title: Alveolar cell stretching in the presence of fibrous particles induces interleukin-8 responses.
abstract: Inhalation of fibrous particulates is strongly associated with lung injury, but the molecular and cellular mechanisms that could explain the fiber-induced pathogenesis are not fully understood. We hypothesized that the physical stress exerted on the alveolar epithelium by the deposited fibers is greatly enhanced by the tidal cyclic motion of the epithelial cells that is associated with breathing, and that this initial mechanical interaction triggers a subsequent cell response. To test this hypothesis, we developed a dynamic model of fiber-induced cell injury using a cell-stretcher device. We exposed a cyclically stretched monolayer of the human alveolar epithelial cell line A549 to glass or crocidolite asbestos fibers for 8 h and then measured the production of the proinflammatory cytokine interleukin (IL)-8 as a readout of fiber-induced cell injury. Cyclic stretching significantly increased IL-8 production in the fiber-treated cultures, suggesting that the physical stress on the cells caused by the fibers was indeed enhanced by the motion. Coating of the asbestos fibers with fibronectin, a glycoprotein abundant in the alveolar lining fluid, further increased the fiber-induced cell response when the cells were cyclically stretched. This response was, however, significantly reduced by introducing into the culture medium, before fiber treatment, soluble RGD (Arg-Gly-Asp)-containing peptides, which specifically block binding to integrin receptors upon RGD attachment. These results suggested that adhesive interactions between protein-coated fibers and cell surface molecules are involved in the fiber-induced pathogenic process. Our novel findings indicate the importance of physical insults in fiber-induced cell stress, and bring to the forefront the need to study the mechanisms involved in this process.
authors.affiliation: Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115, USA. atsuda@hsph.harvard.edu
authors.forename: A
authors.initials: A
authors.lastname: Tsuda
authors.forename: B K
authors.initials: BK
authors.lastname: Stringer
authors.forename: S M
authors.initials: SM
authors.lastname: Mijailovich
authors.forename: R A
authors.initials: RA
authors.lastname: Rogers
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: M L
authors.initials: ML
authors.lastname: Gray
mesh_terms: D017638:Asbestos, Crocidolite / Q000633:toxicity; D002460:Cell Line; D005353:Fibronectins / Q000494:pharmacology; D005898:Glass; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016023:Integrins / Q000502:physiology; D016209:Interleukin-8 / Q000096:biosynthesis*; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology; D010316:Particle Size; D011650:Pulmonary Alveoli / Q000276:immunology / Q000293:injuries* / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D005353:Fibronectins; D018836:Inflammation Mediators; D016023:Integrins; D016209:Interleukin-8; D009842:Oligopeptides; D017638:Asbestos, Crocidolite; C049554:glycyl-arginyl-glycyl-aspartyl-serine