title: Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells.
abstract: BACKGROUND
  Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury.
  
  
  METHODS
  Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively.
  
  
  RESULTS
  TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4.
  
  
  CONCLUSIONS
  These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. pnayak4@gmail.com.
authors.forename: Pritha S
authors.initials: PS
authors.lastname: Nayak
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. ywang@wihri.org.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. tnajrana@wihri.org.
authors.forename: Tanbir
authors.initials: T
authors.lastname: Najrana
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. lpriolo@wihri.org.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Priolo
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. mayrartx@yahoo.com.
authors.forename: Mayra
authors.initials: M
authors.lastname: Rios
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. SShaw@WIHRI.org.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Shaw
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA. jsanchezesteban@wihri.org.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Esteban
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D005333:Fetus; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D020545:Respiratory Mucosa / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D050916:TRPV Cation Channels / Q000096:biosynthesis*
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse