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Role of tumour necrosis factor- receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema

A. I. D'hulst¹, K. R. Bracke¹, T. Maes¹, J. L. De Bleecker², R. A. Pauwels, ¹, G. F. Joos¹ and G. G. Brusselle¹

¹ Depts of Respiratory Diseases, and ² Neurology, Ghent University Hospital, Ghent, Belgium.

CORRESPONDENCE: A. I. D'hulst, Dept of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Fax: 32 92402341. E-mail: an.dhulst{at}UGent.be

Keywords: Chronic obstructive pulmonary disease, cigarette smoking, emphysema, inflammation, tumour necrosis factor- receptors, weight loss

Received: May 19, 2005
Accepted February 27, 2006

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)- has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF- receptors.

To investigate the contribution of each TNF- receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF- R1 knockout (KO) mice, TNF- R2 KO mice and wild type (WT) mice.

CS was found to significantly increase the protein levels of soluble TNF- R1 (by four-fold) and TNF- R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF- R1 KO mice. In TNF- R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF- R2 KO mice in contrast to WT and TNF- R1 KO mice. CS-exposed WT and TNF- R1 KO mice failed to gain weight, whereas the body mass of TNF- R2 KO mice was not affected.

These current findings suggest that both tumour necrosis factor- receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor- receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.

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