Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA)

Golbar, Hossain M.; Izawa, Takeshi; Wijesundera, K.K.; Bondoc, Alexandra; Tennakoon, A.P.; Kuwamura, Mitsuru; Yamate, Jyoji

doi:10.1177/0192623315621191

Cited by 25 publications

(41 citation statements)

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“…TAA can interfere with protein synthesis and enzyme metabolism in the liver, which can lead to chronic liver injury (35,36). Previous studies have demonstrated that TAA could induce hepatic fibrosis in rats (37,38). In the current study, H&E and VG staining revealed a marked increase in the number of necrotic hepatocytes and infiltrating inflammatory cells, with a markedly increased deposition of collagen fibers in the TAA group, as well as liver fibrosis were directly observed.…”

Section: Discussionsupporting

confidence: 57%

Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide‑induced hepatic fibrosis in rats

Zhang

Pan

et al. 2019

Exp Ther Med

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Liver fibrosis is a complex pathological process and an early step in the progression of liver cirrhosis, which can eventually develop into hepatocellular carcinoma. Currently, there is no effective treatment for liver fibrosis. Puerarin is a traditional Chinese herb, which is commonly used in the treatment of various diseases. In addition, it is also believed to have a therapeutic effect in liver fibrosis. However, whether puerarin reduces liver fibrosis via the ERK1/2 signaling pathway to inhibit the activation of hepatic stellate cell (HSC) and excessive collagen deposition in liver fibrosis remains unknown. The aim of the current study was to establish a liver fibrosis in vivo model by intraperitoneal injection of thioacetamide (TAA) and investigate the effect of puerarin in the treatment of liver fibrosis. Hematoxylin and eosin and Van Gieson's staining were used to examine histopathological changes associated with liver fibrosis. Liver hydroxyproline content was examined to determine the total amount of collagen in the liver. The relative protein expression levels of transforming growth factor β1 (TGFβ1), α-smooth muscle actin (α-SMA), collagen type I, fibronectin, ERK1/2 and p-ERK1/2 were determined by western blot analysis. In the TAA group, histopathological changes and collagen fiber content in rat liver tissue samples were significantly increased compared with the control group (P<0.05). In addition, treatment with puerarin significantly decreased histopathological changes and collagen fiber content in rat liver tissue samples (P<0.05). The relative protein expression levels of TGFβ1, α-SMA, collagen type I, fibronectin and p-ERK1/2 were significantly upregulated in the TAA group compared with the control group (P<0.05), whereas puerarin treatment reversed these changes. These findings suggest that treatment with puerarin may reduce HSC activation and alleviate extracellular matrix protein expression levels by inhibiting the TGF-β/ERK1/2 pathway in liver fibrosis.

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Section: Discussionsupporting

confidence: 57%

Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide‑induced hepatic fibrosis in rats

Zhang

Pan

et al. 2019

Exp Ther Med

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“…Once ingested by macrophages, the clodronate causes damage to macrophages via apoptosis, resulting in their depletion/disappearance 42,43) . Hepatic macrophages in rats are easily depleted by an intravenous injection of liposome-encapsulated clodoronate 44,45) . CD163-expressing Kupffer cells are almost completely depleted for long term, indicative of the most sensitive for clodoronate treatment (Fig.…”

Section: -2 Influences On Depletion Of Hepatic Macrophages In Homeomentioning

confidence: 99%

“…To further determine the functions of macrophages in hepatotoxicity, hepatic macrophages were depleted by liposomal clodronate one day before a single administration of a sub-lethal dose of TAA 45) . In clodronate-treated rats, not only M1-macrophages expressing CD68 and MHC class II, but alsoM2-macrophages positive for CD163 and CD204 are markedly decreased.…”

Section: -5 Aggravated Lesion Of Taa-induced Acute Liver Injury Undmentioning

confidence: 99%

Histopathological Analysis of Rat Hepatotoxicity Based on Macrophage Functions: in Particular, an Analysis for Thioacetamide-induced Hepatic Lesions

2016

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Hepatic macrophages play an important role in homeostasis. The functional abnormalities of hepatic macrophages primarily or secondarily influence chemically induced hepatotoxicity. However, the evaluation system based on their functions has not yet been established. Recently, a new concept (M1-/M2-macrophage polarization) was proposed; M1macropahges are induced by INF-γ, and show high phagocytosis/tissue damage, whereas M2-macropahges are induced by IL-4 and play roles in reparative fibrosis by releasing IL-10 and TGF-β1. In hepatogenesis, CD68-expressing M1macrophages predominantly exist in embryos; in neonates, in contrast, CD163-/CD204-expressing M2-macrophages appear along the sinusoids and mature as Kupffer cells. Activated Kupffer cells by liposome decrease AST and ALT values, whereas AST and ALT values are increased under Kupffer cells depleted with clodronate treatment. Since Kupffer cells may be involved in clearance of liver enzymes, macrophage condition should be taken into consideration when hepatotoxicity is analyzed. In TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2factors are already increased before histopathological change; the appearance of CD68-expressing M1-macrophages and CD163-expressing M2-macrophages follows in injured centrilobular lesions, and TGF-β1 and IL-10 are increased for reparative fibrosis. CD68-expressing M1-macrophages co-express MHC class II and Iba-1, whereas CD163-expressing M2-macrophages also express CD204 and Galectin-3. Under macrophage depletion by clodoronate, TAA-treated rat livers show prolonged coagulation necrosis of hepatocytes, and then develop dystrophic calcification without reparative fibrosis. The depletion of hepatic macrophages influences hepatic lesion development. Collectively, a histopathological analysis method for hepatotoxicity according to M1-/M2-macrophage polarization would lead to the refinement of hazard characterization of chemicals in food and feed.

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“…Moreover, acute toxicity has been observed when administering liposomal zoledronic acid, most likely caused by increased cytokine production [168,186]. Furthermore, the long-term effects of macrophage depletion have yet to be investigated, as there are indications that macrophage depletion may aggravate liver lesions in liver injury and impair skeletal muscle repair after muscle injury [187,188]. However, targeting macrophages seems to be a more effective strategy than identifying tumor specific antigens, as these may change over the course of tumor development and expression may vary between different groups of patients [189].…”

Section: Future Perspectivesmentioning

confidence: 99%

Nanomedicine Strategies to Target Tumor-Associated Macrophages

Binnemars-Postma

Storm

Prakash

2017

IJMS

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In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail.

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Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA)

Cited by 25 publications

References 41 publications

Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide‑induced hepatic fibrosis in rats

Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide‑induced hepatic fibrosis in rats

Histopathological Analysis of Rat Hepatotoxicity Based on Macrophage Functions: in Particular, an Analysis for Thioacetamide-induced Hepatic Lesions

Nanomedicine Strategies to Target Tumor-Associated Macrophages

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