Molecular mechanisms of ventilator-induced acute kidney injury : Mechanical ventilation can modulate neutrophil recruitment to the kidney

摘要

Mechanical ventilation is the mainstay therapy for patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS), which exhibit a mortality of approximately 40%. Additionally, mechanical ventilation can also exert its action through the lungs to distant organs, provoking the development of multiple organ dysfunction syndrome (MODS). Thus, there is considerable interest in understanding ventilator-induced MODS with the aim to refine ventilation strategies, or augment supportive therapy, to attenuate organ failure in mechanically ventilated patients. This study focuses on acute kidney injury (AKI) because the kidney is one of the first organs affected by MODS. The goal of this study was to examine candidate biomarkers of AKI, and to contribute to our understanding of the pathophysiological mechanisms at play that result in MODS in response to mechanical ventilation.Organ failure was induced in healthy rats by mechanical ventilation. Three different ventilation strategies were employed, using a pressure-controlled mode, with the positive end-expiratory pressure (PEEP) fixed at 2 cmH2O, while the peak inspiratory pressure (PIP) was increased in 5 cmH2O increments between 10 cmH2O and 20 cmH2O. All three ventilation strategies induced lung injury, as assessed by elevated protein levels in the bronchoalveolar lavage (BAL) fluid after 8 h mechanical ventilation. However, only the 20 cmH2O PIP group displayed elevated BAL fluid protein levels after 4 h mechanical ventilation. No significant increase in serum creatinine levels at either time-point was noted in any of the experimental groups. Of the new, emerging biomarkers of AKI such as lipocalin-2 and Kim1, no significant increase in the mRNA expression levels of lipocalin-2 was detected in the kidney between 4 h and 8 h mechanical ventilation with the 10 cmH2O PIP and 15 cmH2O PIP strategies, however, pronounced changes were seen in the 20 cmH2O PIP group. A comparable situation was observed for Kim1 expression. Comparing lipocalin-2 and Kim1, both exhibited a time-dependent increase in gene expression in the kidneys of mechanically-ventilated rats. Additionally lipocalin-2 appeared earlier, compared to Kim1, in the evolution of ventilator-induced AKI. There were no differences observed in the recruitment of macrophages and T-cells in any of the mechanically ventilated groups. However, an increase in the number of neutrophils was observed in the kidneys of rats ventilated with 20 cmH2O PIP, where the greatest degree of lung damage, and the greatest increase in lipocalin-2 and Kim1 expression was also observed. These data suggest that mechanical ventilation can modulate neutrophil infiltration into the kidney.