Sukriti Sukriti

The endothelial monolayer partitioning underlying tissue from blood components in the vessel wall maintains tissue fluid balance and host defense through dynamically opening intercellular junctions. Edemagenic agonists disrupt endothelial barrier function by signaling the opening of the intercellular junctions leading to the formation of protein-rich edema in the interstitial tissue, a hallmark of tissue inflammation that, if left untreated, causes fatal diseases, such as acute respiratory distress syndrome. In this review, we discuss how intercellular junctions are maintained under normal conditions and after stimulation of endothelium with edemagenic agonists. We have focused on reviewing the new concepts dealing with the alteration of adherens junctions after inflammatory stimulus.

Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca(2+) entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca(2+) signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca(2+) entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca(2+) entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca(2+) entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R-associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca(2+) entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.

Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, we show that circulating MAIT cells are reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis while they accumulate in liver fibrotic septa. Using two models of chronic liver injury, we demonstrate that MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice are resistant. Co-culture experiments indicate that MAIT cells enhance the proinflammatory properties of monocyte-derived macrophages, and promote mitogenic and proinflammatory functions of fibrogenic cells, via distinct mechanisms. Our results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells may constitute an attractive antifibrogenic strategy during chronic liver injury.

BACKGROUND AND AIM: The risk of acquiring hepatitis B virus (HBV) infection through exposure to blood or its products is highest amongst health care workers (HCWs). Despite potential risks, a proportion of HCWs never get vaccinated. India is second to China in the numbers of people with chronic HBV. This study aimed to investigate the vaccination practices and the prevalence of HBV infection in HCWs in India. METHODS: A total of 2162 HCWs were screened for the presence of serological markers of HBV and hepatitis C virus (HCV). Occult HBV infection was tested by detection of HBV-DNA for surface and core regions by nested polymerase chain reaction in HBsAg-negative and IgG anti-hepatitis core antigen-positive subjects. RESULTS: Only 1198 (55.4%) of the 2162 HCWs screened had been vaccinated; and 964 (44.6%) were not vaccination-status conscious; of these HCWs, 600 (27.7%) had never been vaccinated and 364 (16.4%) were unaware of their vaccination status. Protective (> 10 IU/mL) anti-hepatitis B surface (anti-HBs) antigen titers were seen in only 61.7%. The anti-HBs titers were found to be lower with the passage of time; the median anti-HBs titers in subjects who were vaccinated > 10 years ago were significantly lower than those who had been vaccinated < 5 years ago (P < 0.001). One percent of HCWs were HBsAg-positive, and 24.7% of 700 HCWs screened had past exposure (IgG-anti-HBc-positive). Occult HBV was detected in 5% of 120 positive subjects with past exposure; all had anti-HBs titers > 10 IU/mL. CONCLUSIONS: Even today, 28% HCWs in India are unvaccinated and 17% are unaware of their vaccination status. This data suggests that use of hepatitis B immune globulin be mandatory in needle-pricked HCWs in India, and that implementation of awareness strategies is urgent. Since the anti-HBs titers decline in a fair proportion, there is justification for giving a booster dose of vaccine 10 years after primary vaccination to HCWs in India.

Albumin is a potent scavenger of reactive oxygen species (ROS). However, modifications in albumin structure may reduce its antioxidant properties and modulate its immune-regulatory functions. We examined alterations in circulating albumin in severe alcoholic hepatitis (SAH) patients and their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways. Albumin modifications and plasma oxidative stress were assessed in SAH patients (n = 90), alcoholic cirrhosis patients (n = 60), and healthy controls (n = 30) using liquid chromatography/mass spectrometry and spectrophotometry. Activation and intracellular ROS were measured in healthy neutrophils after treatment with purified albumin from the study groups. Gene expression of SAH neutrophils was analyzed and compared to gene expression from healthy neutrophils after stimulation with purified albumin from SAH patient plasma. SAH-albumin showed the highest albumin oxidative state (P < 0.05) and prominent alteration as human nonmercaptalbumin 2 (P < 0.05). Plasma oxidative stress (advanced oxidative protein product) was higher in SAH versus alcoholic cirrhosis patients and healthy controls (P < 0.05). Neutrophil gelatinase-associated lipocalin, myeloperoxidase, and intracellular ROS levels were highest in SAH-albumin-treated neutrophils (P < 0.05). Genes associated with neutrophil activation, ROS production, intracellular antioxidation, and leukocyte migration plus genes for proinflammatory cytokines and various toll-like receptors were overexpressed in SAH neutrophils compared to healthy neutrophils (P < 0.05). Expression of the above-mentioned genes in SAH-albumin-stimulated healthy neutrophils was comparable with SAH patient neutrophils, except for genes associated with apoptosis, endoplasmic reticulum stress, and autophagy (P < 0.05). CONCLUSIONS: In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro-oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017;65:631-646).