Downregulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia

Biliary atresia (BA) is an immune related disorder and STAT3 is a key signalling molecule in inflammation. This study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants CXCL1 and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10x single cells RNAseq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared to control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 upregulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human biliary epithelial cells together with upregulated IL-8 expression. RNAseq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon related anti-viral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon responsive neutrophils resulting in biliary epithelial cell damage in BA.

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Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

Journal of Virology ◽

10.1128/jvi.02094-06 ◽

2006 ◽

Vol 81 (4) ◽

pp. 1671-1679 ◽

Cited By ~ 49

Author(s):

Steven R. Allen ◽

Mubeen Jafri ◽

Bryan Donnelly ◽

Monica McNeal ◽

David Witte ◽

...

Keyword(s):

Bile Duct ◽

Epithelial Cell ◽

Biliary Atresia ◽

Murine Model ◽

Clinical Signs ◽

Bile Duct Obstruction ◽

Biliary Epithelial Cell ◽

Newborn Mice ◽

Live Virus ◽

Duct Obstruction

ABSTRACT Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.

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Intrahepatic biliary epithelial cell damage and inflammation in portal tract in association with chronic colitis-harboring TCRα−/− mice

Hepatology Research ◽

10.1016/j.hepres.2005.10.007 ◽

2006 ◽

Vol 34 (1) ◽

pp. 3-8 ◽

Cited By ~ 5

Author(s):

I HARUTA ◽

E HASHIMOTO ◽

Y KATO ◽

H MIYAKAWA ◽

N SHIBATA ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Damage ◽

Portal Tract ◽

Biliary Epithelial Cell ◽

Chronic Colitis

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Histological evaluation of cochlear hair cell damage from noise-induced hearing loss in chinchillas

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159217 ◽

1990 ◽

Vol 48 (3) ◽

pp. 332-333

Author(s):

R.V. Harrison ◽

R.J. Mount ◽

P. White ◽

N. Fukushima

Keyword(s):

Hair Cell ◽

Evoked Potential ◽

Cell Damage ◽

Acoustic Trauma ◽

Histological Evaluation ◽

Cell Integrity ◽

Functional Changes ◽

Cochlear Hair Cell ◽

Left And Right ◽

Contralateral Ear

In studies which attempt to define the influence of various factors on recovery of hair cell integrity after acoustic trauma, an experimental and a control ear which initially have equal degrees of damage are required. With in a group of animals receiving an identical level of acoustic trauma there is more symmetry between the ears of each individual, in respect to function, than between animals. Figure 1 illustrates this, left and right cochlear evoked potential (CAP) audiograms are shown for two chinchillas receiving identical trauma. For this reason the contralateral ear is used as control.To compliment such functional evaluations we have devised a scoring system, based on the condition of hair cell stereocilia as revealed by scanning electron microscopy, which permits total stereociliar damage to be expressed numerically. This quantification permits correlation of the degree of structural pathology with functional changes. In this paper wereport experiments to verify the symmetry of stereociliar integrity between two ears, both for normal (non-exposed) animals and chinchillas in which each ear has received identical noise trauma.

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Undigestible Gliadin Peptide Nanoparticles Penetrate Mucus and Reduce Mucus Production Driven by Intestinal Epithelial Cell Damage

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.1c02177 ◽

2021 ◽

Author(s):

Guangxin Feng ◽

Kaining Han ◽

Yanlei Li ◽

Qian Yang ◽

Weiting Feng ◽

...

Keyword(s):

Epithelial Cell ◽

Intestinal Epithelial Cell ◽

Cell Damage ◽

Intestinal Epithelial ◽

Mucus Production ◽

Gliadin Peptide ◽

Peptide Nanoparticles

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Nepetoidin B from Salvia plebeia R. Br. Inhibits Inflammation by Modulating the NF-κB and Nrf2/HO-1 Signaling Pathways in Macrophage Cells

Antioxidants ◽

10.3390/antiox10081208 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1208

Author(s):

Mina Kim ◽

Ji Yeong Kim ◽

Hee Sun Yang ◽

Jeong-Sook Choe ◽

In Guk Hwang

Keyword(s):

Defense Mechanisms ◽

Inflammatory Diseases ◽

Cell Damage ◽

Treated Group ◽

Raw 264.7 Cells ◽

Resonance Spectroscopy ◽

Raw 264.7 ◽

Related Factor ◽

Anti Inflammatory ◽

Factor Α

Salvia plebeia has been used to treat a variety of inflammatory diseases, as well as colds and bronchitis. Macrophages have antioxidant defense mechanisms to cope with the intracellular reactive oxygen species (ROS) produced as part of the immune response. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway in inflamed macrophages is an appealing target due to its protective effect against ROS-induced cell damage. In this study, nepetoidin B (NeB) was first isolated from S. plebeia and identified by nuclear magnetic resonance spectroscopy. NeB reduced pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β) in LPS-activated RAW 264.7 cells by inhibiting the NF-κB signaling pathway. In the NeB-treated group, catalase and superoxide dismutase levels were significantly higher, and ROS expression decreased. By activating Nrf2 signaling, NeB enhanced HO-1 expression. Furthermore, when the cells were pretreated with tin protoporphyrin (an HO-1 inhibitor), the anti-inflammatory effects of NeB were reduced. Therefore, NeB may activate the Nrf2/ HO-1 pathway. These results reveal the NeB isolated from S. plebeia exerts anti-inflammatory effects by modulating NF-κB signaling and activating the Nrf2/HO-1 pathway in LPS-stimulated RAW 264.7 cells.

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The impact of fluid status and decremental PEEP strategy on cardiac function and lung and kidney damage in mild-moderate experimental acute respiratory distress syndrome

Respiratory Research ◽

10.1186/s12931-021-01811-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Nazareth N. Rocha ◽

Cynthia S. Samary ◽

Mariana A. Antunes ◽

Milena V. Oliveira ◽

Matheus R. Hemerly ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Epithelial Cell ◽

Distress Syndrome ◽

Cell Damage ◽

Kidney Injury ◽

Fluid Administration ◽

Kidney Damage ◽

Fluid Status ◽

Pulmonary Arterial ◽

Lung And Kidney

Abstract Background We evaluated the effects of abrupt versus gradual PEEP decrease, combined with standard versus high-volume fluid administration, on cardiac function, as well as lung and kidney damage in an established model of mild-moderate acute respiratory distress syndrome (ARDS). Methods Wistar rats received endotoxin intratracheally. After 24 h, they were treated with Ringer’s lactate at standard (10 mL/kg/h) or high (30 mL/kg/h) dose. For 30 min, all animals were mechanically ventilated with tidal volume = 6 mL/kg and PEEP = 9 cmH2O (to keep alveoli open), then randomized to undergo abrupt or gradual (0.2 cmH2O/min for 30 min) PEEP decrease from 9 to 3 cmH2O. Animals were then further ventilated for 10 min at PEEP = 3 cmH2O, euthanized, and their lungs and kidneys removed for molecular biology analysis. Results At the end of the experiment, left and right ventricular end-diastolic areas were greater in animals treated with high compared to standard fluid administration, regardless of PEEP decrease rate. However, pulmonary arterial pressure, indicated by the pulmonary acceleration time (PAT)/pulmonary ejection time (PET) ratio, was higher in abrupt compared to gradual PEEP decrease, independent of fluid status. Animals treated with high fluids and abrupt PEEP decrease exhibited greater diffuse alveolar damage and higher expression of interleukin-6 (a pro-inflammatory marker) and vascular endothelial growth factor (a marker of endothelial cell damage) compared to the other groups. The combination of standard fluid administration and gradual PEEP decrease increased zonula occludens-1 expression, suggesting epithelial cell preservation. Expression of club cell-16 protein, an alveolar epithelial cell damage marker, was higher in abrupt compared to gradual PEEP decrease groups, regardless of fluid status. Acute kidney injury score and gene expression of kidney injury molecule-1 were higher in the high versus standard fluid administration groups, regardless of PEEP decrease rate. Conclusion In the ARDS model used herein, decreasing PEEP abruptly increased pulmonary arterial hypertension, independent of fluid status. The combination of abrupt PEEP decrease and high fluid administration led to greater lung and kidney damage. This information adds to the growing body of evidence that supports gradual transitioning of ventilatory patterns and warrants directing additional investigative effort into vascular and deflation issues that impact lung protection.

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c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation

AJP Cell Physiology ◽

10.1152/ajpcell.00163.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. C522-C529 ◽

Cited By ~ 38

Author(s):

Justine Elliott ◽

Nadezhda N. Zheleznova ◽

Patricia D. Wilson

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Epithelial Cells ◽

Collecting Duct ◽

Specific Inhibitor ◽

Cell Phenotype ◽

Epithelial Cell Proliferation ◽

Matrix Adhesion ◽

Cyst Lining

c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY418)-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY418-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α2β1-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.

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Effect of hyperglycemia on brain pH levels in areas of focal incomplete cerebral ischemia in monkeys

Journal of Neurosurgery ◽

10.3171/jns.1986.65.5.0693 ◽

1986 ◽

Vol 65 (5) ◽

pp. 693-696 ◽

Cited By ~ 46

Author(s):

W. Richard Marsh ◽

Robert E. Anderson ◽

Thoralf M. Sundt

Keyword(s):

Adverse Effect ◽

Cerebral Ischemia ◽

Cell Damage ◽

Treated Group ◽

Squirrel Monkeys ◽

Control Group ◽

Content Type ◽

Brain Ph ◽

Fine Print ◽

Incomplete Ischemia

✓ The adverse effect of a minimal cerebral blood flow (CBF) in models of global ischemia has been noted by many investigators. One factor believed important in this situation is the level of blood glucose, since a continued supply of this metabolite results in increased tissue lactate, decreased brain pH, and increased cell damage. The authors have extended these observations to a model of focal incomplete ischemia. Brain pH was measured in fasted squirrel monkeys in regions of focal incomplete ischemia after transorbital occlusion of the middle cerebral artery (MCA). In both control and hyperglycemic animals, CBF was reduced to less than 30% of baseline. At 3 hours after MCA occlusion, brain pH in the control group was 6.66 ± 0.68 as compared to 6.27 ± 0.26 in the glucose-treated group. This difference was statistically significant by Student's unpaired t-test (p < 0.05). Thus, hyperglycemia results in decreased tissue pH in regions of focal incomplete cerebral ischemia in monkeys.

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