Novel protection strategy for pulmonary transplantation.
BACKGROUND
Ischemia-reperfusion injury continues to represent a significant challenge to successful lung transplantation. Traditional pulmonary ischemic protection is performed using hypothermic hyperkalemic depolarizing solutions to reduce the metabolic demands of the ischemic organ. Measures to further reduce the effects of ischemic injury have focused on the reperfusion period. We tested the hypothesis that novel physiologic hyperpolarizing solutions-using ATP-dependent potassium channel (K(ATP)) openers-given at the induction of ischemia, will reduce cellular injury and provide superior graft function even after prolonged periods of ischemia.


METHODS
An isolated blood-perfused ventilated rabbit lung model was used to study lung injury. Airway, left atrial, and pulmonary artery pressures were measured continuously during the 2-h reperfusion period. Oxygenation, as a surrogate of graft function, was measured using intermittent blood gas analysis of paired left atrial and pulmonary artery blood samples. Graft function was measured by oxygen challenge technique (F(i)O(2) = 1.0). Wet-to-dry ratio was measured at the conclusion of the 2-h reperfusion period. Control (Group I) lungs were perfused with modified Euro-Collins solution (depolarizing) and reperfused immediately (no ischemia). Traditional protection lungs were perfused with modified Euro-Collins flush solution and stored for 4 h (Group II) or 18 h (Group III) at 4 degrees C before reperfusion. Novel protection (Group IV) lungs were protected with a hyperpolarizing solution containing 100 nM Aprikalim, a specific K(ATP) channel opener, added to the modified Euro-Collins flush solution and underwent 18 h of ischemic storage at 4 degrees C before reperfusion.


RESULTS
Profound graft failure was measured after 18 h of ischemic storage with traditional protection strategies (Group III). Graft function was preserved by protection with hyperpolarizing solutions even for prolonged ischemic periods (Group IV). Wet-to-dry weight ratio, airway, left atrial, and pulmonary artery pressures were not significantly different between the groups.


CONCLUSIONS
We have created a model of predictable lung injury. Membrane hyperpolarization with a K(ATP) channel opener (PCO) provides superior prolonged protection from ischemia-reperfusion injury in an in vitro model of pulmonary transplantation.
Vaida
A M
AM
Cardiovascular & Thoracic Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, Box 980068, Medical College of Virginia Hospitals & Physicians of Virginia Commonwealth University Health System, Richmond, Virginia 23298-0068, USA.
Tang
D G
DG
Allen
C
C
Wise
R M
RM
Higgins
R S D
RS
Cohen
N M
NM
D000818:Animals; D001794:Blood Pressure; D005260:Female; D006325:Heart Atria; D006982:Hypertonic Solutions; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D016040:Lung Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D019188:Organ Preservation Solutions; D010100:Oxygen / Q000008:administration & dosage / Q000097:blood; D010847:Picolines / Q000008:administration & dosage*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery; D011714:Pyrans / Q000008:administration & dosage*; D011817:Rabbits; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D012996:Solutions
C037096:Euro-Collins' solution; D006982:Hypertonic Solutions; D019188:Organ Preservation Solutions; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D012996:Solutions; C061043:aprikalim; D010100:Oxygen