| First Author | Duarte S | Year | 2018 |
| Journal | Am J Pathol | Volume | 188 |
| Issue | 8 | Pages | 1820-1832 |
| PubMed ID | 29870740 | Mgi Jnum | J:264742 |
| Mgi Id | MGI:6193241 | Doi | 10.1016/j.ajpath.2018.05.002 |
| Citation | Duarte S, et al. (2018) Adeno-Associated Virus-Mediated Gene Transfer of Tissue Inhibitor of Metalloproteinases-1 Impairs Neutrophil Extracellular Trap Formation and Ameliorates Hepatic Ischemia and Reperfusion Injury. Am J Pathol 188(8):1820-1832 |
| abstractText | Matrix metalloproteinase-9 (MMP-9) is abundantly expressed by infiltrating leukocytes and contributes to the pathogenesis of hepatic ischemia and reperfusion injury (IRI). On the other hand, its physiological inhibitor, the tissue inhibitor of metalloproteinases-1 (TIMP-1), is available in insufficient levels to hamper MMP-9 activity during hepatic IRI. In this study, we generated recombinant adeno-associated virus type 8 vectors (rAAV8) encoding mouse TIMP-1 driven by a liver-specific thyroxine-binding globulin promoter as a strategy to increase the levels of TIMP-1 during liver IRI. Biodistribution analysis confirmed selective overexpression of TIMP-1 in livers of rAAV8-TIMP-1 vector treated C57BL/6 mice. rAAV8-TIMP-1-treated mice showed reduced MMP-9 activity, diminished leukocyte trafficking and activation, lowered transaminase levels, and improved histology after liver IRI. Moreover, the rAAV8-TIMP-1 vector therapy enhanced significantly the 7-day survival rate of TIMP-1(-/-) mice subjected to hepatic IRI. Neutrophils are the first cells recruited to inflamed tissues and, once activated, they release nuclear DNA-forming web-like structures, known as neutrophil extracellular traps. It was found that TIMP-1 has the ability to reduce formation of neutrophil extracellular traps and, consequently, limit the impact of neutrophil extracellular trap-mediated cytotoxicity in hepatic IRI. This is the first report demonstrating that TIMP-1 overexpression is hepatoprotective in ischemia and reperfusion injury. Hence, TIMP-1 may represent a promising molecule for drug development to treat liver IRI. |
