INTRODUCTION. Mechanical ventilation (MV) is a life-saving therapy for many patients with respiratory failure but has detrimental consequences resulting in ventilator-induced lung injury (VILI). MV can potentially lead to the development of an overwhelming inflammatory response and multiple organ dysfunction syndrome (MODS). Acute renal failure (ARF) is the most prevalent form of organ dysfunction in patients treated with MV. However, the factors leading from mechanical stress to the initiation and propagation of VILI and ARF remain uncertain. Poly (ADP-ribose) polymerase (PARP) enzyme has been shown to be overactivated during VILI. Pharmacological inhibition of PARP by PJ-34 reduced lung injury and preserved kidney function with a decreased renal apoptosis. We hypothesized that pharmacological inhibition of PARP by PJ-34 mitigates kidney dysfunction by preserving endothelium function. METHODS. 24 Sprague Dawley rats (weight 310 ± 10 g) received intratracheal instillation of lipopolysaccharide at 10 mg/kg, followed by 3.5 hrs mechanical ventilation with either high tidal volume (Vt) of 19 ml/kg and PEEP 0 cmH 2 O (HV) in the presence or absence of the PARP inhibitor PJ-34, or low Vt of 6 ml/kg and PEEP 5 cmH 2 O (LV) serving as a control group. Arterial blood gases, hemodynamic measurements and urinary output were analyzed hourly. Renal blood flow was assessed at the beginning and at the end of the experiment. Kidney interlobar arteries were isolated thereafter and endothelium dependent vasodilation was tested by incubating the arteries with acetylcholine. RESULTS. As expected, we found that lung injury was increased in the HV group compared to the LV group and PJ-34 treatment mitigates lung dysfunction in HV group. Kidney endothelium function was tested by its ability to induce dilatation after acetylcholine stim- ulation. Interlobar renal arteries isolated from the HV group showed an impaired ability to dilate compared to the LV group. Endothelium dysfunction was also associated with reduction in renal blood flow of approximately 80% in the HV group compared to the LV group and with decreased urine production. Treatment with PJ-34 restored vascular reactivity, renal blood flow, and preserved urine production. PJ-34 protective effect is probably due to its ability to reduce NF-kB as shown by a decreased intensity of NF-kB nuclear staining in kidney sections in PJ-34 treated group. CONCLUSION. Application of PJ-34 reduces kidney dysfunction in a rat model of VILI by preserving endothelium function, probably reducing NF-kB activation. Our study suggests a novel potential therapeutic approach to mitigate the consequences of VILI by using the PARP inhibitors. GRANT ACKNOWLEDGEMENT. ECCRN Basic Science Award 2006.
THE ROLE OF POLY(ADP-RIBOSE) POLYMERASE 1 (PARP-1) IN ACUTE RENAL FAILURE ASSOCIATED WITH VENTILATOR INDUCED LUNG INJURY
VASCHETTO, Rosanna;DELLA CORTE, Francesco;
2008-01-01
Abstract
INTRODUCTION. Mechanical ventilation (MV) is a life-saving therapy for many patients with respiratory failure but has detrimental consequences resulting in ventilator-induced lung injury (VILI). MV can potentially lead to the development of an overwhelming inflammatory response and multiple organ dysfunction syndrome (MODS). Acute renal failure (ARF) is the most prevalent form of organ dysfunction in patients treated with MV. However, the factors leading from mechanical stress to the initiation and propagation of VILI and ARF remain uncertain. Poly (ADP-ribose) polymerase (PARP) enzyme has been shown to be overactivated during VILI. Pharmacological inhibition of PARP by PJ-34 reduced lung injury and preserved kidney function with a decreased renal apoptosis. We hypothesized that pharmacological inhibition of PARP by PJ-34 mitigates kidney dysfunction by preserving endothelium function. METHODS. 24 Sprague Dawley rats (weight 310 ± 10 g) received intratracheal instillation of lipopolysaccharide at 10 mg/kg, followed by 3.5 hrs mechanical ventilation with either high tidal volume (Vt) of 19 ml/kg and PEEP 0 cmH 2 O (HV) in the presence or absence of the PARP inhibitor PJ-34, or low Vt of 6 ml/kg and PEEP 5 cmH 2 O (LV) serving as a control group. Arterial blood gases, hemodynamic measurements and urinary output were analyzed hourly. Renal blood flow was assessed at the beginning and at the end of the experiment. Kidney interlobar arteries were isolated thereafter and endothelium dependent vasodilation was tested by incubating the arteries with acetylcholine. RESULTS. As expected, we found that lung injury was increased in the HV group compared to the LV group and PJ-34 treatment mitigates lung dysfunction in HV group. Kidney endothelium function was tested by its ability to induce dilatation after acetylcholine stim- ulation. Interlobar renal arteries isolated from the HV group showed an impaired ability to dilate compared to the LV group. Endothelium dysfunction was also associated with reduction in renal blood flow of approximately 80% in the HV group compared to the LV group and with decreased urine production. Treatment with PJ-34 restored vascular reactivity, renal blood flow, and preserved urine production. PJ-34 protective effect is probably due to its ability to reduce NF-kB as shown by a decreased intensity of NF-kB nuclear staining in kidney sections in PJ-34 treated group. CONCLUSION. Application of PJ-34 reduces kidney dysfunction in a rat model of VILI by preserving endothelium function, probably reducing NF-kB activation. Our study suggests a novel potential therapeutic approach to mitigate the consequences of VILI by using the PARP inhibitors. GRANT ACKNOWLEDGEMENT. ECCRN Basic Science Award 2006.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
