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-a 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.

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

“…The S370 residue of PTEN is phosphorylated by casein kinase 2 (CK2), and this phosphorylation reduces PTEN activity (36,53). We therefore determined whether bpV(phen), a potent inhibitor of PTEN (32), relieves the effect of TIMAP silencing on Akt phosphorylation. Pilot experiments showed that bpV(phen) increased S473 Akt phosphorylation in a concentration-dependent fashion in TIMAP-depleted and in cells treated with control siRNA, with a maximal effect at a concentration of 20 M (not shown).…”

Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats

“…21 Rat lung tissue was exposed and different groups of rat lung gross morphology pictures were obtained. Representative lung tissue sections from 2 and 6 h after surgery (n ¼ 7 animals per group) were fixed in 4% formaldehyde, and were prepared for H&E staining following routine methods.…”

Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

“…Thus, to facilitate further study of PTPMT1 and its role in ␤-cell metabolism in particular, we undertook a search for inhibitors of the enzyme. There is good precedence for the use of smallmolecule inhibitors of phosphatases in the interrogation of the biology of these enzymes, and selective inhibitors of phosphatases may well prove valuable in the treatment of diseases affected by their dysregulation (Lai et al, 2009).…”