Albumin protects the liver from tumor necrosis factor α‐induced immunopathology

Abstract

Besides its oncotic power, albumin exerts pleiotropic actions, including binding, transport, and detoxification of endogenous and exogenous molecules, antioxidant activity, and modulation of immune and inflammatory responses. In particular, recent studies have demonstrated that albumin reduces leukocyte cytokine production.Here, we investigated whether albumin also has the ability to protect tissues from the damaging actions of these inflammatory mediators. We circumscribed our investigation to tumor necrosis factor (TNF) α, which exemplifies the connection between immunity and tissue injury. In vivo experiments in analbuminemic mice showed that these mice exhibit a more pronounced response to a model of TNFα-mediated liver injury induced by the administration of lipopolysaccharide (LPS) and D-galactosamine (D-gal). A tissue protective action against LPS/D-gal liver injury was also observed during the administration of human albumin to humanized mice expressing the human genes for albumin and neonatal Fc receptor (hAlb +/+ /hFcRn +/+ ) with preestablished carbon tetrachloride (CCl 4 )-induced early cirrhosis. The cytoprotective actions of albumin against TNFα-induced injury were confirmed ex vivo, in precision-cut liver slices, and in vitro, in primary hepatocytes in culture. Albumin protective actions were independent of its scavenging properties and were reproduced by recombinant human albumin expressed in Oryza sativa. Albumin cytoprotection against TNFα injury was related to inhibition of lysosomal cathepsin B leakage accompanied by reductions in mitochondrial cytochrome c release and caspase-3 activity. These data provide evidence that in addition to reducing cytokines, the albumin molecule also has the ability to protect tissues against inflammatory injury. K E Y W O R D S albumin, cytokine-induced tissue injury, liver cells, liver injury, mitochondrial damage 2 of 15 | DURAN-GÜELL Et AL. | Precision-cut liver slicesControl C57BL/6J mice (n = 15) were anesthetized with ketamine/xylazine. The inferior cava vein was cutoff and blood was allowed to drain for 1 minute. The liver was

Albumin in Advanced Liver Diseases: The Good and Bad of a Drug!

“…(24) It protects the liver from TNFα-induced immunopathologies. (25) HSA contributes to endothelial stabilization and maintenance of capillary permeability by helping with the formation/preservation of glycocalyx and by maintaining the subendothelial space. (26) Some of these functions are carried out effectively by HAS (Tables 1 and 2).…”

Essential role for albumin in preserving liver cells from TNFα‐induced mitochondrial injury

“…When hepatocytes are under transcriptional arrest, TNFα-induced mitochondrial injury translates into programmed cell death (apoptosis). 13,20 To investigate how important is the albumin molecule in this situation, we repeated the mitochondrial flux analysis in the presence of actinomycin D. Figure 4A shows a lollipop chart of the pairwise comparisons of the utilization of energy substrates between hepatocytes incubated with TNFα+ actinomycin D in comparison to vehicle. Unlike hepatocytes treated with TNFα alone (Figure 3A), acylcarnitines were not the top utilized mitochondrial substrates in hepatocytes exposed to TNFα+ actinomycin D (Figure 4A).…”

“…Likewise, in the extravascular compartment and interstitium, albumin exhibits non‐oncotic properties in addition to maintaining the osmotic gradient 11,12 . For instance, in the liver parenchyma, albumin protects hepatocytes from TNFα‐induced cell‐death under conditions of actinomycin D transcriptional arrest 13 . The antiapoptotic actions of albumin on liver cells were demonstrated to be unrelated to the scavenging properties of this molecule, 13 placing albumin as a key element in liver tissue homeostasis.…”

Lysosomal hydrolases, from waste-bags effectors to essential multipurpose enzymes in liver fibrosis

“…In agreement with these results, cathepsin B knock-out mice displayed higher resistance to hepatocyte apoptosis and increased survival, when subjected to a model of tumor necrosis factor-α (TNF-α)-induced acute liver damage, driven by decreased activation of the canonical apoptotic pathway [26][27][28]. More recent evidence attributed the cytoprotective effect of albumin, against TNF-α-induced liver inflammatory injury, to its effect preventing LMP and cathepsin B leakage from the lysosome, thereby reducing apoptosis triggered by the release of cytochrome c from the mitochondria [29].…”