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oai:repisalud.isciii.es:20.500.12105/201632024-11-29T01:43:37Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc García-Cosío, Borja author Jahn, Andreas author Iglesias, Amanda author Shafiek, Hanaa author Busquets, Xavier author Agusti, Alvar author 2015-12-07 Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before. Methods: The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-kappa B) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 mu M) and/or the HDAC enhancer theophylline (10 mu M). Results: Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-kappa B and induced the secretion of several cytokines (IL-6, IL-8, IL-1 beta, IL-10 and TNF-alpha) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-kappa B activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-kappa B activation. Conclusions: These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-kappa B mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity. Cosio BG, Jahn A, Iglesias A, Shafiek H, Busquets X, Agusti García-Navarro A. Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD. BMC Pulm Med. 2015 Dec 07;15:157. 1471-2466 http://hdl.handle.net/20.500.13003/10579 http://hdl.handle.net/20.500.12105/20163 26642881 10.1186/s12890-015-0155-3 BMC Pulmonary Medicine 2-s2.0-84952877044 367144100001 L607200914 COPD exacerbation Glucocorticoids Colonization Histone deacetylase Nuclear Factor-kappa B Theophylline Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD