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

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.

Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties

“…These results confirm recent observations documenting that tPA promotes neutrophil recruitment in I/R injury of kidney or lung. 17,19 Moreover, our data revealed that tPA selectively mediates transendothelial migration of neutrophils in the initial reperfusion phase, whereas at later time points, tPA is already involved in leukocyte intravascular accumulation. These findings point to a highly coordinated involvement of tPA in the leukocyte extravasation process.…”

“…17,19 Consequently, extravasated tPA might mediate neutrophil recruitment via indirect effects. Because of their close vicinity to microvessels and their ability to produce a variety of inflammatory factors (eg, PAF, leukotrienes, or prostaglandins), 25,26 tissue mast cells might serve as target cells of extravasated tPA.…”

“…15 Recently, it has been reported that also tPA is critically involved in the pathogenesis of I/R injury. [16][17][18][19] The underlying mechanisms remained largely unclear.…”

Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice

“…36 Our present results are consistent with the findings that neutrophil extravasation into the interstitium after lung ischemia-reperfusion injury after lung transplantation was blocked in tPA-deficient mice. 37 At the molecular level, this blockage was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/low-density lipoprotein receptor-related protein/NF-B signaling pathway.…”

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

“…In addition, rt-PA has been shown to increase tissue injury and enhance neutrophil tissue infiltration following ischaemiareperfusion injury to the brain 60 , lung 61 and kidneys 62 . The known proinflammatory function of recombinant t-PA has been partly attributed to its direct activating effects on the endothelium and inflammatory cells, as well as through the generation of fibrin degradation products 63 and plasmin 64 .…”