Cigarette smoke induced airway inflammation is independent of NF-κB signalling.
BACKGROUND
COPD 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.


OBJECTIVE
To use a range of assays, genetically modified animals and pharmacological tools to determine the role of NF-κB in CS-induced airway inflammation.


METHODS
NF-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.


RESULTS
We 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.


CONCLUSIONS
In 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.
Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Joseph M D
JM
Rastrick
Christopher S
CS
Stevenson
Suffwan
S
Eltom
Megan
M
Grace
Meirion
M
Davies
Iain
I
Kilty
Steven M
SM
Evans
Manolis
M
Pasparakis
Matthew C
MC
Catley
Toby
T
Lawrence
Ian M
IM
Adcock
Maria G
MG
Belvisi
Mark A
MA
Birrell
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012140:Respiratory Tract Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014026:Nicotiana / Q000737:chemistry; D051996:Transcription Factor RelA / Q000378:metabolism
D000577:Amides; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012906:Smoke; D013876:Thiophenes; D051996:Transcription Factor RelA; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse