Cigarette Smoke Induced Airway Inflammation Is Independent of NF-κB Signalling

Abstract

RationaleCOPD is an inflammatory lung disease largely associated with exposure to cigarette smoke (CS). The mechanism by which CS leads to the pathogenesis of COPD is currently unclear; it is known however that many of the inflammatory mediators present in the COPD lung can be produced via the actions of the transcription factor Nuclear Factor-kappaB (NF-κB) and its upstream signalling kinase, Inhibitor of κB kinase-2 (IKK-2). Therefore the NF-κB/IKK-2 signalling pathway may represent a therapeutic target to attenuate the inflammation associated with COPD.AimTo use a range of assays, genetically modified animals and pharmacological tools to determine the role of NF-κB in CS-induced airway inflammation.MethodsNF-κB pathway activation was measured in pre-clinical models of CS-induced airway inflammation and in human lung tissue from COPD patients. This data was complemented by employing mice missing a functional NF-κB pathway in specific cell types (epithelial and myeloid cells) and with systemic inhibitors of IKK-2.ResultsWe showed in an airway inflammation model known to be NF-κB-dependent that the NF-κB pathway activity assays and modulators were functional in the mouse lung. Then, using the same methods, we demonstrated that the NF-κB pathway appears not to play an important role in the inflammation observed after exposure to CS. Furthermore, assaying human lung tissue revealed that in the clinical samples there was also no increase in NF-κB pathway activation in the COPD lung, suggesting that our pre-clinical data is translational to human disease.ConclusionsIn this study we present compelling evidence that the IKK-2/NF-κB signalling pathway does not play a prominent role in the inflammatory response to CS exposure and that this pathway may not be important in COPD pathogenesis.

Antibacterial Defense of Human Airway Epithelial Cells from Chronic Obstructive Pulmonary Disease Patients Induced by Acute Exposure to Nontypeable Haemophilus influenzae: Modulation by Cigarette Smoke

“…This appears in contrast to some studies that have reported increased NF-κB activation in COPD lung tissue [46][47][48] . However, this is not observed in all studies and it has been suggested that NF-κB signaling may not contribute to COPD pathogenesis [49] . Furthermore, our results are also in line with those of a study showing that long-term passive CS exposure inhibits UVB-induced NF-κB signaling in the skin [50] , and with earlier reports showing impaired IKKα/β phosphorylation and kinase activity caused by posttranslational modifications, mediated for instance by oxidative stress [51,52] .…”

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…In South Africa, where the epidemiology of RA is changing in relation to ethnicity, the prevalence rates of "definite RA" in rural and urban black South African populations reported in 1975 were reported to be 0.18% and 0.9% respectively [97]; in a later study published in 1988, the prevalence of RA in a defined, remote geographic region of South Africa was estimated to be 0.0026% [98]. The corresponding prevalence rates for Taiwan published in 1994 varied from 0.26 -0.93%, with the highest rate recorded in an urban region [99,100]  As mentioned earlier, even in in non-smoking subjects with RA, the levels of several toxic heavy metals in blood and hair samples were reported to be higher than those of healthy control subjects [60]. In the context of the association of atmospheric pollution and RA risk, two aspects of this study are particularly noteworthy.…”

“…On a cautionary note, however, the extent of the involvement of NFκB in the pro-inflammatory effects of smoking has recently been re-visited and questioned, raising the issue of alternative mechanisms of smoke-activated pulmonary inflammation [60].…”

“…In the context of the association of atmospheric pollution and RA risk, two aspects of this study are particularly noteworthy. Firstly, the subjects were resident in a major city (Dublin, Republic of Ireland); secondly, most of the heavy metals tested (As, Cd, Hg) are also present in diesel emissions [60]. In addition, residing in areas with high levels of atmospheric pollution has also been reported to be associated with particularly high concentrations of As in nasal mucosa and nasal polyps [59].…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Yet another IKK-b inhibitor TPCA-1 is effective in a mouse model of neutrophilic inflammation induced by inhaled endotoxin, although it was not effective in a neutrophil elastase-induced inflammation model (Birrell et al, 2006). IKK-b inhibitors have also been ineffective in cigarette smoke-induced lung inflammation in mice (Rastrick et al, 2013). Several IKK-b inhibitors suppressed the release of cytokines and chemokines from human airway smooth muscle and epithelial cells and were mimicked by adenovirus mediated delivery of a dominant-negative IKK-b inhibitor Newton et al, 2007).…”