Research
Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway
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* Corresponding author: Rosanna Vaschetto rosanna.vaschetto@med.unipmn.it
1 Department of Clinical and Experimental Medicine, University of Eastern Piedmont "Amedeo Avogadro", Corso Mazzini 18, 28100, Novara, Italy
2 Department of Pediatric Intensive Care, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
3 Department of Intensive Care, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
4 Institute for Cardiovascular Research, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
5 Department of Physiology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
6 Inotek Pharmaceuticals Corporation, 33 Hayden Avenue, 0242, Lexington, MA, USA
Critical Care 2010, 14:R45 doi:10.1186/cc8932
See related commentary by Matejovic and Radermacher, http://ccforum.com/content/14/3/147
Published: 26 March 2010Abstract
Introduction
Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.
Methods
Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining.
Results
High tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes.
Conclusions
The peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.