bleomycin-induced ALI and PF. Support: NIH PO-1 HL076406, RO-1 HL071147 and FAMRI. This abstract is funded by: NIH, FAMRI. Am J Respir Crit Care Med ...
C28 AUTOPHAGY VERSUS APOPTOSIS: TWIN SONS OF A DIFFERENT MOTHER? / Poster Discussion Session / Tuesday, May 18/8:15 AM-10:45 AM / Room 267-268 (Second Level), Morial Convention Center
Regulation Of Lung Epithelial Apoptosis By Coordinate Expression Of Components Of The Fibrinolytic System Y. Bhandary1, S. K. Shetty1, R. Shetty1, S. Idell2, B. Starcher3, S. Shetty1 1The University of Texas Health Science Center, Tyler, United States of America, 2Univ of Texas Hlth Ctr at Tyler, Tyler, TX, United States of America, 3University of Texas at Tyler, Tyler, TX, United States of America Rationale: Lung epithelial cell (LEC) apoptosis and alveolar fibrin deposition are two major events associated with acute lung injury (ALI) and the subsequent development of progressive pulmonary fibrosis (PF). Extravascular fibrin deposition and disruption of fibrin turnover during ALI, has been attributed to altered alveolar expression of urokinase-type plasminogen activator (uPA), the uPA receptor (uPAR) and PA inhibitor-1 (PAI-1). LEC apoptosis precedes the development of PF and has been linked to increased p53 expression. Methods: We used flow cytometry, TUNEL staining, 3H-thymiding incorporation, Western blotting and immunohistochemical analyses. Small airway and Beas2B epithelial cells were used for in vitro experiments. The bleomycin-induced mouse model of accelerated fibrosis was used for interventional studies. Results: Our results show that uPA regulates both proliferation and apoptosis of LEC through elaboration of p53. p53 is induced in LECs by bleomycin and suppresses uPA and uPAR while reciprocally augmenting PAI-1 expression. These changes occur in association with LEC apoptosis, suggesting that the processes are linked. Inhibition of bleomycin-induced LEC p53 expression by caveolin-1 scaffolding peptide (CSP) reverses reciprocal suppression of uPA and uPAR, inhibits PAI-1 expression and prevents LEC apoptosis. Local or systemic administration of CSP markedly attenuates bleomycin-induced LEC apoptosis and PF in vivo. The process involves inhibition of PAI-1 and a reciprocal increase in uPA and uPAR via blockade of p53 in LEC in mice with bleomycin-induced lung injury. Administration of chimeric message blocking the p53 interaction with PAI-1, uPA and uPAR mRNA likewise prevented ALI and PF, confirming the contribution of these interactions to the protective effect in vivo. Systemic administration of CSP to mice exposed to bleomycin for 1, 7 and 14 days significantly reversed PF as indicated by histological, lung homogenate hydroxyproline and desmosine measurements, as well as immunoblot analyses. Conclusions: These findings document a pivotal role for cross-talk between the fibrinolytic system and p53 in the pathogenesis of bleomycin-induced ALI and PF. Support: NIH PO-1 HL076406, RO-1 HL071147 and FAMRI
This abstract is funded by: NIH, FAMRI
Am J Respir Crit Care Med 181;2010:A4185 Internet address: www.atsjournals.org
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