J. Oct 26, 2015; 117329; P10 Disclosure(s): This grant was funded by CIHR.
Mr. Junbo Zheng
Mr. Junbo Zheng
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Abstract
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P10


Topic: Basic/Translational Science


The role of the P2Y6 purinergic receptor in human neutrophil peptides-mediated inflammatory response in a mouse model of ventilator-associated pneumonia



Junbo Zheng, B. Han, A. Luo, M. Li, A. Grassi, D. Islam, A. Slutsky, H. Zhang

Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China | Anaesthesia and Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Anaesthesia and Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Anaesthesia and Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Health Science, University of Milano Bicocca, Milano, Italy | Anaesthesia and Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Anaesthesia and Critical Care Medicine, Interdepartmental Division of Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital; University of Toronto., Toronto, Canada | Anaesthesia and Critical Care Medicine, Interdepartmental Division of Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital;  University of Toronto., Toronto, Canada

Introduction:

Mechanical ventilation (MV) is an essential supportive approach to manage respiratory failure but it per se can also cause damage to the lungs termed ventilator-induced lung injury (VILI) and ventilator-associated pneumonia (VAP) [1,2]. Human neutrophil peptides (HNPs) are a family of cationic peptides stored in the azurophilic granules of neutrophils and act as antimicrobial agents through charge-charge interaction with microbes. We have previously shown that HNPs also regulate inflammatory responses by interacting with the P2Y6 receptor [3].



Objectives:

To test the hypothesis that blocking P2Y6 receptor would attenuate HNPs induced inflammatory responses, while maintaining their antimicrobial activity in the context of VAP.



Methods:

FVB background control and HNP transgenic mice (HNP+/+) were randomized to receive either P. aeruginosa or vehicle control fluid intranasally. The mice were then mechanically ventilated 48 h later for 2 h at either low pressure (LP, 10 cmH2O inspiratory pressure, 3cmH2O PEEP) or high pressure (HP, 22cmH2O PIP, 0cmH2O PEEP). All mice received 3 doses of P2Y6 receptor antagonist (4 μL/g BW MRS2578) or vehicle control. The first dose was given immediately after P. aeruginosa instillation, followed by a second and third dose 24h and 48h later, respectively. Mice were terminated 72 h after bacterial challenge.



Results: The mice with pneumonia exhibited weight loss, especially under MV. The HNP+/+ mice showed less bacteria load in the bronchoalveolar lavage fluid than the FVB mice. The HNP+/+ mice had greater neutrophil lung infiltration than the FVB mice. Blocking P2Y6 was able to attenuate the HNP-mediated inflammatory responses without affecting the antibacterial property of HNP.

Conclusion: Neutrophil infiltration plays an important role in the development of inflammatory responses during VAP mediated by HNP. Blocking P2Y6, the tentative HNP receptor can attenuate the inflammatory responses while maintaining the antimicrobial properties of HNP.

References:

1. Slutsky AS. Lung injury caused by mechanical ventilation. Chest. 1999;116: 9S–15S.

2. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002;165:867–903.

3. Khine AA, Del Sorbo L, Vaschetto R, et al. Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway. Blood. 2006;107:2936-2942.


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