title: Effect of polarized release of CXC-chemokines from wild-type and cystic fibrosis murine airway epithelial cells.
abstract: The respiratory epithelium lining the airway relies on mucociliary clearance and a complex network of inflammatory mediators to protect the lung. Alterations in the composition and volume of the periciliary liquid layer, as occur in cystic fibrosis (CF), lead to impaired mucociliary clearance and persistent airway infection. Moreover, the respiratory epithelium releases chemoattractants after infection, inciting airway inflammation. However, characterizing the inflammatory response of primary human airway epithelial cells to infection can be challenging because of genetic heterogeneity. Using well-characterized, differentiated, primary murine tracheal cells grown at an air-liquid interface, which provides an in vitro polarized epithelial model, we compared inflammatory gene expression and secretion in wild-type and ΔF508 CF airway cells after infection with Pseudomonas aeruginosa. The expression of several CXC-chemokines, including macrophage inflammatory protein-2, small inducible cytokine subfamily member 2, lipopolysaccharide-induced chemokine, and interferon-inducible cytokine-10, was markedly increased after infection, and these proinflammatory mediators were asymmetrically released from the airway epithelium, predominantly from the basolateral surface. Equal amounts of CXC-chemokines were released from wild-type and CF cells. Secreted mediators were concentrated in the thin, periciliary fluid layer, and the dehydrated apical microenvironment of CF airway epithelial cells amplified the inflammatory signal, potentially resulting in high chemokine concentration gradients across the epithelium. Consistent with this observation, the enhanced chemotaxis of wild-type neutrophils was detected in CF airway epithelial cultures, compared with wild-type cells. These data suggest that P. aeruginosa infection of the airway epithelium induces the expression and polarized secretion of CXC-chemokines, and the increased concentration gradient across the CF airway leads to an exaggerated inflammatory response.
authors.affiliation: Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Farberman
authors.forename: Aida
authors.initials: A
authors.lastname: Ibricevic
authors.forename: Theresa D
authors.initials: TD
authors.lastname: Joseph
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Akers
authors.forename: Raquel
authors.initials: R
authors.lastname: Garcia-Medina
authors.forename: Seth
authors.initials: S
authors.lastname: Crosby
authors.forename: Lane L
authors.initials: LL
authors.lastname: Clarke
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction
chemical_list: D019743:Chemokines, CXC; D016207:Cytokines; D018836:Inflammation Mediators; D019005:Cystic Fibrosis Transmembrane Conductance Regulator