Pi3kδ expression is increased in peripheral lung macrophages in COPD patients

Rationale: In vitro studies and animals models have identified the PI3K/Akt signalling pathway and specifically PI3Kdelta, as playing a potentially important role in the development of glucocorticoid insensitivity in response to oxidative stress including cigarette smoke. Methods: Immunohistochemistry for PI3Kdelta and phospho-Akt (ser473) was performed on peripheral lung from COPD patients (n=17), smokers with normal, lung function (n=14) and non-smokers with normal lung function (n=13). Blood monocytes were isolated from venous blood from healthy volunteers and treated with inhibitors of PI3Kdelta or PI3Kgamma, stimulated with LPS and phospho-Akt levels assessed. Results: PI3Kdelta inhibition, but not gamma blocked Akt phosphorylation in monocyes. PI3K delta expression was elevated in macrophages in the peripheral lung of COPD patients compared to smokers with normal lung function (p=0.0043) and non smokers (p=0.0041). Phosphorylation of Akt (ser473) was also elevated in COPD peripheral lung macrophages compared to smokers with normal lung function (p=0.0069) and non smokers (p=0.0008). Conclusion: In vitro and in vivo models indicate that PI3Kdelta may be important in the development of oxidant mediated glucocorticoid insensitivity. Here we confirm that PI3Kdelta is the major PI3K isoform responsible for the activation of Akt in monocytes and both PI3Kdelta expression and Akt phosphorylation is ele- vated in macrophages in the peripheral lung of COPD patients. This elevated Akt activation may therefore contribute to the reduced glucocorticoid responsiveness seen in COPD