Valproic acid attenuates acute lung injury induced by ischemia-reperfusion in rats.
BACKGROUND
Evidence reveals that histone deacetylase (HDAC) inhibition has potential for the treatment of inflammatory diseases. The protective effect of HDAC inhibition involves multiple mechanisms. Heme oxygenase-1 (HO-1) is protective in lung injury as a key regulator of antioxidant response. The authors examined whether HDAC inhibition provided protection against ischemia-reperfusion (I/R) lung injury in rats by up-regulating HO-1 activity.


METHODS
Acute lung injury was induced by producing 40 min of ischemia followed by 60 min of reperfusion in isolated perfused rat lungs. The rats were randomly allotted to control group, I/R group, or I/R + valproic acid (VPA) group with or without an HO-1 activity inhibitor (zinc protoporphyrin IX) (n = 6 per group).


RESULTS
I/R caused significant increases in the lung edema, pulmonary arterial pressure, lung injury scores, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 concentrations in bronchoalveolar lavage fluid. Malondialdehyde levels, carbonyl contents, and myeloperoxidase-positive cells in lung tissue were also significantly increased. I/R stimulated the degradation of inhibitor of nuclear factor-κB-α, nuclear translocation of nuclear factor-κB, and up-regulation of HO-1 activity. Furthermore, I/R decreased B-cell lymphoma-2, heat shock protein 70, acetylated histone H3 protein expression, and increased the caspase-3 activity in the rat lungs. In contrast, VPA treatment significantly attenuated all the parameters of lung injury, oxidative stress, apoptosis, and inflammation. In addition, VPA treatment also enhanced HO-1 activity. Treatment with zinc protoporphyrin IX blocked the protective effect of VPA.


CONCLUSIONS
VPA protected against I/R-induced lung injury. The protective mechanism may be partly due to enhanced HO-1 activity following HDAC inhibition.
From Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China (S.-Y.W., K.-L.H.); Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China (S.-E.T., K.-L.H.); Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, Republic of China (F.-C.K., G.-C.W.); and Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China (S.-J.C.).
Shu-Yu
SY
Wu
Shih-En
SE
Tang
Fu-Chang
FC
Ko
Geng-Chin
GC
Wu
Kun-Lun
KL
Huang
Shi-Jye
SJ
Chu
D000107:Acetylation; D055371:Acute Lung Injury / Q000209:etiology* / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009929:Organ Size / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D011654:Pulmonary Edema / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications* / Q000517:prevention & control*; D014635:Valproic Acid / Q000494:pharmacology*
D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D051547:Heme Oxygenase-1; D056284:Histone Deacetylase 1