Inhibition of the phosphatase PTEN protects mice against oleic acid-induced acute lung injury.
OBJECTIVE
Injury to the lung parenchyma is a constitutional feature shared by many lung diseases. The protein, phosphatase and tensin homologue deleted on chromosome Ten (PTEN) is a major suppressor of phosphoinositide-3 kinase/Akt signalling, a vital survival pathway in lung parenchymal cells. Based on this, we hypothesized that PTEN inhibition in vivo would enhance cell tolerance to stress thereby preventing acute lung injury.


METHODS
We evaluated the ability of a PTEN inhibitor, potassium bisperoxo (1,10-phenanthroline) oxovanadate [bpV(phen)], to prevent acute lung injury induced by oleic acid (OA) in adult C57BL/6 mice. Lung assessments included bronchoalveolar lavage, tissue morphology, immunostaining for markers of cell death, cell identity, phospho-Akt and phospho-ERK levels and oximetry.


RESULTS
OA induced acute lung injury in a dose- and time-dependent manner. No injury was observed in the vehicle control or bpV(phen) treatment groups. PTEN inhibition by bpV(phen) increased lung tissue levels of phospho-Akt and ERK and but not focal adhesion kinase. This occurred in conjunction with a statistically significant reduction in protein content, lactate dehydrogenase, as well as tumour necrosis factor-alpha and chemokines in bronchoalveolar lavage fluid when compared with OA treatment alone. The incidence of alveolar lesions, consistent with acute lung injury, and terminal uridine deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive cells was also significantly reduced. Importantly, PTEN suppression maintained pulmonary function.


CONCLUSIONS
Treatment with bpV(phen) significantly reduced the severity of acute lung injury in mice indicating that additional investigation is warranted to understand the important role that this phosphatase may play in the lung.
Lai
Ju-Ping
JP
The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Bao
Shengying
S
Davis
Ian C
IC
Knoell
Daren L
DL
D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019301:Oleic Acid; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010618:Phenanthrolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D009942:Organometallic Compounds; D010618:Phenanthrolines; D014409:Tumor Necrosis Factor-alpha; D019301:Oleic Acid; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D007770:L-Lactate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase