Inflammatory chemokine ( C‐C motif) ligand 8 inhibition ameliorates peritoneal fibrosis

Abstract

Peritoneal fibrosis (PF) is an irreversible complication of peritoneal dialysis (PD) that leads to loss of peritoneal membrane function. We investigated PD effluent and serum levels and the tissue expression of chemokine (C‐C motif) ligand 8 (CCL8) in patients with PD. Additionally, we investigated their association with PF in a mouse model. Eighty‐two end‐stage renal disease (ESRD) patients with PD were examined. CCL8 levels were measured via enzyme‐linked immunosorbent assays in PD effluents and serum and analyzed with peritoneal transport parameters. Human peritoneal mesothelial cells (hPMCs) were obtained from the PD effluents of 20 patients. Primary cultured hPMCs were treated with recombinant (r) transforming growth factor (TGF)‐β, and CCL8 expression was assessed via western blotting. As the duration of PD increased, the concentration of CCL8 in PD effluents significantly increased. Correlations between peritoneal transport parameters and dialysate CCL8 levels were observed. Western blotting analysis showed that CCL8 was upregulated via rTGF‐β treatment, accompanied by increases in markers of inflammation, fibrosis, senescence, and apoptosis in hPMCs after induction of fibrosis with rTGF‐β. Anti‐CCL8 monoclonal antibody (mAb) treatment suppressed the rTGF‐β‐induced increase in all analyzed markers. Immunohistochemical analysis revealed that CCL8 along with fibrosis‐ and inflammation‐related markers were significantly increased in the PF mouse model. Functional blockade of CCL8 using a CCR8 inhibitor (R243) abrogated peritoneal inflammation and fibrosis in vivo. In conclusion, high CCL8 levels in PD effluents may be associated with an increased risk of PD failure, and the CCL8 pathway is associated with PF. CCL8 blockade can ameliorate peritoneal inflammation and fibrosis.

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress

“…In CHX-induced damage, Ccl8, the mouse functional analog of human CCL18 [40], was the most upregulated chemokine in the peritoneum, as we have observed in this study. Moreover, the functional blockade of CCL8, using a CCR8 inhibitor, prevented PM thickening and macrophage infiltration into the peritoneum [41,42]. In this study, we have found that JQ1 diminished the peritoneal Ccl8 overexpression.…”

Negative Differential Interlayer Resistance in WSe2 Multilayers via Conducting Channel Migration with Vertical Double-Side Contacts

“…Furthermore, the observed conducting channel migration and the resulting negative differential interlayer resistance occur without heterojunctions at room temperature. Our findings would pave the way for numerous electronic applications based on 2D vdW multilayers such as frequency multiplier, 40,41 random number generator, 42,43 multivalued logic circuits, 44,45 and neuromorphic computing. 46,47 To gain a better understanding of the carrier transport mechanism in 2D vdW multilayers, we briefly illustrate the direction of the vertical channel migration under electrostatic V G and V D bias conditions with VDC (Figure 5a,b).…”

Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study

“…55 Studies showed that STAMBP can increase NACHT, LRR and PYD domains-containing protein 7 (NALP7) inflammasome and IL-1β levels to promote inflammation through deubiquitination. 56 60,61 We discovered that MCP2 can lower the likelihood of spondylolisthesis/spondylolysis, and more research is necessary to determine its involvement in spondylolysis and other nonunions. Among these 91 CIPs, TGF-β1 was not found.…”