Alterations in the sputum proteome and transcriptome in smokers and early-stage COPD subjects.

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases. Cigarette smoking is the main risk factor for COPD. In this parallel-group clinical study we investigated to what extent the transitions in a chronic-exposure-to-disease model are reflected in the proteome and cellular transcriptome of induced sputum samples. We selected 60 age- and gender-matched individuals for each of the four study groups: current asymptomatic smokers, smokers with early stage COPD, former smokers, and never smokers. The cell-free sputum supernatant was analyzed by quantitative proteomics and the cellular mRNA fraction by gene expression profiling. The sputum proteome of current smokers clearly reflected the common physiological responses to smoke exposure, including alterations in mucin/trefoil proteins and a prominent xenobiotic/oxidative stress response. The latter response also was observed in the transcriptome, which additionally demonstrated an immune-cell polarization change. The former smoker group showed nearly complete attenuation of these biological effects. Thirteen differentially abundant proteins between the COPD and the asymptomatic smoker group were identified including TIMP1, APOA1, C6orf58, and BPIFB1 (LPLUNC1). In summary, our study demonstrates that sputum profiling can capture the complex and reversible physiological response to cigarette smoke exposure, which appears to be only slightly modulated in early-stage COPD.

Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model.

RATIONALE: The model most often used to study the pathogenesis of pulmonary fibroses is the bleomycin (BLM)-induced lung fibrosis model. Several treatments have been efficacious in this model, but not in the clinic. OBJECTIVES: To describe the time course of inflammation and fibrosis in the BLM model and to study the effect of timing of antiinflammatory and antifibrotic treatments on efficacy. METHODS AND MEASUREMENTS: Rats were given single intratracheal injections of BLM on Day 0. At specified time points, 10 rats were killed and their lungs studied for proinflammatory cytokines and for profibrotic growth factor mRNA. After a single intratracheal injection of BLM on Day 0, rats were treated from Day 1 or 10 daily with oral prednisolone (10 mg/kg) or oral imatinib mesylate (50 mg/kg) for 21 d. RESULTS: After BLM administration, the expression of inflammatory cytokines was elevated and returned to background levels at later time points. Profibrotic gene expression peaked between Days 9 and 14 and remained elevated till the end of the experiment, suggesting a "switch" between inflammation and fibrosis in this interval. Antiinflammatory treatment (oral prednisolone) was beneficial when commenced at Day 1, but had no effect if administered from Day 10 onward. However, imatinib mesylate was effective independently of the dosing regime. CONCLUSIONS: The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.