Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation.
BACKGROUND
Chronic 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.


METHODS
C3H/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.


RESULTS
In 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.


CONCLUSIONS
We 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.
Maes
Tania
T
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium. tania.maes@Ugent.be
Bracke
Ken R
KR
Vermaelen
Karim Y
KY
Demedts
Ingel K
IK
Joos
Guy F
GF
Pauwels
Romain A
RA
Brusselle
Guy G
GG
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D039521:CD11c Antigen / Q000032:analysis; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000473:pathology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D012906:Smoke; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D053508:Matrix Metalloproteinase 12