Valproic acid attenuates acute lung injury induced by ischemia-reperfusion in rats

Anesthesiology. 2015 Jun;122(6):1327-37. doi: 10.1097/ALN.0000000000000618.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acute Lung Injury / etiology*
  • Acute Lung Injury / prevention & control*
  • Animals
  • Antioxidants / metabolism
  • Body Weight / drug effects
  • Capillary Permeability / drug effects
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Male
  • Organ Size / drug effects
  • Protein Carbonylation / drug effects
  • Pulmonary Edema / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / complications*
  • Reperfusion Injury / prevention & control*
  • Valproic Acid / pharmacology*


  • Antioxidants
  • Histone Deacetylase Inhibitors
  • Histones
  • Valproic Acid
  • Heme Oxygenase-1
  • Histone Deacetylase 1