Thromboxane A{sub 2} receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment

Journal Article · Wed Feb 15 04:00:00 EST 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2011.12.013· OSTI ID:22215245

Minamino, Tsutomu ^[1]; Ito, Yoshiya ^[2]; Ohkubo, Hirotoki ^[1]; Hosono, Kanako; Suzuki, Tatsunori ^[1]; Sato, Takehito ^[1]; Ae, Takako; Shibuya, Akitaka ^[3]; Sakagami, Hiroyuki ^[4]; Narumiya, Shuh ^[5]; Koizumi, Wasaburo ^[3]; Majima, Masataka ^[1]

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1. Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)
2. Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)
3. Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)
4. Departments of Anatomy, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)
5. Department of Pharmacology, Kyoto University School of Medicine, Kyoto, 606-8315 (Japan)

It is thought that thromboxane A{sub 2} (TxA{sub 2}) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA{sub 2} is involved in liver repair. The objective of the present study was to examine the role of TxA{sub 2} receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl{sub 4}) was used to induce liver injury in TP knockout (TP{sup −/−}) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48 h, respectively, and then declined. In TP{sup −/−} mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP{sup −/−} mice, the accumulation of hepatic CD11b{sup +}/F4/80{sup +} macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C―C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl{sub 4}-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression. -- Highlights: ► TP enhances liver regeneration by CCl{sub 4}. ► TP accumulates macrophages. ► TP up-regulates MCP-1.

• OSTI ID: 22215245
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 259; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
ANIMAL TISSUES
CARBON TETRACHLORIDE
GROWTH FACTORS
INJURIES
LIVER
MACROPHAGES
MICE
MONOCYTES
RECEPTORS
TOXICITY