Beta Defensin-2 Is Reduced in Central but Not in Distal Airways of Smoker COPD Patients

Elisabetta Pace,Maria Ferraro,Loredana Pipitone,Marta Ida Minervini,Patrizio Vitulo,Malcolm Johnson,Angela Marina Montalbano,Giuseppina Chiappara,Mark Gjomarkaj,Liboria Siena

doi:10.1371/journal.pone.0033601

Abstract

BackgroundAltered pulmonary defenses in chronic obstructive pulmonary disease (COPD) may promote distal airways bacterial colonization. The expression/activation of Toll Like receptors (TLR) and beta 2 defensin (HBD2) release by epithelial cells crucially affect pulmonary defence mechanisms.MethodsThe epithelial expression of TLR4 and of HBD2 was assessed in surgical specimens from current smokers COPD (s-COPD; n = 17), ex-smokers COPD (ex-s-COPD; n = 8), smokers without COPD (S; n = 12), and from non-smoker non-COPD subjects (C; n = 13).ResultsIn distal airways, s-COPD highly expressed TLR4 and HBD2. In central airways, S and s-COPD showed increased TLR4 expression. Lower HBD2 expression was observed in central airways of s-COPD when compared to S and to ex-s-COPD. s-COPD had a reduced HBD2 gene expression as demonstrated by real-time PCR on micro-dissected bronchial epithelial cells. Furthermore, HBD2 expression positively correlated with FEV1/FVC ratio and inversely correlated with the cigarette smoke exposure. In a bronchial epithelial cell line (16 HBE) IL-1β significantly induced the HBD2 mRNA expression and cigarette smoke extracts significantly counteracted this IL-1 mediated effect reducing both the activation of NFkB pathway and the interaction between NFkB and HBD2 promoter.ConclusionsThis study provides new insights on the possible mechanisms involved in the alteration of innate immunity mechanisms in COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is an increasingly serious global health problem [1] and it is expected to be the third most common cause of death in 2020 [2].Distal airway bacterial colonization may occur in chronic obstructive pulmonary disease (COPD) patients, who often have altered pulmonary defenses [3]
The number of packs/year was similar between S and s-COPD but it was significantly higher in s-COPD than in ex-s-COPD (p,0.01)
TLR4 expression was increased in the epithelium of distal airways in S, in s-COPD and in ex-s-COPD when compared to C

Summary

Introduction

Distal airway bacterial colonization may occur in COPD patients, who often have altered pulmonary defenses [3]. A key component of the innate defences against infections is represented by the toll like receptor (TLR) family [4]. Upon activation of TLR by endogenous and exogenous ligands, the release of chemokines including IL8 and IP-10 and of defensins may occur [5]. The airway epithelium is active in airway defence mechanisms releasing cytoprotective mucus and defensins [7] and plays an important role in coordinating local inflammation and immune responses through the generation of cytokines and chemokines [8]. Altered pulmonary defenses in chronic obstructive pulmonary disease (COPD) may promote distal airways bacterial colonization. The expression/activation of Toll Like receptors (TLR) and beta 2 defensin (HBD2) release by epithelial cells crucially affect pulmonary defence mechanisms

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