Ac-SDKP Attenuates Activation of Lung Macrophages and Bone Osteoclasts in Rats Exposed to Silica by Inhibition of TLR4 and RANKL Signaling Pathways

Jin, Fuyu; Geng, Fei; Xu, Danfeng; Li, Yaqian; Li, Tian; Yang, Xinyu; Liu, Shupeng; Zhang, Hui; Wei, Zhongqiu; Li, Shifeng; Gao, Xuemin; Cai, Wenchen; Mao, Na; Xue, Yu; Liu, Heliang; Sun, Ying; Fang, Yang; Xu, Hong

doi:10.2147/jir.s306883

Cited by 18 publications

(25 citation statements)

References 43 publications

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“…We previously demonstrated that Ac-SDKP alleviates the inflammatory response of macrophages in silicotic rats [ 3 ]. In this study, we explored whether Ac-SDKP exerts anti-inflammatory effects by regulating the energy metabolism of macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…Silicosis is a serious and fatal occupational lung disease and is mainly caused by inhalation of free crystalline silicon dioxide (SiO 2 ) or silica dust [ 1 , 2 ]. Chronic inhalation of silica into the lungs of rats leads to activation of lung macrophages and lung inflammation, which promotes a proteolytic phenotype in macrophages and downregulates the elastin level in lungs, eventually leading to fibrosis [ 3 ]. Macrophages involved in the proinflammatory response must rapidly provide energy to fuel the inflammatory response, which is accomplished through glycolysis and high lactate production [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally present immunoregulatory active peptide, which is generated from the N-terminal sequence of its precursor thymosin β4 (Tβ4) by meprin α [ 2 , 13 ]. Our group found that Ac-SDKP played an anti-fibrotic role in an experimental silicotic model by inhibiting the epithelial-mesenchymal transformation [ 14 , 15 , 16 ], myofibroblast transformation [ 17 ], and macrophage activation and by alleviating pulmonary inflammation [ 3 ]. It has been reported that Ac-SDKP inhibits diabetic nephropathy and has anti-fibrotic effects by regulating the glycolytic pathway [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

Mao

Yang

Yin

et al. 2021

IJMS

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Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

Mao

Yang

Yin

et al. 2021

IJMS

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“…Furthermore, OC-STAMP induced a phenotypic switch in macrophage polarization and suppressed the M1 proinflammatory state [ 22 ]. We have been described the potential proinflammatory effect of OC-STAMP in macrophages, as a member of the RANKL signaling pathway in silicosis [ 8 ]. In the present study, we found a different mechanism of OC-STAMP in AEC2 and promoted EMT, ER-stress, and cellular senescence in MLE-12 cells, which could be blocked by Ocstamp -siRNA or 4-PBA.…”

Section: Discussionmentioning

confidence: 99%

“…In our preliminary study, we found that the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling pathway, a classic signaling pathway for regulating osteoclast differentiation, is activated in the lungs of silicotic rats, and it promoted lung inflammation and proteolytic phenotype of macrophages [ 8 ]. Interestingly, we found that the expression of osteoclast stimulatory transmembrane protein (OC-STAMP) was found in AEC2, unlike the RANKL and RANK expression in lung macrophages.…”

Section: Introductionmentioning

confidence: 99%

OC‐STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis

Yang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.

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Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches

Mohammed,

Al-Saedi,

Mohammed

et al. 2024

Cell Biochem Biophys

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Ac-SDKP Attenuates Activation of Lung Macrophages and Bone Osteoclasts in Rats Exposed to Silica by Inhibition of TLR4 and RANKL Signaling Pathways

Cited by 18 publications

References 43 publications

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

OC‐STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis

Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches

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