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

Bijesh Puthusseri, Amarnath Marudamuthu, Nivedita Tiwari, Jian Fu, Steven Idell, Sreerama Shetty

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish
Pages (from-to)L783-L796
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number6
StatePublished - 2017

Bibliographical note

Funding Information:
This study was supported in part by a Flight Attendant Medical Research Institute Clinical Innovator Award (FAMRI-ID-123010), the American Heart Association (15GRNT25800004), and National Institutes of Health Grants R01-HL1-33067-01 and R21-ES-025815 (S. Shetty).

Publisher Copyright:
© 2017 the American Physiological Society.


  • Alveolar epithelial cell
  • Apoptosis
  • P53
  • Surfactant protein C
  • Urokinase

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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