Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

BACKGROUND AND OBJECTIVE@#Acute liver failure (ALF) is a type of disease with high mortality and rapid progression with no specific treatment methods currently available. Glucocorticoids exert beneficial clinical effects on therapy for ALF. However, the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to determine. The purpose of this study was to investigate the specific immunological mechanism of dexamethasone (Dex) on treatment of ALF induced by lipopolysaccharide (LPS)/D-galactosamine (D-GaIN) in mice.@*METHODS@#Male C57BL/6 mice were given LPS and D-GaIN by intraperitoneal injection to establish an animal model of ALF. Dex was administrated to these mice and its therapeutic effect was observed. Hematoxylin and eosin (H&E) staining was used to determine liver pathology. Multicolor flow cytometry, cytometric bead array (CBA) method, and next-generation sequencing were performed to detect changes of messenger RNA (mRNA) in immune cells, cytokines, and Kupffer cells, respectively.@*RESULTS@#A mouse model of ALF can be constructed successfully using LPS/D-GaIN, which causes a cytokine storm in early disease progression. Innate immune cells change markedly with progression of liver failure. Earlier use of Dex, at 0 h rather than 1 h, could significantly improve the progression of ALF induced by LPS/D-GaIN in mice. Numbers of innate immune cells, especially Kupffer cells and neutrophils, increased significantly in the Dex-treated group. In vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor (Gr). Sequencing of Kupffer cells revealed that Dex could increase mRNA transcription level of nuclear receptor subfamily 4 group A member 1 (Nr4a1), and that this effect disappeared after Gr inhibition.@*CONCLUSIONS@#In LPS/D-GaIN-induced ALF mice, early administration of Dex improved ALF by increasing the numbers of innate immune cells, especially Kupffer cells and neutrophils. Gr-dependent Nr4a1 upregulation in Kupffer cells may be an important ALF effect regulated by Dex in this process.

Regeneración hepática en enfermedad de hígado graso no-alcohólica / Liver regeneration in nonalcoholic fatty liver disease

La esteatosis hepática es el acúmulo de grasa en los hepatocitos, que puede ser la consecuencia del proceso de regeneración hepática o de procesos patológicos como la enfermedad del hígado graso alcohólica y no-alcohólica. A pesar de su importancia, en ambos casos el mecanismo exacto en que la esteatosis influye en la regeneración hepática es escasamente comprendido. Estudios previos han demostrado que los pacientes que presentan hígado graso expresan una regeneración hepática dispar, posiblemente debido a la acumulación de especies reactivas de oxígeno generada por procesos inflamatorios ocasionados por activación de las células de Kupffer. En este artículo se revisan distintos factores que afectan la regeneración hepática, tratando de comprender el mecanismo involucrado en la regeneración dispar en hígados con esteatosis ocasionada por una enfermedad de hígado graso no-alcohólica.

Steatosis is the accumulation of fat in hepatocytes, which may be the result of liver regeneration or pathological processes such as alcoholic and nonalcoholic fatty liver disease. Despite its importance, in both cases the exact mechanism that prevails in fatty liver regeneration is poorly understood. Previous studies have shown that patients with fatty liver express dispar regeneration, possibly due to the accumulation of reactive oxygen species generated by inflammatory processes caused by activation of Kupffer cells. In this article we review several factors that affect liver regeneration, trying to understand the underlying mechanism of dispar regeneration in fatty liver as a consequence of nonalcoholic fatty liver disease.

The Role of Activated Hepatic Stellate Cells in Liver Fibrosis, Portal Hypertension and Cancer Angiogenesis / 대한간학회지

Although hepatic stellate cells, which are liver specific pericytes, have been recognized within the vasculature of the sinusoid for more than one hundred years, the biology and function of these cells is unclear. Recent studies have highlighted the key role of stellate cells in a number of fundamental processes that include wound healing/fibrosis, vasoregulation, and vascular remodeling/angiogenesis. In the liver, these processes are particularly important in the development of cirrhosis, portal hypertension and cancer. This article highlights the recent advances in our understanding of the biology of hepatic stellate cells and discusses some of the recently-ascribed functions that are relevant to liver fibrosis, portal hypertension and cancer angiogenesis.

Modulation of Kupffer cell activity by Tinospora cordifolia in liver damage.

Kupffer cells are major determinants of outcome of liver injury. Their activity was therefore studied in a model of chronic liver disease. The effect of Tinospora cordifolia, an indigenous agent with proven hepatoprotective activity, was evaluated on Kupffer cell function, using carbon clearance test as a parameter. Rats were divided into two major groups. In Gp I which served as normal control t1/2 of carbon was 9.48 +/- 4.14 min. GpII received horse-serum in a dose of 0.5 ml/100 gm b.w. i.p. for a period of 12 weeks and was divided into three sub-groups. In Gp IIA at the end of 12 weeks half-life of carbon was found to be significantly increased to 19.86 +/- 7.95 min (p < 0.01). Indicating suppressed Kupffer cell function in chronic liver damage. In Gp IIB treated with vehicle for 4 more weeks there was significant prolongation of half-life to 38.32 +/- 10.61 min (p < 0.01), indicating perpetuation of damage in absence of damaging agent. Whereas in Gp IIc, treated with Tinospora cordifolia t 1/2 was decreased to 14.24 7.74 min (p < .01), as compared to vehicle control indicating a significant improvement in Kupffer cell function and a trend towards normalization.

Effect of ricin on acute phase response in rats.

Ricin, a highly toxic protein from castor beans was administered (ip) to rats in a dose of 1.25 micrograms/100 g to selectively deplete at least 60-70% of Kupffer cells. This dose spared hepatocytes. This rat model was used to study acute phase protein synthesis and the role of Kupffer cells in acute phase response (APR). Ricin itself induced an APR, similar in pattern but of lower magnitude, than that induced by turpentine. However, the effect of combination of ricin and turpentine on APR was not additive. Kupffer cells appear to play permissive role in APR through mediators like hepatocytes stimulating factors.