The
phosphatidylinositol 3-kinase (PI3K) pathway is activated in
chronic obstructive pulmonary disease (
COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of
phosphatase and
tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in
COPD.
PTEN protein expression was measured in the peripheral lung of
COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette
smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-
buthionine-sulfoximine (BSO) to deplete intracellular
glutathione. The impact of PTEN knockdown by RNA interference on
cytokine production was also examined. In peripheral lung,
PTEN protein was significantly decreased in patients with
COPD compared with the subjects without
COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with
PTEN protein levels (r = -0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased
PTEN protein, which was reversed by N-acetyl
cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory
cytokines, such as
IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces
PTEN protein levels, which may result in increased PI3K signaling and amplification of
inflammation in
COPD.