Enhanced fibrinolysis protects against lung ischemia–reperfusion injury

Objective

Ischemia–reperfusion injury continues to plague the field of lung transplantation, resulting in suboptimal outcomes. In acute lung injury, processes such as ventilator-induced injury, sepsis, or acute respiratory distress syndrome, extravascular fibrin has been shown to promote lung dysfunction and the acute inflammatory response. This study investigates the role of the fibrinolytic cascade in lung ischemia–reperfusion injury and investigates the interplay between the fibrinolytic system and the inflammatory response.

Methods

Mice lacking the plasminogen activator inhibitor-1 gene (PAI-1 knock out, PAI-1 KO; and thus increased lysis of endogenous fibrin) and wild-type mice underwent in situ left lung ischemia and reperfusion. Fibrin content in the lung was evaluated by immunoblotting. Reperfusion injury was assessed by histologic and physiologic parameters. Proinflammatory mediators were measured in bronchoalveolar lavage fluid and plasma using enzyme-linked immunosorbent assays.

Results

Ischemia–reperfusion causes fibrin deposition in murine lungs. Less fibrin was seen in PAI-1 KO mice than in wild-type mice subjected to the same ischemia–reperfusion conditions. By histologic criteria, more evidence of ischemia–reperfusion injury was noted (thickening of the interstium, cellular infiltration in the alveoli) in the wild-type than in PAI-1 KO mice. Physiologic parameters also revealed more ischemia–reperfusion injury in the wild-type than in PAI-1 KO mice. Cytokine and chemokines were elevated more in the wild-type group than the PAI-1 KO group.

Conclusions

Lung ischemia–reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition may reduce ischemia–reperfusion injury and inflammation. This finding may lead to novel treatment strategies for ischemia–reperfusion.

CTSNet classification: 9, 12

Abbreviations and Acronyms: BAL, bronchoalveolar lavage, ELISA, enzyme-linked immunosorbent assay, IR, ischemia–reperfusion, IRI, ischemia–reperfusion injury, KC, keratinocyte chemoattractant, KO, knock out, IL-10, interleukin 10, MCP-1, monocyte chemoattractant protein-1, MIP-2, macrophage inflammatory protein-2, PAI-1, plasminogen activator inhibitor-1, PCR, polymerase chain reaction, PE, polyethylene, RT-qPCR, real-time quantitative polymerase chain reaction, TNF-α, tumor necrosis factor-alpha, WT, wild type