title: TLR4 upregulation underpins airway neutrophilia in smokers with chronic obstructive pulmonary disease and acute respiratory failure.
abstract: Activation of Toll-like receptors (TLR) seems to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Upon TLR activation the release of defensins, including human beta defensin 2 (HBD-2), may occur. In this study, we explored the innate responses in patients with respiratory failure, with and without COPD, requiring intubation and mechanical ventilation. Mini-bronchoalveolar lavage (mini-BAL) samples were collected from nonsmoker subjects without COPD (n = 10), smokers without COPD (n = 6), and smokers with COPD (n = 15). TLR4, TLR2, and HBD-2 expression was evaluated by immunocytochemistry; interleukin (IL)-8, IP-10, and HBD-2 concentrations were evaluated by enzyme-linked immunosorbent assay; chemotactic activity toward neutrophils and lymphocytes; and cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] and by flow cytometry with anti-TLR4 and with HBD-2 depleted and not depleted mini-BAL). COPD mini-BAL showed increased neutrophil numbers, reduced neutrophil apoptosis, increased TLR4 and HBD-2 expression, increased neutrophil chemotactic activity, reduced IP-10 concentrations, and reduced lymphocyte chemotactic activity compared with those in nonsmoker subjects without COPD. In the smokers without COPD the mini-BAL showed reduced TLR4 and HBD-2 expression, higher IP-10 concentrations, and higher chemotactic activity than in patients with COPD. The blocking of TLR4 activation and HBD-2 depletion increased neutrophil apoptosis. No differences were observed for TLR2 expression and IL-8 concentrations. This study strengthens the contribution of TLR4 to promoting airway neutrophilia in COPD.
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy. pace@ibim.cnr.it
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pace
authors.forename: Antonino
authors.initials: A
authors.lastname: Giarratano
authors.forename: Maria
authors.initials: M
authors.lastname: Ferraro
authors.forename: Andreina
authors.initials: A
authors.lastname: Bruno
authors.forename: Liboria
authors.initials: L
authors.lastname: Siena
authors.forename: Salvatore
authors.initials: S
authors.lastname: Mangione
authors.forename: Malcolm
authors.initials: M
authors.lastname: Johnson
authors.forename: Mark
authors.initials: M
authors.lastname: Gjomarkaj
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002633:Chemotaxis / Q000502:physiology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D007964:Leukocytosis / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D012131:Respiratory Insufficiency / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D023083:beta-Defensins / Q000235:genetics / Q000276:immunology
chemical_list: D016209:Interleukin-8; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D023083:beta-Defensins