New Insights into the Steen Solution Properties: Breakthrough in Antioxidant Effects via NOX2 Downregulation

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Abstract

Ex vivo lung perfusion (EVLP) allows perfusion and reconditioning of retrieved lungs for organ transplantation. The Steen solution is specifically designed for this procedure but the mechanism through which it elicits its activity is still to be fully clarified. We speculated that Steen solution may encompass antioxidant properties allowing a reestablishment of pulmonary tissue homeostasis. Blood samples from 10 healthy volunteers were recruited. Platelets and white cells were incubated with Steen solution or buffer solution as control and stimulated with suitable agonists. Reactive oxidant species (ROS), soluble NOX2 (sNOX2-derived peptide), a marker of NADPH oxidase activation, p 47 phox translocation to cell membrane and isoprostanes production, as marker of oxidative stress, and nitric oxide (NO), a powerful vasodilator and antioxidant molecule, were measured upon cell stimulation. The Steen solution significantly inhibited p 47 phox translocation and NOX2 activation in platelets and white cells. Consistent with this finding was the reduction of oxidative stress as documented by a significantly lowered formation of ROS and isoprostanes by both platelets and white cells. Finally, cell incubation with Steen solution resulted in enhanced generation of NO. Herewith, we provide the first evidence that Steen solution possesses antioxidant properties via downregulation of NADPH oxidase activity and enhanced production of NO.

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Normothermic ex vivo lung perfusion in clinical lung transplantation.

Marcelo Cypel, Jonathan C Yeung, Mingyao Liu … (2011)

More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).

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Transplantation of lungs from a non-heart-beating donor.

Stig Steen, Trygve Sjoberg, Leif Pierre … (2001)

In animals, we have previously done successful lung transplantations using organs from non-heart-beating donors. We have also developed an ex-vivo system of assessing the function of such organs before transplantation. The next stage was to try the technique in human beings. Bearing in mind the sensitive ethical issues involved, our first aim was to find out what procedures would be acceptable, and to use the results to guide a clinical lung transplantation from a non-heart-beating donor. The ethical acceptability of the study was gauged from the results of a broad information programme directed at the general public in Sweden, and from discussions with professionals including doctors, nurses, hospital chaplains, and judges. The donor was a patient dying of acute myocardial infarction in a cardiac intensive-care unit after failed cardiopulmonary resuscitation. The next of kin gave permission to cool the lungs within the intact body, and intrapleural cooling was started 65 min after death. Blood samples were sent for virological testing and cross matching. The next of kin then had time to be alone with the deceased. After 3 h, the body was transported to the operating theatre and the heart-lung block removed. The lungs were assessed ex vivo, and the body was transported to the pathology department for necropsy. No contraindications to transplantation were found, and the right lung was transplanted successfully into a 54-year-old woman with chronic obstructive pulmonary disease. The donor lung showed excellent function only 5 min after reperfusion and ventilation, and during the first 5 months of follow-up, the function of the transplanted lung has been good. About half the deaths in Sweden are caused by cardiac and cerebrovascular disease. This group could be a potential source of lung donors. When all hospitals and ambulance personnel in Sweden have received training in non-heart-beating lung donation, we hope that there will be enough donor lungs of good quality for all patients needing a lung transplant.