Christopher S. Stevenson

Cigarette smoke-triggered inflammation is considered to play a central role in the development of chronic obstructive pulmonary disease by a mechanism that may involve enhanced proinflammatory gene transcription. Histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription. Disruption in the nuclear histone acetylation:deacetylation balance (chromatin remodeling) may result in excessive transcription of specific proinflammatory genes in the lungs. In this study we show that cigarette smoke exposure results in an influx of inflammatory cells and chromatin modifications in rat lungs. This was associated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase concomitant with increased histone 3 phospho-acetylation, histone 4 acetylation, and increased DNA binding of the redox-sensitive transcription factor nuclear factor-kappaB, independent of inhibitory protein-kappaB degradation, and activator protein 1. We also observed decreased histone deacetylase 2 activity, which is due to protein modification by aldehydes and nitric oxide products present in cigarette smoke. Furthermore, we show that corticosteroid treatment has no effect on smoke-induced proinflammatory mediator release. These findings suggest a possible molecular mechanism by which cigarette smoke drives proinflammatory gene transcription and an inflammatory response in the lungs.

Chronic obstructive pulmonary disease (COPD) is a prevalent, heterogeneous disorder with varying presentation and progression but with a limited number of disease-modifying therapies (1). This marked heterogeneity impedes identification of subpopulations at risk for accelerated progression, thwarting therapeutic advances. Most COPD studies have included populations with mean ages older than 60 years (2). However, it is increasingly evident that lung function trajectories in COPD differ significantly and that differences are detectable in young adulthood (3–5). In this Perspective, we highlight the need to distinguish “early disease” from late “mild disease,” propose an operational definition of early COPD for use in research studies, and attempt to unify current views on potential disease mechanisms. We focus on smoking, the chief etiologic factor for COPD in the industrialized world. Whether pathogenic mechanisms and effective treatments are shared with the sizable fraction of COPD in never-smokers or resulting from biomass fuel, electronic nicotine delivery systems, and other exposures, are separate, significant questions. We argue that refocusing investigation on early COPD could revolutionize understanding and therapies of this leading cause of worldwide death.

RATIONALE: There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity. OBJECTIVES: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke-induced glucocorticoid insensitivity. METHODS: Wild-type, PI3Kgamma knock-out and PI3Kdelta kinase dead knock-in transgenic mice were used in a model of cigarette smoke-induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD. MEASUREMENTS AND MAIN RESULTS: In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3Kdelta kinase dead knock-in but not PI3Kgamma knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD. CONCLUSIONS: These data show that therapeutic inhibition of PI3Kdelta may restore glucocorticoid function in oxidative stress-induced glucocorticoid insensitivity.

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.