title: p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232;
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Saxon
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232;
authors.forename: Allyson G
authors.initials: AG
authors.lastname: McLoed
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232; and.
authors.forename: Bradley W
authors.identifier: http://orcid.org/0000-0001-6200-5235
authors.initials: BW
authors.lastname: Richmond
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232;
authors.forename: Whitney
authors.initials: W
authors.lastname: Barham
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232;
authors.forename: Fiona E
authors.identifier: http://orcid.org/0000-0003-1636-7942
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232; and Department of Veterans Affairs Medical Center, Nashville, TN 37232 timothy.blackwell@vanderbilt.edu.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000473:pathology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D052003:NF-kappa B p52 Subunit