Inhibition of the phosphatase PTEN protects mice against oleic acid-induced acute lung injury.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

• Authors: Ju-Ping Lai, Shengying Bao, Ian C Davis, Daren L Knoell
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 156 Issue 1 Pg. 189-200 (Jan 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19134000 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Organometallic Compounds
• Phenanthrolines
• Tumor Necrosis Factor-alpha
• Oleic Acid
• bisperoxo(1,10-phenanthroline)oxovanadate(1-)
• L-Lactate Dehydrogenase
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• PTEN Phosphohydrolase

Topics

• Acute Lung Injury (chemically induced, enzymology, prevention & control)
• Animals
• Bronchoalveolar Lavage Fluid
• Chemokines (metabolism)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• In Situ Nick-End Labeling
• L-Lactate Dehydrogenase (metabolism)
• Lung (enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Oleic Acid
• Organometallic Compounds (administration & dosage, pharmacology, therapeutic use)
• PTEN Phosphohydrolase (antagonists & inhibitors)
• Phenanthrolines (administration & dosage, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (metabolism)