Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation

Yunge Zhao, Ashish K. Sharma, Damien J. Lapar, Irving L. Kron, Gorav Ailawadi, Yuan Liu, David R. Jones, Victor E. Laubach, Christine L. Lau

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Ischemia-reperfusion (IR) injury following lung transplantation remains a major source of early morbidity and mortality. Histologically, this inflammatory process is characterized by neutrophil infiltration and activation. We previously reported that lung IR injury was significantly attenuated in plasminogen activator inhibitor-1-deficient mice. In this study, we explored the potential role of tissue plasminogen activator (tPA) in a mouse lung IR injury model. As a result, tPA knockout (KO) mice were significantly protected from lung IR injury through several mechanisms.At the cellular level, tPA KO specifically blocked neutrophil extravasation into the interstitium, and abundant homotypic neutrophil aggregation (HNA) was detected in the lung microvasculature of tPA KO mice after IR. At the molecular level, inhibition of neutrophil extravasation was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/ LDL receptor-related protein/NF- κB signaling pathway, whereas increased P-selectin triggered HNA. At the functional level, tPA KO mice incurred significantly decreased vascular permeability and improved lung function following IR. Protection from lung IR injury in tPA KO mice occurs through a fibrinolysis-independent mechanism. These results suggest that tPA could serve as an important therapeutic target for the prevention and treatment of acute IR injury after lung transplantation.

Original languageEnglish (US)
Pages (from-to)L718-L729
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume300
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Tissue Plasminogen Activator
Reperfusion Injury
Neutrophils
Lung
Knockout Mice
Lung Transplantation
Reperfusion
Ischemia
Low Density Lipoprotein Receptor-Related Protein-1
CD31 Antigens
Neutrophil Activation
P-Selectin
Neutrophil Infiltration
Plasminogen Activator Inhibitor 1
Capillary Permeability
Fibrinolysis
Microvessels
Morbidity
Mortality

Keywords

  • NF-κB
  • P-selectin
  • PECAM-1
  • tPA knockout

ASJC Scopus subject areas

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

Cite this

Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. / Zhao, Yunge; Sharma, Ashish K.; Lapar, Damien J.; Kron, Irving L.; Ailawadi, Gorav; Liu, Yuan; Jones, David R.; Laubach, Victor E.; Lau, Christine L.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 300, No. 5, 01.05.2011, p. L718-L729.

Research output: Contribution to journalArticle

Zhao, Yunge ; Sharma, Ashish K. ; Lapar, Damien J. ; Kron, Irving L. ; Ailawadi, Gorav ; Liu, Yuan ; Jones, David R. ; Laubach, Victor E. ; Lau, Christine L. / Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011 ; Vol. 300, No. 5. pp. L718-L729.
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