A bioactive product lipoxin A4 attenuates liver fibrosis in an experimental model by regulating immune response and modulating the expression of regeneration genes

Kurtoğlu, Elçin Latıfe; Kayhan, Basak; Gül, Mehmet; Kayhan, Burçak; Kayhan, Meral Akdoğan; Karaca, Zeynal Mete; Yeşilada, Elif; Yılmaz, Sezai

doi:10.5152/tjg.2019.18276

Cited by 18 publications

(8 citation statements)

References 32 publications

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“…In addition, we measured the level of LXA 4 , one of Fpr2 ligands, in our experimental animal models. LXA 4 has been shown to have anti-inflammatory effects in the various disease models including acute liver failure and obesity 13 , 34 , 35 . Hepatic LXA 4 amount rarely had a significant difference between male and female mice (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.

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Section: Discussionmentioning

confidence: 99%

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis

et al. 2022

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“…The results provided in Figure 11 surprisingly did not show any dramatic increases in the levels of both IL-6 and TNF-α compared to the control, including the radiation group. The reason for this lack of response in the levels of both IL-6 and TNF-α (see Figure 11 B,C) in response to pro-inflammatory action of radiation could be attributed to the increased levels of PGE2 and LXA4 (see Figure 13 ), which are known to suppress the production of these cytokines [ 60 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. However, it is noteworthy that some studies showed that PGE2 and increased COX-2 expression enhance IL-6 production, and suggested that the inhibition of COX-2 is critical to suppress IL-6 [ 78 , 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

Rengachar

Bhatt

Polavarapu³

et al. 2022

Biomolecules

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Radiation is pro-inflammatory in nature in view of its ability to induce the generation of reactive oxygen species (ROS), cytokines, chemokines, and growth factors with associated inflammatory cells. Cells are efficient in repairing radiation-induced DNA damage; however, exactly how this happens is not clear. In the present study, GLA reduced DNA damage (as evidenced by micronuclei formation) and enhanced metabolic viability, which led to an increase in the number of surviving RAW 264.7 cells in vitro by reducing ROS generation, and restoring the activities of desaturases, COX-1, COX-2, and 5-LOX enzymes, TNF-α/TGF-β, NF-kB/IkB, and Bcl-2/Bax ratios, and iNOS, AIM-2, and caspases 1 and 3, to near normal. These in vitro beneficial actions were confirmed by in vivo studies, which revealed that the survival of female C57BL/6J mice exposed to lethal radiation (survival~20%) is significantly enhanced (to ~80%) by GLA treatment by restoring altered levels of duodenal HMGB1, IL-6, TNF-α, and IL-10 concentrations, as well as the expression of NF-kB, IkB, Bcl-2, Bax, delta-6-desaturase, COX-2, and 5-LOX genes, and pro- and anti-oxidant enzymes (SOD, catalase, glutathione), to near normal. These in vitro and in vivo studies suggest that GLA protects cells/tissues from lethal doses of radiation by producing appropriate changes in inflammation and its resolution in a timely fashion.

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“…These activities of LXA 4 are regulated by the G protein-coupled ALX/FPR2 receptor 18,19 . LXA4 reportedly reduces DM-related renal fibrosis by targeting TGF-β/Smad signaling and suppresses liver fibrosis in experimental models by regulating the immune responses and modulating the expression of regeneration genes 20,21 . It also lowers TGF-β levels in bleomycin-induced pulmonary fibrosis and exhibits an anti-fibrotic effect 22 .…”

Section: Introductionmentioning

confidence: 99%

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

et al. 2020

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Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A 4 (LXA 4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA 4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA 4 reduced IR-induced increases in lung consolidation volume. The flexiVent TM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA 4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA 4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA 4 could serve as a potent therapeutic agent for alleviating RILI.

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A bioactive product lipoxin A4 attenuates liver fibrosis in an experimental model by regulating immune response and modulating the expression of regeneration genes

Cited by 18 publications

References 32 publications

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

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