Nebulized phosphodiesterase III inhibitor during warm ischemia attenuates pulmonary ischemia-reperfusion injury.
BACKGROUND
The control of warm ischemia-reperfusion injury is crucial in managing donors after cardiac death for lung transplantation. We focused on transalveolar administration as a drug-delivery route for such donors. Milrinone is a phosphodiesterase 3 inhibitor that inhibits the breakdown of cyclic adenosine monophosphate and selectively relaxes smooth muscle. We hypothesized that nebulized milrinone would mitigate warm ischemia-reperfusion injury of lung.


METHODS
This study was conducted with an isolated rat lung perfusion model. Lungs were excised, exposed to 55-minute ischemia at 37 degrees C, and reperfused for 60 minutes. During ischemia, nebulized milrinone (n = 6) or saline (n = 6) was inhaled. Lungs were continuously perfused without ischemia as a sham group (n = 6). Airway resistance, pulmonary vascular resistance, pulmonary compliance, weight gain and blood gas were measured. Adenine nucleotide levels and apoptosis were investigated in the reperfused lungs.


RESULTS
Milrinone nebulization decreased post-ischemic pulmonary vascular resistance (0.98 +/- 0.05 and 1.74 +/- 0.17 cm H(2)O/ml.min at 60 minutes of reperfusion in the milrinone and control groups, respectively [p < 0.01]). It did not alter cyclic adenosine monophosphate levels, but it did elevate adenosine triphosphate levels (9.87 +/- 0.38 and 6.91 +/- 0.45 in the milrinone and control groups, respectively [p < 0.01]) and suppressed apoptosis (3.83 +/- 0.91 and 46.17 +/- 3.39 of mean apoptotic cell numbers in the milrinone and control groups, respectively [p < 0.01]).


CONCLUSIONS
Milrinone nebulization decreased post-ischemic pulmonary vascular resistance, elevated adenosine triphosphate levels, and suppressed apoptosis. Nebulized milrinone has some protective effects against warm ischemia.
Zhang
Jitian
J
Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Chen
Fengshi
F
Zhao
Xiangdong
X
Aoyama
Akihiro
A
Okamoto
Toshihiro
T
Fujinaga
Takuji
T
Shoji
Tsuyoshi
T
Sakai
Hiroaki
H
Cui
Youbin
Y
Bando
Toru
T
Date
Hiroshi
H
D000336:Aerosols; D000818:Animals; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects / Q000502:physiology; D016040:Lung Transplantation / Q000009:adverse effects / Q000502:physiology*; D008297:Male; D020105:Milrinone / Q000008:administration & dosage / Q000627:therapeutic use*; D023421:Models, Animal; D009330:Nebulizers and Vaporizers; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*; D014655:Vascular Resistance / Q000187:drug effects*
D000336:Aerosols; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D004253:DNA Nucleotidylexotransferase; D020105:Milrinone