Airway epithelium controls lung inflammation and injury through the NF-kappa B pathway.
Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.
Cheng
Dong-sheng
DS
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Han
Wei
W
Chen
Sabrina M
SM
Sherrill
Taylor P
TP
Chont
Melissa
M
Park
Gye-Young
GY
Sheller
James R
JR
Polosukhin
Vasiliy V
VV
Christman
John W
JW
Yull
Fiona E
FE
Blackwell
Timothy S
TS
D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014132:Trachea / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B