title: Regulation of p53-mediated changes in the uPA-fibrinolytic system and in lung injury by loss of surfactant protein C expression in alveolar epithelial cells.
abstract: Pulmonary surfactant protein C (SP-C) expression by type II alveolar epithelial cells (AECs) is markedly reduced in diverse types of lung injuries and is often associated with AEC apoptosis. It is unclear whether loss of SP-C contributes to the increased p53 and urokinase-type plasminogen activator (uPA) system cross-talk and apoptosis of AECs. Therefore, we inhibited SP-C expression in human and murine AECs using lentivirus vector expressing shRNA and tested p53 and downstream changes in the uPA-fibrinolytic system. Inhibition of SP-C expression in AECs induced p53 and activated caspase-3, indicating AEC apoptosis. We also found that bleomycin or cigarette smoke exposure failed to inhibit SP-C expression or apoptosis in AECs in p53- and plasminogen activator inhibitor-1 (PAI-1)-deficient mice. Depletion of SP-C expression by lentiviral SP-C shRNA in PAI-1-deficient mice failed to induce p53 or apoptosis in AECs, whereas it increased both AEC p53 and apoptosis in wild-type and uPA-deficient mice. SP-C inhibition in AECs also increased in CXCL1 and CXCL2 and their receptor CXCR2 as well as ICAM-1 expression, which is indicative of a proinflammatory response. Overexpression of p53-binding 3'-UTR sequences in AECs inhibited PAI-1 induction while maintaining uPA and uPAR protein and mRNA expression. Furthermore, caveolin-1 expression and phosphorylation were increased in AECs, indicating an intricate link between caveolin-1 and Src kinase-mediated cell signaling and AEC apoptosis due to loss of SP-C expression through p53 and uPA system-mediated cross-talk. The role of uPA, PAI-1, and p53 in the regulation of AEC apoptosis after injury was also determined in knockout mice.
authors.affiliation: Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Bijesh
authors.initials: B
authors.lastname: Puthusseri
authors.affiliation: Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Amarnath
authors.initials: A
authors.lastname: Marudamuthu
authors.affiliation: Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.affiliation: Texas Lung Injury Institute, 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, University of Texas Health Science Center at Tyler, Tyler, Texas; and sreerama.shetty@uthct.edu.
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000107:Acetylation; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D004789:Enzyme Activation; D005342:Fibrinolysis; D006801:Humans; D055370:Lung Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051242:Caveolin 1; D017395:Plasminogen Activator Inhibitor 1; D037721:Pulmonary Surfactant-Associated Protein C; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D019061:src-Family Kinases; D014568:Urokinase-Type Plasminogen Activator; D053148:Caspase 3
keywords: alveolar epithelial cell; apoptosis; p53; surfactant protein C; urokinase