Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Abstract

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-κB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-κB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IκB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-κB 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-κB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IκB 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-κB 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.

Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

“…S1A). Next, we purified mSFTPC.rtTA and (tet-O) 7 -L188Q SFTPC-myc constructs, as well as a construct expressing a tetracycline-controlled transcriptional silencer (tTS) under the murine SFTPC promoter (mSFTPC.tTS) to prevent basal leakiness of transgene expression (9) (Fig. S1B) and performed simultaneous pronuclear microinjection of the three DNA constructs into fertilized oocytes from C57BL/6J mice.…”

“…Scoring of lung fibrosis (15,17), fibroblasts (15), and TUNEL staining (9) and determination of collagen content by hydroxyproline assay (38) were performed as previously described.…”

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

“…2 Epithelial cells generate cytokines, chemokines, and antimicrobial peptides in response to inflammatory stimuli, 25,26 and airway epithelium controls lung inflammation and injury through NF-κB. 27 Numerous experimental studies have used human A549 alveolar and BEAS-2B bronchial epithelial cell lines to examine the acute lung inflammatory response induced by LPS, as an acceptable, validated, and suitable in vitro airway epithelial injury model based on the initial steps of the development of sepsis and ARDS [11][12][13][14][15][16]25,[28][29][30] and continue being extensively used. [31][32][33][34][35] We selected E. coli LPS because it has been used in most endotoxin-induced lung injury models 36,37 and LPS is a key pathogen recognition molecule for sepsis 27 that induces apoptosis in lung cells.…”

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

“…19 To inhibit epithelial NF-kB signaling in the lungs of these mice, EGFR L858R mice were mated to transgenic mice that express a dox-inducible dominant negative IkBa (DN-IkB). 20 This DN-IkB is unable to be phosphorylated and degraded, thereby blocking translocation of the NF-kB heterodimers into the nucleus and preventing target gene transcription. Upon dox administration, these triple transgenic mice (designated EGFR L858R DN-IkB mice) express EGFR…”