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

Ju Ping Lai, Shengying Bao, Ian C. Davis, Daren L. Knoell

Research output: Contribution to journalArticle

37 Citations (Scopus)

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-α 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.

Original languageEnglish (US)
Pages (from-to)189-200
Number of pages12
JournalBritish Journal of Pharmacology
Volume156
Issue number1
DOIs
StatePublished - Jan 1 2009

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PTEN Phosphohydrolase
Acute Lung Injury
Oleic Acid
Lung
Focal Adhesion Protein-Tyrosine Kinases
1-Phosphatidylinositol 4-Kinase
Oximetry
DNA Nucleotidylexotransferase
Uridine
Bronchoalveolar Lavage Fluid
Lung Injury
Bronchoalveolar Lavage
Inbred C57BL Mouse
L-Lactate Dehydrogenase
Chemokines
Phosphoric Monoester Hydrolases
Lung Diseases
Potassium
Cell Death
Therapeutics

Keywords

  • Apoptosis
  • BpV(phen)
  • Cell death
  • Epithelium
  • Lung
  • PTEN
  • Phosphatase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of the phosphatase PTEN protects mice against oleic acid-induced acute lung injury. / Lai, Ju Ping; Bao, Shengying; Davis, Ian C.; Knoell, Daren L.

In: British Journal of Pharmacology, Vol. 156, No. 1, 01.01.2009, p. 189-200.

Research output: Contribution to journalArticle

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KW - Phosphatase

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