Modulation of Ventilator-Induced Lung Injury by ATP-P2X7 Receptor Signaling Axis

Abstract RATIONALE: While mechanical ventilation (VM) is a life-saving therapy for patients with acute lung injury, its improper use, such as an inappropriate application of large tidal volumes (VT), can lead to ventilator-induced lung injury (VILI). VILI is associated with abundant extracellular ATP in the alveoli. Activation of cell-surface P2X7 receptors (P2X7R) by ATP is important in inflammation and immunity in the lungs, but the role of the ATP-P2X7R axis in the development of VILI remains poorly understood. Therefore, this study aimed to investigate how P2X7R affects VILI. METHODS: Wild-type (WT) and P2X7R knock-out (KO) C57BL/6 mice were subjected to low-VT MV (VT = 8 ml/kg, respiratory rate (RR) = 150 breaths/minute) or high-VT MV (VT = 24 ml/kg, RR = 70 breaths/minute) for four hours with a computer-controlled ventilator for small animals (flexiVent). During MV, respiratory mechanics were measured every 30 minutes. As a two-hit model, mice were exposed to 400 ppm of chlorine gas for 5 minutes 24 hours before MV. At the end of MV, mice were sacrificed, bronchoalveolar lavage (BAL) was performed, and lungs were harvested. To determine the severity of VILI based on MV settings and mouse strain, changes in the alveolar-capillary barrier, inflammatory response and evidence of physiological dysfunction were evaluated. RESULTS: After low-VT or high-VT ventilation, WT mice displayed negligible signs of VILI. Only WT mice exposed to chlorine 24 hours prior to high-VT MV exhibited VILI, namely characterized by increased resistance, decreased compliance and elevated protein levels in BAL fluid, compared to those, which underwent low-VT MV. Interestingly, VILI severity decreased in chlorine-exposed KO mice subjected to high-VT MV in comparison to WT mice. Furthermore, RT-qPCR showed no significant differences in the mRNA expression of IL-1β and TNF-α between WT and KO mice that were exposed to chlorine prior to high-VT MV. However, there was a significantly increased expression of IL-6 in chlorine-exposed WT mice under high-VT ventilation, compared to KO mice. CONCLUSION: Our findings suggest that ATP-activated P2X7R may play a role in the pathogenesis of VILI in mice with pre-existing oxidative stress-induced lung damage through a pathway involving the pro-inflammatory cytokine IL-6. This study should contribute to a better understanding of the ATP-P2X7R axis and its role in the modulation of VILI.

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