title: Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury.
abstract: Repair of the lung epithelium after injury is integral to the pathogenesis and outcomes of diverse inflammatory lung diseases. We previously reported that β-catenin signaling promotes epithelial repair after inflammatory injury, but the β-catenin target genes that mediate this effect are unknown. Herein, we examined which β-catenin transcriptional coactivators and target genes promote epithelial repair after inflammatory injury. Transmigration of human neutrophils across cultured monolayers of human lung epithelial cells resulted in a fall in transepithelial resistance and the formation of discrete areas of epithelial denudation ("microinjury"), which repaired via cell spreading by 96 h. In mice treated with intratracheal (i.t.) LPS or keratinocyte chemokine, neutrophil emigration was associated with increased permeability of the lung epithelium, as determined by increased bronchoalveolar lavage (BAL) fluid albumin concentration, which decreased over 3-6 days. Activation of β-catenin/p300-dependent gene expression using the compound ICG-001 accelerated epithelial repair in vitro and in murine models. Neutrophil transmigration induced epithelial expression of the β-catenin/p300 target genes Wnt-induced secreted protein (WISP) 1 and cysteine-rich (Cyr) 61, as determined by real-time PCR (qPCR) and immunostaining. Purified neutrophil elastase induced WISP1 upregulation in lung epithelial cells, as determined by qPCR. WISP1 expression increased in murine lungs after i.t. LPS, as determined by ELISA of the BAL fluid and qPCR of whole lung extracts. Finally, recombinant WISP1 and Cyr61 accelerated repair, and Cyr61-neutralizing antibodies delayed repair of the injured epithelium in vitro. We conclude that β-catenin/p300-dependent expression of WISP1 and Cyr61 is critical for epithelial repair and represents a potential therapeutic target to promote epithelial repair after inflammatory injury.
authors: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USA. zemansr@njhealth.org
authors: Rachel L
authors: RL
authors: Zemans
authors: Jazalle
authors: J
authors: McClendon
authors: Yael
authors: Y
authors: Aschner
authors: Natalie
authors: N
authors: Briones
authors: Scott K
authors: SK
authors: Young
authors: Lester F
authors: LF
authors: Lau
authors: Michael
authors: M
authors: Kahn
authors: Gregory P
authors: GP
authors: Downey
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050881:E1A-Associated p300 Protein / Q000378:metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
chemical_list: D055511:CCN Intercellular Signaling Proteins; C501848:CCN1 protein, human; C116396:CCN4 protein, human; D055515:Cysteine-Rich Protein 61; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human