Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system

Abstract

Alveolar type II (ATII) cell apoptosis and depressed fibrinolysis that promotes alveolar fibrin deposition are associated with acute lung injury (ALI) and the development of pulmonary fibrosis (PF). We therefore sought to determine whether p53-mediated inhibition of urokinase-type plasminogen activator (uPA) and induction of plasminogen activator inhibitor-1 (PAI-1) contribute to ATII cell apoptosis that precedes the development of PF. We also sought to determine whether caveolin-1 scaffolding domain peptide (CSP) reverses these changes to protect against ALI and PF. Tissues as well as isolated ATII cells from the lungs of wild-type (WT) mice with BLM injury show increased apoptosis, p53, and PAI-1, and reciprocal suppression of uPA and uPA receptor (uPAR) protein expression. Treatment of WT mice with CSP reverses these effects and protects ATII cells against bleomycin (BLM)-induced apoptosis whereas CSP fails to attenuate ATII cell apoptosis or decrease p53 or PAI-1 in uPA-deficient mice. These mice demonstrate more severe PF. Thus p53 is increased and inhibits expression of uPA and uPAR while increasing PAI-1, changes that promote ATII cell apoptosis in mice with BLM-induced ALI. We show that CSP, an intervention targeting this pathway, protects the lung epithelium from apoptosis and prevents PF in BLM-induced lung injury via uPA-mediated inhibition of p53 and PAI-1.

Plasminogen Activator Inhibitor-1 Suppresses Profibrotic Responses in Fibroblasts from Fibrotic Lungs

“…However, recent reports indicate that PAI-1-deficient NL-fibroblasts resist cigarette smoke-induced replicative senescence (16), although PAI-1 deficiency aggravates kidney (17), pleural (18), and cardiac fibrosis (19). These findings challenge the well established concept that global expression of PAI-1 in all lung cells powerfully exerts an exclusively pro-fibrogenic effect (12,15,20). Based on our recent observations, we inferred that PAI-1-induced changes in ATII cell viability (12,13,15) could differ from those induced in FL-fibroblasts that contribute to the expanding population of mesenchymal cells in lungs undergoing fibrotic repair.…”

“…PAI-1 levels are significantly increased in lung tissues, BAL fluids, and the ATII cells of patients with diverse lung diseases such as acute lung injury, its most severe clinical counterpart acute respiratory distress syndrome, or IPF, as well as in mice with cigarette smoke-and BLM-induced lung injuries (12,13). On the contrary, PAI-1 suppression prevents lung inflammation, ATII cell senescence and apoptosis, and the development of lung fibrosis (12)(13)(14)(15).…”

“…On the contrary, PAI-1 suppression prevents lung inflammation, ATII cell senescence and apoptosis, and the development of lung fibrosis (12)(13)(14)(15). However, recent reports indicate that PAI-1-deficient NL-fibroblasts resist cigarette smoke-induced replicative senescence (16), although PAI-1 deficiency aggravates kidney (17), pleural (18), and cardiac fibrosis (19).…”

Stem Cells and Lung Injury

“…The ALI is primarily initiated by inflammatory cell migration and their deposition in the alveolar epithelial cells, which is then, triggers the impairment of fibrinolytic system during the progression [3]. Studies shows that the role of pro-inflammatory and anti-inflammatory cytokines are very important for repair mechanism, but the abnormal function of this biomarkers may results in the apoptosis of alveolar epithelial cells and progressive deposition of extracellular matrix (ECM) in the lung tissues [4].…”

Immunophenotyping and Protein Profiling of Fontan-associated Plastic Bronchitis Airway Casts

“…On the basis of this initial survey, the cytokine profile of PB is proinflammatory, which substantiates the involvement of inflammatory processes in the airway cast formation. The cytokine profile of PB relative to that of BAL from another fibrininflammatory lung illness, ALI (27,28), and healthy control subjects can be found in the online supplement.…”