title: Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity.
abstract: Epithelial injury is a central event in the pathogenesis of many inflammatory and fibrotic lung diseases like acute respiratory distress syndrome, pulmonary fibrosis, and iatrogenic lung injury. Mechanical stress is an often underappreciated contributor to lung epithelial injury. Following injury, differentiated epithelia can assume a myofibroblast phenotype in a process termed epithelial to mesenchymal transition (EMT), which contributes to aberrant wound healing and fibrosis. We demonstrate that cyclic mechanical stretch induces EMT in alveolar type II epithelial cells, associated with increased expression of low molecular mass hyaluronan (sHA). We show that sHA is sufficient for induction of EMT in statically cultured alveolar type II epithelial cells and necessary for EMT during cell stretch. Furthermore, stretch-induced EMT requires the innate immune adaptor molecule MyD88. We examined the Wnt/β-catenin pathway, which is known to mediate EMT. The Wnt target gene Wnt-inducible signaling protein 1 (wisp-1) is significantly up-regulated in stretched cells in hyaluronan- and MyD88-dependent fashion, and blockade of WISP-1 prevents EMT in stretched cells. In conclusion, we show for the first time that innate immunity transduces mechanical stress responses through the matrix component hyaluronan, and activation of the Wnt/β-catenin pathway.
authors.affiliation: Laboratory of Respiratory Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Heise
authors.forename: Vandy
authors.initials: V
authors.lastname: Stober
authors.forename: Chaitra
authors.initials: C
authors.lastname: Cheluvaraju
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
mesh_terms: D000818:Animals; D055511:CCN Intercellular Signaling Proteins; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D006820:Hyaluronic Acid / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D006820:Hyaluronic Acid