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Defective lung macrophage function in lung cancer ± chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2?

ABSTRACT: In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective 'efferocytosis'), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.

SUBMITTER: Dehle FC

PROVIDER: S-EPMC3637201 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Project description:COPD is a common and disabling lung disease for which very few therapeutic options are currently available. We reasoned that global gene expression profiling of COPD lungs could reveal previously unidentified disease pathways for potential therapeutic interventions. Forty-eight human lung samples were obtained from lungs or lobes resected for small peripheral lung lesions (5 non-smokers, 21 GOLD 0, 9 GOLD 1, 10 GOLD 2 and 3 GOLD 3 patients). mRNA from the specimens was profiled using Agilent’s Functional ID v2.0 array which contains 23,720 sequences. Quantitative morphometric analysis of the specimens revealed that the samples contained a variable proportion of airways, blood vessels and parenchyma. Incorporating these data into a model relating gene expression to % predicted forced expiratory flow between 25 and 75% of forced expiratory volume (FEF 25-75 % P) revealed a signature gene set of 203 transcripts. Genes involved in extracellular matrix synthesis/degradation, oxidative stress and cell proliferation were among the up-regulated genes whereas genes which participate in nicotine metabolism, elastic fiber homeostasis and anti-inflammatory response were down-regulated. Immunohistochemistry confirmed expression of urokinase (PLAU), urokinanse receptor (PLAUR) and thrombospondin (THBS1) by alveolar macrophages and small airway epithelial cells. Genes in this pathway have been shown to be involved in transforming growth factor beta-1 (TGF?1) and matrix metalloproteinase (MMP) activation and are subject to inhibition by serpin E2. Interestingly, both TGF?1 and serpin E2 have been identified as candidate genes in COPD genetic linkage and association studies. The results thus provide a possible link between these two powerful approaches to identify potential therapeutic targets. (255 words) Forty-eight human lung samples were obtained from lungs or lobes resected for small peripheral lung lesions (5 non-smokers, 21 GOLD 0, 9 GOLD 1, 10 GOLD 2 and 3 GOLD 3 patients). mRNA from the specimens was profiled using Agilent’s Functional ID v2.0 array which contains 23,720 sequences. Quantitative morphometric analysis of the specimens revealed that the samples contained a variable proportion of airways, blood vessels and parenchyma. Incorporating these data into a model relating gene expression to % predicted forced expiratory flow between 25 and 75% of forced expiratory volume (FEF 25-75 % P) revealed a signature gene set of 203 transcripts.

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Defective lung macrophage function in lung cancer ± chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2?

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