Passive Smoking Impairs Histone Deacetylase-2 in Children With Severe Asthma

Abstract

Background:Parental smoking is known to worsen asthma symptoms in children and to make them refractory to asthma treatment, but the molecular mechanism is unclear. Oxidative stress from tobacco smoke has been reported to impair histone deacetylase-2 (HDAC2) via phosphoinositide-3-kinase (PI3K)/Akt activation and, thus, to reduce corticosteroid sensitivity. The aim of this study was to investigate passive smoking-dependent molecular abnormalities in alveolar macrophages (AMs) by comparing passive smoke-exposed children and non-passive smoke-exposed children with uncontrolled severe asthma.Methods:BAL fluid (BALF) was obtained from 19 children with uncontrolled severe asthma (10 non-passive smoking-exposed subjects and nine passive smoking-exposed subjects), and HDAC2 expression/activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in AMs were evaluated.Results:Parental smoking reduced HDAC2 protein expression by 54% and activity by 47%, with concomitant enhancement of phosphorylation of Akt1 and HDAC2. In addition, phosphorylation levels of Akt1 correlated positively with HDAC2 phosphorylation levels and negatively with HDAC2 activity. Furthermore, passive smoke exposure reduced the inhibitory effects of dexamethasone on tumor necrosis factor-α-induced CXCL8 release in AMs. There were relatively higher neutrophil counts and CXCL8 concentrations in BALF and lower Asthma Control Test scores compared with non-passive smoke-exposed children with uncontrolled severe asthma.Conclusions:Passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation in children with severe asthma. This novel mechanism will be a treatment target in children with severe asthma and stresses the need for a smoke-free environment for asthmatic children.

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…4C). Downregulation of HDAC2 level involves posttranslational modifications such as serine phosphorylation and proteasomal degradation, and the phosphorylation of HDAC2 is dependent on PI3K/Akt signaling pathway (26)(27)(28). We also observed a corresponding suppression of serine phosphorylation of LPS/IFN-g-induced HDAC2 by andrographolide in a concentration-dependent manner (Fig.…”

“…We detected prominent serine phosphorylation of HDAC2 in Raw 264.7 cells in response to LPS/ IFN-g, which might subsequently contribute to its own degradation. Activation of the PI3K/Akt signaling pathway has been well correlated with HDAC2 phosphorylation in alveolar macrophages isolated from the BAL fluid of cigarette smoke-exposed children (28). Moreover, inhibition of the PI3K/Akt pathway has been shown to restore steroid sensitivity in a cigarette smoke-induced airway inflammation mouse model and in PBMCs from COPD patients via a recovery of HDAC2 level and activity (23,27).…”

Allergy in severe asthma

“…Although it is considered predominantly nonallergic, a significant proportion of patients with adult-onset disease are atopic (34%) (61). In those with severe disease, a worse prognosis is apparent in smokers and ex-smokers (62), and, as described later on, smoke exposure has a detrimental effect on severe asthma, resulting in reduced corticosteroid responsiveness, regardless of age (63). Distinguishing and specific features of adult-onset asthma include association with comorbidities, such as obesity, and a predominance in middle-aged women (64).…”

Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

“…GR then recruits HDAC2, which leads to transcriptional repression [52]. It is interesting to note that also in severe asthmatics, there are indications that decreased HDAC2 expression and activity can be linked to steroid resistance [53], and that passive smoking reduced HDAC2 expression in severe asthmatic children [54].Altogether, even though HDACi have been reported to reduce inflammation in asthma and COPD models, it should be noted that not much is known about the expression and activity of individual HDAC isoenzymes in asthma or COPD. The roles of HDACs in asthma and COPD need to be more clearly defined.…”

“…GR then recruits HDAC2, which leads to transcriptional repression [52]. It is interesting to note that also in severe asthmatics, there are indications that decreased HDAC2 expression and activity can be linked to steroid resistance [53], and that passive smoking reduced HDAC2 expression in severe asthmatic children [54].…”