title: Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.
abstract: 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-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 μM) and/or the HDAC enhancer theophylline (10 μM).
  
  
  RESULTS
  Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1β, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB 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-κB activation.
  
  
  CONCLUSIONS
  These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB 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.
authors.affiliation: Hospital Universitario Son Espases-IdISPa, Palma de Mallorca, Spain. borja.cosio@ssib.es.|CIBER Enfermedades Respiratorias, Madrid, Spain. borja.cosio@ssib.es.|Department of Respiratory Medicine, Hospital Universitario Son Espases, Carretera de Valldemossa 79, 07010, Palma de Mallorca, Spain. borja.cosio@ssib.es.
authors.forename: Borja G
authors.initials: BG
authors.lastname: Cosío
authors.affiliation: Hospital Universitario Son Espases-IdISPa, Palma de Mallorca, Spain. andreas.jahn@ssib.es.|CIBER Enfermedades Respiratorias, Madrid, Spain. andreas.jahn@ssib.es.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jahn
authors.affiliation: Hospital Universitario Son Espases-IdISPa, Palma de Mallorca, Spain. Amanda.iglesias@ssib.es.|CIBER Enfermedades Respiratorias, Madrid, Spain. Amanda.iglesias@ssib.es.
authors.forename: Amanda
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Hospital Universitario Son Espases-IdISPa, Palma de Mallorca, Spain. whitecoat_med@yahoo.com.|University of Alexandria, Alexandria, Egypt. whitecoat_med@yahoo.com.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Shafiek
authors.affiliation: IUNICs, Universidad de las Islas Baleares, Palma de Mallorca, Spain. Xavier.busquets@uib.es.
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.affiliation: CIBER Enfermedades Respiratorias, Madrid, Spain. aagusti@clinic.ub.es.|Institut del tórax, Hospital Clinic, Barcelona, Spain. aagusti@clinic.ub.es.
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006192:Haemophilus Infections / Q000276:immunology* / Q000378:metabolism; D006193:Haemophilus influenzae; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000378:metabolism; D012907:Smoking / Q000276:immunology* / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D003907:Dexamethasone; D013806:Theophylline; D006655:Histone Deacetylases