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STAT4 activation in smokers and patients with chronic obstructive pulmonary disease

Activation of the transcription factor signal transducer and activator of transcription (STAT)‐4 is critical for the differentiation of T‐helper 1 cells/type‐1 cytotoxic T‐cells and the production of interferon (IFN)‐γ. Expression of STAT4, phospho‐STAT4, IFN‐γ and T‐box expressed in T‐cells (T‐bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)‐derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59±16% predicted), 14 smokers with normal lung function (FEV1 106±12% pred) and 12 nonsmoking subjects (FEV1 111±14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho‐STAT4+ cells was increased (240 (22–406) versus 125 (0–492) versus 29 (0–511) cells·mm−2) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho‐STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN‐γ+ cells. Similar results were seen in BAL (2.8 (0.2–5.9) versus 1.03 (0.09–1.6) versus 0.69 (0–2.3) lymphocytes·mL−1×103). In all smokers who underwent lavage, phospho‐STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNγ+ lymphocytes. T‐bet expression was not altered in bronchial biopsies and BAL‐derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T‐helper 1 cell/type‐1 cytotoxic T‐cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.