PURPOSE OF THE STUDY.
The oxidative stress from tobacco smoke impairs histone deacetylase–2 (HDAC2) via phosphorylation of phosphoinositide-3-kinase (PI3K)/Akt activation, leading to corticosteroid insensitivity. This study tested the hypothesis that passive exposure to tobacco smoke is associated with reduced HDAC2 in alveolar macrophages in children with severe, refractory asthma.
The study population included children aged 8.5 to 13.5 years with severe asthma, already receiving inhaled corticosteroids plus a long-acting β-agonist.
Bronchoalveolar lavage fluid was obtained from all children during bronchoscopy. Subjects were divided into those exposed to passive tobacco smoke (PS) and those not exposed to PS. Exposure was assessed by using parent surveys and was supported by measurement of cotinine levels in the saliva and urine. Fractional exhaled nitric oxide levels were also measured. HDAC2 expression and activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in alveolar macrophages were assessed.
Parental reports of smoking correlated with measurable cotinine levels in the urine and saliva of the children. PS exposure reduced HDAC2 protein expression and activity. PS exposure also reduced the inhibitory effects of dexamethasone of tumor necrosis factor α–induced CXCL8 release in the alveolar macrophages. Children exposed to PS had higher neutrophil counts and CXCL8 expression in bronchoalveolar lavage fluid and lower Asthma Control Test scores compared with those not exposed.
PS exposure in children impairs HDAC2 function via PI3K signaling activation. This finding agrees with previous studies in adults. The high levels of oxidative stress and their end products seem to induce corticosteroid insensitivity with dysfunction of HDAC2. This study supports the conclusion that PS exposure not only worsens asthma symptoms but induces a state of steroid resistance in an already difficult-to-control asthma population.
It is well known that secondhand tobacco smoke exposure is related to exacerbation of asthma in children and can be a risk factor for persistent asthma in later childhood. This study shows the molecular basis for this finding in children with severe asthma and how PS exposure can induce steroid insensitivity. Patients with severe asthma are already difficult to treat, and steroid resistance makes it even more difficult. This finding highlights the need, even more so, for parental education regarding the effects of tobacco smoke exposure on their children with asthma.
- Copyright © 2014 by the American Academy of Pediatrics