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001-es BibID:BIBFORM082948
Első szerző:Tornai Dávid (hepatológia, biomarker kutatás)
Cím:Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice / David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo
Dátum:2019
ISSN:2471-254X
Megjegyzések:Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage- and pathogen-associated molecular patterns contribute to a self-perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM-1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand-independent TREM-1 inhibitory peptides that were formulated into human high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA/E31-HDL. As revealed in vitro, macrophages endocytosed these rationally designed complexes through scavenger receptors. A 5-week alcohol feeding with the Lieber-DeCarli diet in mice resulted in increased serum alanine aminotransferase (ALT), liver steatosis, and increased proinflammatory cytokines in the liver. TREM-1 messenger RNA (mRNA) expression was significantly increased in alcohol-fed mice, and TREM-1 inhibitors significantly reduced this increase. TREM-1 inhibition significantly attenuated alcohol-induced spleen tyrosine kinase (SYK) activation, an early event in both TLR4 and TREM-1 signaling. The TREM-1 inhibitors significantly inhibited macrophage (epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 [F4/80], clusters of differentiation [CD]68) and neutrophil (lymphocyte antigen 6 complex, locus G [Ly6G] and myeloperoxidase [MPO]) markers and proinflammatory cytokines (monocyte chemoattractant protein 1 [MCP-1], tumor necrosis factor ? [TNF-?], interleukin-1? [IL-1?], macrophage inflammatory protein 1? [MIP-1?]) at the mRNA level compared to the HDL vehicle. Administration of TREM-1 inhibitors ameliorated liver steatosis and early fibrosis markers (?-smooth muscle actin [?SMA] and procollagen1? [Pro-Col1?]) at the mRNA level in alcohol-fed mice. However, the HDL vehicle also reduced serum ALT and some cytokine protein levels in alcohol-fed mice, indicating HDL-related effects. Conclusion: HDL-delivered novel TREM-1 peptide inhibitors ameliorate early phases of inflammation and neutrophil and macrophage recruitment and activation in the liver and attenuate hepatocyte damage and liver steatosis. TREM-1 inhibition represents a promising therapeutic approach for further investigations in ALD.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Hepatology Communications. - 3 : 1 (2019), p. 99-115. -
További szerzők:Furi István Shen, Zu T. Sigalov, Alexander B. Coban, Sahin Szabó Gyöngyi
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