p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment.

Saxon JA, Cheng DS, Han W, Polosukhin VV, McLoed AG, Richmond BW, Gleaves LA, Tanjore H, Sherrill TP, Barham W, Yull FE, Blackwell TS
J Immunol. 2016 196 (4): 1891-9

PMID: 26773153 · PMCID: PMC4744539 · DOI:10.4049/jimmunol.1501555

Although numerous studies have demonstrated a critical role for canonical NF-κB signaling in inflammation and disease, the function of the noncanonical NF-κB pathway remains ill-defined. In lung tissue from patients with acute respiratory distress syndrome, we identified increased expression of the noncanonical pathway component p100/p52. To investigate the effects of p52 expression in vivo, we generated a novel transgenic mouse model with inducible expression of p52 in Clara cell secretory protein-expressing airway epithelial cells. Although p52 overexpression alone did not cause significant inflammation, p52 overexpression caused increased lung inflammation, injury, and mortality following intratracheal delivery of Escherichia coli LPS. No differences in cytokine/chemokine expression were measured between p52-overexpressing mice and controls, but increased apoptosis of Clara cell secretory protein-positive airway epithelial cells was observed in transgenic mice after LPS stimulation. In vitro studies in lung epithelial cells showed that p52 overexpression reduced cell survival and increased the expression of several proapoptotic genes during cellular stress. Collectively, these studies demonstrate a novel role for p52 in cell survival/apoptosis of airway epithelial cells and implicate noncanonical NF-κB signaling in the pathogenesis of acute respiratory distress syndrome.

Copyright © 2016 by The American Association of Immunologists, Inc.

MeSH Terms (17)

Animals Apoptosis Blotting, Western Disease Models, Animal Enzyme-Linked Immunosorbent Assay Humans Immunohistochemistry Lipopolysaccharides Mice Mice, Transgenic NF-kappa B p52 Subunit Pneumonia Real-Time Polymerase Chain Reaction Respiratory Distress Syndrome Respiratory Mucosa Signal Transduction Up-Regulation

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