Alveolar type II epithelial cell (ATII) apoptosis and proliferation of mesenchymal cells are the hallmarks of idiopathic pulmonary fibrosis a damaging disease of unfamiliar cause Nomilin characterized by alveolar epithelial injury and progressive fibrosis. inactive dominating bad p53 in ATII cells showed augmented apoptosis whereas those deficient in p53 resisted BLM-induced ATII cell apoptosis. Inhibition of p53 transcription failed to suppress PAI-1 or induce uPA mRNA in BLM-treated ATII cells. ATII cells from mice with BLM injury showed augmented binding of p53 to uPA uPA receptor (uPAR) and PAI-1 mRNA. p53-binding sequences from uPA uPAR and PAI-1 mRNA 3′ untranslated areas neither interfered with p53 DNA binding activity nor p53-mediated promoter transactivation. However increased manifestation of p53-binding sequences from uPA uPAR and PAI-1 mRNA 3′ untranslated areas in ATII cells suppressed PAI-1 and induced uPA after BLM treatment leading to inhibition of ATII cell apoptosis and pulmonary fibrosis. Our findings show that disruption of p53-fibrinolytic system cross talk may serve as a novel intervention strategy to prevent lung injury and pulmonary fibrosis. Idiopathic pulmonary fibrosis is definitely a progressive and fatal lung disease that is refractory to current therapy. A better understanding of the underlying mechanisms is necessary for development of novel treatments. Dysregulated fibrinolysis and induction of p53 are often associated with lung injury and precede development of pulmonary fibrosis.1 These changes occur inside Nomilin a mouse model of bleomycin (BLM)-induced lung injury and accelerated pulmonary fibrosis.1 p53 Manifestation raises substantially in type II alveolar epithelial (ATII) cells after BLM- or cigarette Nomilin smoke-induced lung injury 1 in association with induction of plasminogen activator inhibitor-1 (PAI-1) and suppression of urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) manifestation. We have previously reported that p53 binds to 35- 37 ?and 70-nucleotide sequences within the 3′ Nomilin untranslated region (UTR) of uPA uPAR and PAI-1 mRNAs.4-6 Insertion of p53-binding sequences into the 3′ UTR of β-globin mRNA destabilizes this otherwise stable transcript 4 which indicates that these sequences affect mRNA stability. Subsequent studies by additional Nomilin groups have shown that p53 induction of PAI-1 manifestation requires p53 serine phosphorylation 7 which facilitates connection of the C-terminal website with the PAI-1 3′ UTR. We found that the 3′ UTR binding sequences can individually compete with endogenous uPA uPAR or PAI-1 mRNA for binding to p53 protein leading to induction of uPA and uPAR4 5 and attenuation of PAI-1 levels.6 We also found that mice deficient in p53 or PAI-1 resist lung injury induced by BLM or cigarette smoke whereas mice deficient in uPA remain highly susceptible to BLM-induced lung injury and pulmonary fibrosis.1 Therefore we hypothesized that simultaneous inhibition of p53 binding to uPA uPAR and PAI-1 mRNAs would reduce PAI-1 induction and restore uPA expression in ATII cells despite elevated p53 levels. These changes in PAI-1 and uPA levels are expected to reduce apoptosis of ATII cells and development of pulmonary fibrosis after BLM-induced lung injury. In the present study we tested our hypothesis using lentiviral constructs expressing p53-binding sequences from 3′ UTRs of uPA uPAR and PAI-1 mRNAs under the control of lung HIF3A surfactant protein (SP)-B promoter. SP-B is definitely expressed only in ATII and bronchiolar (Clara) epithelial cells in the lungs8 9 and Nomilin promoter directs transgene manifestation in ATII and Clara epithelial cells in mice.10 Recombinant lentivirus was given in mice before or after initiation of BLM-induced lung injury and effects on uPA and PAI-1 levels ATII cell apoptosis and indices of lung fibrosis were identified. Results shown that overexpression of p53-binding sequence reduced PAI-1 but augmented uPA manifestation. More important BLM-induced ATII cell apoptosis and development of pulmonary fibrosis were reduced without inhibition of p53 manifestation in the lungs. Overall our findings demonstrated for the first time that the improved relationships of p53 with the 3′ UTR of uPA uPAR and PAI-1 mRNAs contribute to lung injury and remodeling and that disrupting of these relationships reverses lung injury and.