The tenascins are a family of large extracellular glycoproteins designated tenascin-C (cytotactin, TNC*), tenascin-X (TNX), tenascin-R (restrictin, TNR), and tenascin-W (TNW). Their functions in vivo are largely unknown, despite a large literature describing their myriad effects in vitro 1. We recently demonstrated an association of TNX-deficiency with the Ehlers-Danlos syndrome (EDS) 2, 3, a disorder of collagen metabolism causing hyperextensible skin and joints 4,5. Gene targeting studies showed that TNX regulates collagen deposition 6, probably through direct interaction with the collagen fibril. TNC is also collagen fibril-associated and preliminary studies show that TNC can correct the cellular defect in TNX-deficient fibroblasts, suggesting functional redundancy. TNX and/or TNC are induced in fibrotic conditions of heart, liver, skin and lung 1, leading us to wonder whether deficiency of these proteins might restrain fibrosis. Bleomycin-induced pulmonary fibrosis, a widely employed model of lung injury, is of particular interest because TNC is highly induced while TNX is down-regulated 7. Preliminary studies show that Tnc null mice are protected from bleomycin-induced lung injury and fibrosis, while Tnx null mice have greater early mortality, but less late fibrosis. We hypothesize that TNC interacts with known epithelial and mesenchymal integrins, thereby modulating the expression of inflammatory chemokines by alveolar epithelium and facilitating TGF-beta-dependent myofibroblast activation and fibrosis. In contrast to bleomycin lung injury in mice, TNX is induced in humans with pulmonary fibrosis. We hypothesize that TNX over-expression will increase collagen accumulation occurring after bleomycin-induced lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024075-28
Application #
7252526
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
28
Fiscal Year
2006
Total Cost
$378,239
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Barrette, Anne Marie; Roberts, Jessica K; Chapin, Cheryl et al. (2016) Antiinflammatory Effects of Budesonide in Human Fetal Lung. Am J Respir Cell Mol Biol 55:623-632
Gonzales, Linda W; Gonzalez, Robert; Barrette, Anne Marie et al. (2015) Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease. J Histochem Cytochem 63:908-21
Raymond, Wilfred W; Xu, Xiang; Nimishakavi, Shilpa et al. (2015) Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. PLoS One 10:e0125797
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LaFemina, Michael J; Sutherland, Katherine M; Bentley, Trevor et al. (2014) Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol 51:550-8
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Chapin, Cheryl; Bailey, Nicole A; Gonzales, Linda W et al. (2012) Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung. Am J Physiol Lung Cell Mol Physiol 302:L216-25
Heine, Vivi M; Griveau, Amelie; Chapin, Cheryl et al. (2011) A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury. Sci Transl Med 3:105ra104
Gonzalez, Robert F; Allen, Lennell; Gonzales, Linda et al. (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58:891-901

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