Thromboxane A2 receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment

Minamino, Tsutomu; Yoshiya, Ikuto; Ohkubo, Hirotoki; Hosono, Kanako; Suzuki, Tatsunori; Sato, Takehito; Ae, Takako; Shibuya, Akitaka; Sakagami, Hiroyuki; Narumiya, Shuh; Koizumi, Wasaburo; Murakami, Masataka

doi:10.1016/j.taap.2011.12.013

Cited by 27 publications

(19 citation statements)

References 39 publications

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“…We previously showed that macrophage accumulation during hepatotoxicity is necessary for the repair of the liver and associated microvasculature [16], [32]. Recent evidence suggests that VEGFR1 mediates monocyte/macrophage infiltration to local inflammatory sites [8], [12], and that VEGFR1 promotes the recruitment of VEGFR1-expressing macrophages to repair acetaminophen-induced liver injury [16].…”

Section: Discussionmentioning

confidence: 99%

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

et al. 2014

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Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.

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Section: Discussionmentioning

confidence: 99%

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

et al. 2014

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“…Our data are consistent with reports that there are multiple subpopulations of phenotypically distinct alternatively activated macrophages that respond to liver injury, and that they are derived from different precursors (Si et al, 2010). F4/80 is a 160 kD membrane-associated glycoprotein and a member of the G-protein coupled receptor family present on mature macrophages and on alternatively activated macrophages participating in wound repair (Hume et al, 1983; Leenen et al, 1994; Volarevic et al, 2011; Minamino et al, 2012). We found that F4/80 was highly expressed by subpopulations of resident Kupffer cells in livers of wild type mice treated with control, which is in accord with previous studies (Dambach et al, 2002; Kinoshita et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Regulation of alternative macrophage activation in the liver following acetaminophen intoxication by stem cell-derived tyrosine kinase

Gardner

Hankey

Mishin

et al. 2012

Toxicology and Applied Pharmacology

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Stem cell-derived tyrosine kinase (STK) is a transmembrane receptor reported to play a role in macrophage switching from a classically activated/proinflammatory phenotype to an alternatively activated/wound repair phenotype. In the present studies, STK−/− mice were used to assess the role of STK in acetaminophen-induced hepatotoxicity as evidence suggests that the pathogenic process involves both of these macrophage subpopulations. In wild type mice, centrilobular hepatic necrosis and increases in serum transaminase levels were observed within 6 hr of acetaminophen administration (300 mg/kg, i.p.). Loss of STK resulted in a significant increase in sensitivity of mice to the hepatotoxic effects of acetaminophen and increased mortality, effects independent of its metabolism. This was associated with reduced levels of hepatic glutathione, rapid upregulation of inducible nitric oxide synthase, and prolonged induction of heme oxygenase-1, suggesting excessive oxidative stress in STK−/− mice. F4/80, a marker of mature macrophages, was highly expressed on subpopulations of Kupffer cells in livers of wild type, but not STK −/− mice. Whereas F4/80+ macrophages rapidly declined in the livers of wild type mice following acetaminophen intoxication, they increased in STK−/− mice. In wild type mice hepatic expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-12, products of classically activated macrophages, increased after acetaminophen administration. Monocyte chemotactic protein-1 (MCP-1) and its receptor, CCR2, as well as IL-10, mediators involved in recruiting and activating anti-inflammatory/wound repair macrophages, also increased in wild type mice after acetaminophen. Loss of STK blunted the effects of acetaminophen on expression of TNFα, IL-1β, IL-12, MCP-1 and CCR2, while expression of IL-10 increased. Hepatic expression of CX3CL1, and its receptor, CX3CR1 also increased in STK−/− mice treated with acetaminophen. These data demonstrate that STK plays a role in regulating macrophage recruitment and activation in the liver following acetaminophen administration, and in hepatotoxicity.

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“…In addition to its autocrine roles in hemostasis, TXA 2 has been reported to promote the recruitment of macrophages and fibroblasts, which contribute to tissue repair by secreting growth factors and extracellular matrix components . Thus, in a model of acute toxic liver injury, TP receptor signaling was responsible for timely tissue regeneration …”

Section: Roles Of Eicosanoids In Tissue Repairmentioning

confidence: 99%

“…The first days after injury are referred to as the “inflammatory phase”, which is characterized by the infiltration of neutrophils and monocytes/macrophages. Eicosanoids such as leukotrienes (LTs) and thromboxane A 2 (TXA 2 ) contribute to the recruitment and activation of these cells (Figure ) . Activated wound macrophages produce chemokines, eicosanoids (e.g.…”

Section: Introductionmentioning

confidence: 99%

Eicosanoids in tissue repair

Bieren

2019

Immunol Cell Biol

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Trauma or infection can result in tissue damage, which needs to be repaired in a well‐orchestrated manner to restore tissue function and homeostasis. Lipid mediators derived from arachidonic acid (termed eicosanoids) play central and versatile roles in the regulation of tissue repair. Here, I summarize the current state‐of the‐art regarding the functional activities of eicosanoids in tissue repair responses during homeostasis and disease. I also describe how eicosanoids are produced during tissue damage and repair in a time‐, cell‐ and tissue‐dependent fashion. In particular, recent insights into the roles of eicosanoids in epithelial barrier repair are reviewed. Furthermore, the distinct roles of different eicosanoids in settings of pathological tissue repair such as chronic wounds, scarring or fibrosis are discussed. Finally, an outlook is provided on how eicosanoids may be targeted by future therapeutic strategies to achieve physiological tissue repair and prevent scarring and loss of tissue function in various disease contexts.

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Thromboxane A2 receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment

Cited by 27 publications

References 39 publications

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

Regulation of alternative macrophage activation in the liver following acetaminophen intoxication by stem cell-derived tyrosine kinase

Eicosanoids in tissue repair

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