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

Abstract

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

MicroRNA Expression in Induced Sputum of Smokers and Patients with Chronic Obstructive Pulmonary Disease

“…In a mouse model of COPD, TNFR-II knockout mice were protected against cigarette smoke-induced inflammation and emphysema (39). In addition, other groups have shown that TNFR-II is increased in the sputum of patients with COPD (40,41).…”

Cigarette Smoke Impairs Clearance of Apoptotic Cells through Oxidant-dependent Activation of RhoA

“…Because our data show that CS-impaired efferocytosis also depends on intact TNF-a signaling, we cannot rule out the possibility that oxidants may act at two points in the pathway; early when associated with CS and later at a point downstream of TNF-a. The role of TNF-a in this pathway is certainly relevant because of its potential importance in the development of COPD (76)(77)(78)(79)(80)(81).…”

Tumor necrosis factor-α serum levels in healthy smokers and nonsmokers

“…30 A recent study conducted by D'hulst and coworkers 31 demonstrated that p75 receptor knockout mice were protected against cigarette smoke induced pulmonary emphysema. The authors also showed that cigarette smoke exposure increased the inflammatory infiltrate in the bronchoalveolar lavage fluid of wild type, p55 knockout or p75 knockout mice, in comparison with air-exposed mice.…”