• Tania Maes, Ken R Bracke, Karim Y Vermaelen, Ingel K Demedts, Guy F Joos, Romain A Pauwels, and Guy G Brusselle.
• Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium. tania.maes@Ugent.be
• Int. Arch. Allergy Immunol. 2006 Jan 1; 141 (4): 354-68.

BackgroundChronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. We investigated whether Toll-like receptor 4 (TLR4) is implicated in cigarette smoke (CS)-induced pulmonary inflammation in a murine model of COPD.MethodsC3H/HeOuJ (Tlr4(WT)) and C3H/HeJ (Tlr4(defective)) mice were exposed to air or CS for 5 weeks (subacute) and 26 weeks (chronic), and pulmonary inflammation was evaluated.ResultsIn Tlr4(WT) mice, subacute and chronic CS exposure induced a substantial pulmonary infiltration of macrophages, neutrophils, lymphocytes and dendritic cells (DCs), that was absent in air-exposed mice. CS exposure increased the costimulatory marker expression on DCs, the levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage (BAL) fluid and induced the pulmonary expression of matrix metalloproteinase-12 (MMP-12), TLR4 and TLR2. In contrast, after subacute CS exposure, Tlr4(defective) mice showed a limited (5-fold lower) increase of DCs and lymphocytes in BAL fluid, lower costimulatory marker expression on DCs and lower MCP-1 and TNF-alpha levels in BAL fluid compared to Tlr4(WT) animals. After chronic CS exposure, however, the difference in pulmonary inflammation between Tlr4(WT) and Tlr4(defective) mice was less pronounced and both strains showed similar MCP-1 and TNF-alpha levels in BAL and similar pulmonary MMP-12, TLR4 and TLR2 expression.ConclusionsWe demonstrated that the TLR4 mutation in C3H/HeJ mice is protective against CS-induced pulmonary influx of neutrophils, DCs and lymphocytes upon subacute CS exposure. However, TLR4 is only of minor importance in chronic CS-induced inflammation in mice.

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