title: Role of p53-fibrinolytic system cross-talk in the regulation of quartz-induced lung injury.
abstract: Silica is the major component of airborne dust generated by wind, manufacturing and/or demolition. Chronic occupational inhalation of silica dust containing crystalline quartz is by far the predominant form of silicosis in humans. Silicosis is a progressive lung disease that typically arises after a very long latency and is a major occupational concern with no known effective treatment. The mechanism of silicosis is not clearly understood. However, silicosis is associated with increased cell death, expression of redox enzymes and pro-fibrotic cytokines and chemokines. Since alveolar epithelial cell (AEC) death and disruption of alveolar fibrinolysis is often associated with both acute and chronic lung injuries, we explored whether p53-mediated changes in the urokinase-type plasminogen activator (uPA) system contributes to silica-induced lung injury. We further sought to determine whether caveolin-1 scaffolding domain peptide (CSP), which inhibits p53 expression, mitigates lung injury associated with exposure to silica. Lung tissues and AECs isolated from wild-type (WT) mice exposed to silica exhibit increased apoptosis, p53 and PAI-1, and suppression of uPA expression. Treatment of WT mice with CSP inhibits PAI-1, restores uPA expression and prevents AEC apoptosis by suppressing p53, which is otherwise induced in mice exposed to silica. The process involves CSP-mediated inhibition of serine-15 phosphorylation of p53 by inhibition of protein phosphatase 2A-C (PP2A-C) interaction with silica-induced caveolin-1 in AECs. These observations suggest that changes in the p53-uPA fibrinolytic system cross-talk contribute to lung injury caused by inhalation of silica dust containing crystalline quartz and is protected by CSP by targeting this pathway.
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.
authors.forename: Yashodhar P
authors.initials: YP
authors.lastname: Bhandary
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.
authors.forename: Shwetha K
authors.initials: SK
authors.lastname: Shetty
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.
authors.forename: Amarnath S
authors.initials: AS
authors.lastname: Marudamuthu
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA; Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.affiliation: Occupational Medicine, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA; Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Pinson
authors.affiliation: Occupational Medicine, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Levin
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA. Electronic address: sreerama.shetty@uthct.edu.
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D000818:Animals; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology*; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011791:Quartz / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D011791:Quartz; D014568:Urokinase-Type Plasminogen Activator
keywords: Acute lung injury; Alveolar type II cell apoptosis; Fibrinolytic system; Silicosis