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

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-α has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-α receptors. To investigate the contribution of each TNF-α receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-α R1 knockout (KO) mice, TNF-α R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-α R1 (by four-fold) and TNF-α 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-α R1 KO mice. In TNF-α R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-α R2 KO mice in contrast to WT and TNF-α R1 KO mice. CS-exposed WT and TNF-α R1 KO mice failed to gain weight, whereas the body mass of TNF-α R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-α receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-α 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.