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Role of lymphotoxin- in cigarette smoke-induced inflammation and lymphoid neogenesis

¹ Dept of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, ² Dept of Rheumatology, Laboratory of Molecular Immunology and Inflammation, Ghent University Hospital, Ghent, and ³ Unit of Pneumology and Microbiology, Dept of Pneumology, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium.

CORRESPONDENCE: G. G. Brusselle, Dept of Respiratory Medicine, Ghent University Hospital 7K12E, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: guy.brusselle{at}ugent.be

Keywords: Chronic obstructive pulmonary disease, cigarette smoking, cytokines and chemokines, lymphotoxin-, mouse models

Received: July 4, 2008
Accepted December 29, 2008

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-, crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis.

We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammation in vivo in LT knockout (LT^-/-) and wild-type (WT) mice and studied the expression of lymphoid chemokines by lung fibroblasts in vitro.

T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LT^-/- mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LT^-/- mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LT^-/- mice. In vitro lymphotoxin-β receptor (LTβR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, in vitro exposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTβR^-/-, lung fibroblasts.

In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTβ–LTβR-dependent fashion. However, LT is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.