title: Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent.
abstract: Pleural organization follows acute injury and is characterized by pleural fibrosis, which may involve the visceral and parietal pleural surfaces. This process affects patients with complicated parapneumonic pleural effusions, empyema, and other pleural diseases prone to pleural fibrosis and loculation. Pleural mesothelial cells (PMCs) undergo a process called mesothelial mesenchymal transition (MesoMT), by which PMCs acquire a profibrotic phenotype characterized by cellular enlargement and elongation, increased expression of α-smooth muscle actin (α-SMA), and matrix proteins including collagen-1. Although MesoMT contributes to pleural fibrosis and lung restriction in mice with carbon black/bleomycin-induced pleural injury and procoagulants and fibrinolytic proteases strongly induce MesoMT in vitro, the mechanism by which this transition occurs remains unclear. We found that thrombin and plasmin potently induce MesoMT in vitro as does TGF-β. Furthermore, these mediators of MesoMT activate phosphatidylinositol-3-kinase (PI3K)/Akt and NF-κB signaling pathways. Inhibition of PI3K/Akt signaling prevented TGF-β-, thrombin-, and plasmin-mediated induction of the MesoMT phenotype exhibited by primary human PMCs. Similar effects were demonstrated through blockade of the NF-κB signaling cascade using two distinctly different NF-κB inhibitors, SN50 and Bay-11 7085. Conversely, expression of constitutively active Akt-induced mesenchymal transition in human PMCs whereas the process was blocked by PX866 and AKT8. Furthermore, thrombin-mediated MesoMT is dependent on PAR-1 expression, which is linked to PI3K/Akt signaling downstream. These are the first studies to demonstrate that PI3K/Akt and/or NF-κB signaling is critical for induction of MesoMT.
authors.affiliation: Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Shuzi
authors.initials: S
authors.lastname: Owens
authors.affiliation: Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Ann
authors.initials: A
authors.lastname: Jeffers
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Jake
authors.initials: J
authors.lastname: Boren
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsukasaki
authors.affiliation: Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Koenig
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ikebe
authors.affiliation: Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.affiliation: Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and torry.tucker@uthct.edu.
authors.forename: Torry A
authors.initials: TA
authors.lastname: Tucker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005341:Fibrinolysin / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010994:Pleura / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D006490:Hemostatics; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin; D005341:Fibrinolysin
keywords: NF-κB; PI3K; TGF-β; meso-mesenchymal transition; mesothelial cell plasticity; plasmin; pleural mesothelial cells; thrombin