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Chun-Yu Lo,1 Hung-Yu Huang,1 Jung-Ru He,1 Tzu-Ting Huang,1 Chih-Chen Heh,1 Te-Fang Sheng,1 Kian Fan Chung,2 Han-Pin Kuo,1 Chun-Hua Wang1 1Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan; 2Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Background: Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.Patients and methods: Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS) were enrolled. Spirometry was performed during enrollment and repeated after 5years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.Results: A greater reduction in forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC), FEV1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR - NS and AHR - S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.Conclusion: AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers. Keywords: smoking, airway hyperresponsiveness, alveolar macrophage, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase&nbsp

Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n = 59) and those with wild-type EGFR (n = 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p = 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p = 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p = 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p = 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

Background Adjuvant tumor cell vaccine with chemotherapy against non-small cell lung cancer (NSCLC) shows limited clinical response. Whether it provokes effective cellular immunity in tumor microenvironment is questionable. Concomitant active tuberculosis in NSCLC (TBLC) resembles locoregional immunotherapy of tumor cell vaccine; thus, maximally enriches effective anti-tumor immunity. This study compares the survival and immunological cell profile in TBLC over NSCLC alone. Methods Retrospective review of NSCLC patients within 1-year-period of 2007 and follow-up till 2010. Results A total 276 NSCLC patients were included. The median survival of TBLC is longer than those of NSCLC alone (11.6 vs. 8.8 month, p