Aging is associated with gradual changes in liver structure and physiological/pathological functions in hepatic cells including hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). LSECs are specialized hepatic endothelial cells that regulate liver homeostasis. These cells actively impact the hepatic microenvironment as they have fenestrations and a thin morphology to allow substance exchange between circulating blood and the liver tissue. As aging occurs, LSECs have a reduction in both the number and size of fenestrations, which is referred to as pseudocapillarization. This along with the aging of the liver leads to increased oxidative stress, decreased availability of nitric oxide, decreased hepatic blood flow, and increased inflammatory cytokines in LSECs. Vascular aging can also lead to hepatic hypoxia, HSC activation, and liver fibrosis. In this review, we described the basic structure of LSECs, and the effect of LSECs on hepatic inflammation and fibrosis during aging process. We briefly summarized the changes of hepatic microcirculation during liver inflammation, the effect of aging on the clearance function of LSECs, the interactions between LSECs and immunity, hepatocytes or other hepatic nonparenchymal cells, and the therapeutic intervention of liver diseases by targeting LSECs and vascular system. Since LSECs play an important role in the development of liver fibrosis and the changes of LSEC phenotype occur in the early stage of liver fibrosis, the study of LSECs in the fibrotic liver is valuable for the detection of early liver fibrosis and the early intervention of fibrotic response.

Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal How to cite this article:

Background Reversion of activated hepatic stellate cells (HSCs) to quiescence is likely to be a promising pathway in liver fibrosis regression. The development of senescence in HSCs during alcoholic liver injury may lead to liver compensation against fibrosis. The current study aims to characterize the functional role of miR‐34a regulated cellular senescence during alcohol‐associated hepatitis. Methods Senescence related gene and miR‐34a expression was assessed using a PCR Array and/or real‐time PCR analysis. Cellular senescence in cultured HSCs were measured by SA‐β‐gal staining. Senescence mediators were defined in LPS treated hepatic stellate cells in vitro, and in TLR‐4 knockout mice or morpholino antisense oligomer against miR‐34a (miR‐34a Morpho/AS) treated mice with chronic ethanol feeding in vivo. Results We identified that 5 weeks of ethanol feeding significantly increased the total liver histopathology score and miR‐34a expression, along with the activation of hepatic stellate cells marked by enhanced α‐SMA staining. Treatment of HSCs with LPS (20 ng/ml) for 24 hr significantly increased miR‐34a expression, along with the enhanced SA‐β‐gal activity, up‐regulated α‐SMA/Collagen A1 expression and increased cellular viability. Silencing of miR‐34a decreased LPS‐induced activation in HSCs by downregulation of fibrosis markers α‐SMA, Col1a1 and TIMP‐1, and increased SA‐β‐gal activity as well as the cellular senescence marker CCl2, whereas silencing of the LPS receptor, TLR4, decreased this marker in the same group of HSCs, suggesting anti‐miR‐34a reversed LPS‐mediated HSC activation through inducing cellular senescence. Furthermore, the expression of miR‐34a and verified miR‐34a related senescence marker CCl2 were significantly altered in hepatic stellate cells from ethanol‐fed mouse liver specimens compared to controls. TLR4 knockout mice and miR‐34a Morpho/AS treated mice displayed less sensitivity to alcoholic injury, along with enhanced SA‐β‐gal activity and CCl2 level in HSCs, and recovered expressions of α‐SMA, Col1a1 and TIMP‐1. Summary and Conclusion Our results show that miR‐34a mediated cellular senescence is essential for the potential reversion from activated to quiescent hepatic stellate cells during alcohol‐associated hepatitis. These findings provide new insight into the function of microRNA regulated cellular senescence in human HSCs and increase opportunities for the development of novel treatment paradigms for the management of alcohol‐associated liver diseases.