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Pulmonary MnSOD is nitrated following hepatic ischemia-reperfusion
Keith D Gray1, Lee-Ann MacMillan-Crow, Misho O Simovic
1Department of Surgery at Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Background:
Ischemia-reperfusion (I/R) of remote organs is a common cause of lung injury. We observed that lung injury after partial hepatic I/R in mice coincides with the appearance of 3-nitrotyrosine (NT) in the lung tissue, a marker of peroxynitrite involvement and oxidant stress. Peroxynitrite can cause mitochondrial dysfunction by inactivation of manganese superoxide dismutase (MnSOD), the major antioxidant enzyme in mitochondria. Our aims were to examine whether pulmonary MnSOD is a target of nitration following hepatic I/R and whether nitrated MnSOD (N-MnSOD) correlates with acute lung injury.
Methods:
Five 20-25-g male C57BL/6 mice underwent laparotomy, and atraumatic occlusion of the portal and arterial blood supply to the upper three lobes of the liver for 90 min. This warm ischemic period was followed by 4 h of reperfusion, and the animals were then euthanized. Lung injury was assessed by LDH and protein levels in bronchoalveolar lavage (BAL) fluid. Pulmonary MnSOD activity in pulmonary homogenates was measured by the cytochrome c reduction method. The presence of N-MnSOD was determined by immunoprecipitation (IP) and Western Blot analysis. Controls (N = 5) underwent sham operation.
Results:
Elevated plasma transaminases confirmed hepatic injury. Lung injury was demonstrated by elevation in BAL protein and LDH levels (495.7 (48.4) versus 644.9 (37.3) [p < 0.05] and 56.5 (11.8) versus 345.2 (80) [p < 0.01], respectively). Immunoprecipitation and Western blot demonstrated N-MnSOD in the lung tissue of I/R animals but not controls. MnSOD activity decreased following I/R (8.1 (0.7) versus 10.8 (0.3) [p < 0.05]).
Conclusions:
Pulmonary MnSOD is both nitrated and inactivated following hepatic I/R and is associated with acute lung injury. These findings suggest that MnSOD incapacitance may contribute to I/R-induced lung injury and provide a therapeutic target in attenuating multisystem injury following hepatic I/R.
Insights
Hepatic ischemia-reperfusion (I/R) causes lung injury by nitrating and inactivating manganese superoxide dismutase (MnSOD). This inactivation of MnSOD contributes to acute lung injury, offering a potential therapeutic target.
Area of Science:
- Organ injury and transplantation
- Mitochondrial dysfunction
- Oxidative stress and inflammation
Background:
- Remote organ injury, specifically lung injury, is a frequent complication of hepatic ischemia-reperfusion (I/R).
- 3-nitrotyrosine (NT), a marker of oxidant stress and peroxynitrite activity, appears in lung tissue following hepatic I/R.
- Peroxynitrite can impair mitochondrial function by inactivating manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme.
Purpose of the Study:
- To investigate if pulmonary MnSOD is nitrated after hepatic I/R.
- To determine if nitrated MnSOD (N-MnSOD) correlates with the development of acute lung injury.
- To explore the role of MnSOD inactivation in hepatic I/R-induced lung injury.
Main Methods:
- Partial hepatic I/R was induced in mice by occluding blood supply to liver lobes for 90 minutes, followed by 4 hours of reperfusion.
- Lung injury was assessed by measuring lactate dehydrogenase (LDH) and protein levels in bronchoalveolar lavage (BAL) fluid.
- Pulmonary MnSOD activity was measured, and the presence of N-MnSOD was detected using immunoprecipitation and Western Blot analysis.
Main Results:
- Hepatic injury was confirmed by elevated plasma transaminases.
- Animals subjected to hepatic I/R exhibited significantly increased BAL protein and LDH levels, indicating acute lung injury.
- Immunoprecipitation and Western blot analysis confirmed the presence of N-MnSOD in lung tissue of I/R mice, and MnSOD activity was significantly reduced compared to controls.
Conclusions:
- Hepatic I/R leads to nitration and inactivation of pulmonary MnSOD.
- The nitration and inactivation of MnSOD are associated with the development of acute lung injury following hepatic I/R.
- Targeting MnSOD inactivation presents a potential therapeutic strategy for mitigating multisystem injury after hepatic I/R.
