TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury

Abstract

Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is the major endogenous regulator of matrix metalloproteinase-9 (MMP-9). In this study, we investigated the functional significance of TIMP-1 expression in a well-established mouse model of partial liver IRI. Compared to wild-type mice, TIMP-1−/− mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP-1 deficiency led to lethal liver IRI, as over 60% of the TIMP-1−/− mice died post-reperfusion, whereas all TIMP-1+/+ mice recovered and survived surgery. Lack of TIMP-1 expression was accompanied by markedly high levels of MMP-9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP-1−/− livers were characterized by massive leukocyte infiltration and by upregulation of proinflammatory mediators, including TNF-α, IFN-γ, and iNOS, post-IRI. The inability of TIMP-1−/− mice to express TIMP-1 increased the levels of active caspase-3 and depressed the expression of Bcl-2 and the phosphorylation of Akt, emphasizing an important role for TIMP-1 expression on hepatocyte survival. Using independent parameters of regeneration, 5-bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP-1 deficient livers after IRI. Inhibition of the cell cycle progression by TIMP-1 deficiency was linked to depressed levels of cyclins-D1 and -E and to disrupted c-Met signaling pathway, as evidenced by reduced phosphorylated c-Met expression and elevated c-Met ectodomain shedding post-liver IRI. In conclusion, these results support a critical protective function for TIMP-1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver IRI.

TIMP1 in conditioned media of human adipose stromal cells protects neurons against oxygen-glucose deprivation injury

“…TIMP1 inhibits apoptosis in a variety of cell types, including stellate cells, B cells, epithelial cells and mesangial cells through MMP-dependent and MMP-independent mechanisms [5,6]. Introuclear MMPs were reported to promote neuronal apoptosis induced by OGD [13].…”

MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

“…MMP-mediated shedding of c-met tyrosine kinase (cMet), the hepatocyte growth factor receptor, may have also contributed to the impaired liver regeneration of steatotic livers in settings of high MMP-9 activity. [15] Further experimentation is needed to better understand the intricate MMP-dependent mechanisms that underlie hepatic regeneration following an IR-insult.…”

“…[14, 15] Liver specimens embedded in paraffin were processed for hematoxylin and eosin (H&E) staining. Liver steatosis was assessed by Oil Red O staining.…”

Cell-specific translational profiling in acute kidney injury

“…IRI-associated activation was localized to the nephron, as predicted (Figure 7), and costaining with fluorophore-conjugated LTL antibody confirmed induction in proximal tubular epithelial cells ( Figure 8A). Tissue inhibitor of metalloproteinase-1 (Timp1) is a major endogenous regulator of matrix metalloproteinase-9 (MMP-9) that plays important roles in liver IRI, fibrosis, and regeneration (30). RNA in situ hybridization revealed that its expression correlates predominantly within the interstitial cell population after IRI treatment (Figure 7).…”