Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin

Abstract

Rationale: Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated.Objectives: To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD.Methods: The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-a-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting.Measurements and Main Results: mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity.Conclusions: mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.

mTOR pathway activation drives lung cell senescence and emphysema

“…Concomitantly, exposure to oxidative stress due to cigarette smoke and chronic inflammation may promote premature cell senescence (5,33). Consistent with this possibility, mTOR was required for oxidative stress-induced cell senescence to occur (17,34), and mTOR activation was associated with oxidative stress in peripheral blood mononuclear cells from patients with COPD (35,36). Previous studies also documented a role of oxidative stress and mTOR activation in response to cigarette smoke exposure (37), and some effects of rapamycin on cell senescence have been related to changes in oxidative stress (17).…”

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

“…Caloric restriction is strongly associated with longevity, and this is possibly mediated by two main pathways involved in nutrient sensing: mechanistic target of rapamycin (mTOR) and insulin-like growth factor (IGF1) signalling [101,102]. The activity of mTOR, an important protein kinase in cell metabolism and nutrient sensing, is increased in total lung tissue and leukocytes of COPD patients [103], as well as in CSE-treated bronchial epithelial cells [79]. In addition, SIRT6 is considered to attenuate the IGF1-mTOR pathway.…”

Differential expression of GAS5 in rapamycin‐induced reversion of glucocorticoid resistance

“…9 GAS5 is a member of the 5 0 terminal oligopyrimidine (5 0 TOP) class of RNAs, whose transcript levels are controlled by the mammalian target of rapamycin (mTOR) pathway. 10,11 An increasing number of reports indicate that other immunosuppressive agents, among which rapamycin, the inhibitor of mTOR, can reverse GC resistance in different human cell lines, [12][13][14][15][16] suggesting that the poor response to GCs may derive from an impaired cross-talk between the GC and mTOR signalling pathways. However, the molecular mechanism involved in the synergistic effect of these agents has not yet been clarified.…”