Ac-SDKP increases α-TAT 1 and promotes the apoptosis in lung fibroblasts and epithelial cells double-stimulated with TGF-β1 and silica

Li, Shifeng; Xu, Hong; Xue, Yu; Niu, Siyu; Zhang, Qiaodan; Xu, Danfeng; Zhang, Lijuan; Wei, Zhongqiu; Gao, Xuemin; Cai, Wenchen; Zhang, Guizhen; Li, Dan; Wang, Ruimin; Fang, Yang

doi:10.1016/j.taap.2019.02.015

Cited by 32 publications

(35 citation statements)

References 24 publications

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“…Of course, collagen is produced by fibroblasts stimulated by activated alveolar macrophages following silica exposure, and collagen plays an important role in fibrosis and nodular lesions characterized as silicosis [16,55]. Collagen deposition has been monitored using various experimental silicosis models in an effort to examine various molecular targets for the inhibition of progressive fibrosis caused by silica exposure, such as N-acetyl-seryl-asoarthyl-lysyl-proline (Ac-SDKP; anti-fibrotic tetrapeptide) [56,57], BMSCs (as mentioned above) [58], pirfenidone (specific drug for idiopathic pulmonary fibrosis), and nicorandil (an antianginal and potassium channel opener agent) [59,60].…”

Section: Silicosis and Ligands For Integrin Familymentioning

confidence: 99%

Role of Nephronectin in Pathophysiology of Silicosis

Lee

Honda

Yamamoto

et al. 2019

IJMS

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Silicosis is a typical form of pneumoconiosis and is characterized as a type of lung fibrosis. Silica particles are captured and recognized upon by alveolar macrophages via the macrophage receptor with collagenous structure (MARCO) scavenger receptor, and thereafter the inflammasome is activated. Thereafter, various chemokines/cytokines play their roles to eventually form fibrosis. Additionally, silica particles chronically activate T helper cells which sets the background for the formation of silicosis-associated autoimmune disturbances. The occurrence and progression of lung fibrosis, the extracellular matrix-related molecules such as integrins and their ligands including fibronectin, vitronectin, laminin, and collagens, all play important roles. Here, the roles of these molecules in silicosis-related lung fibrosis are reviewed from the literature. Additionally, the measurement of serum nephronectin (Npnt), a new member of the integrin family of ligands, is discussed, together with investigations attempting to delineate the role of Npnt in silica-induced lung fibrosis. Serum Npnt was found to be higher in silicosis patients compared to healthy volunteers and seems to play a role in the progression of fibrosis with other cytokines. Therefore, serum Npnt levels may be employed as a suitable marker to monitor the progression of fibrosis in silicosis patients.

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Section: Silicosis and Ligands For Integrin Familymentioning

confidence: 99%

Role of Nephronectin in Pathophysiology of Silicosis

Lee

Honda

Yamamoto

et al. 2019

IJMS

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“…Silicosis is a major occupational health hazard throughout the world. 1 Previous studies by our group found that macrophage activation, myofibroblast differentiation, and epithelial-mesenchymal transition (EMT) are important factors in the pathogenesis of silicosis, 2,3 while several other studies have confirmed that activation of the local renin-angiotensin system (RAS) in lung tissue is involved in the development of pulmonary fibrosis. [4][5][6] However, the pathomechanisms of silicosis remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

et al. 2020

DDDT

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The role of angiotensin-converting enzyme 2 (ACE2) in silicosis remains unknown, although previous studies have suggested that ACE2 may be beneficial. We, therefore, investigated the effect of ACE2 on silicosis, particularly with regard to its role in regulating the epithelial-mesenchymal transition (EMT) induced by silica, with the aim to uncover a new potential target for the treatment of pulmonary fibrosis. Materials and Methods: We employed wild-type mice treated with diminazene aceturate (DIZE, an ACE2 activator, 15 mg/kg/day for 4 weeks), hACE2-transgenic mice (overexpress the ACE2 gene), and the mouse lung type II epithelial cell line treated with DIZE (10 −7 M for 48 h) or angiotensin-(1-7) [Ang-(1-7)] (10 −4 M for 48 h), following induced fibrotic responses to determine the protective potential of ACE2. Silicosis models were established by orotracheal instillation of SiO 2 (2.5 mg/mouse). Immunostaining was used to determine αsmooth muscle actin (α-SMA) expression. The activities of angiotensin-converting enzyme (ACE) and ACE2 and the levels of angiotensin II (Ang II) and Ang-(1-7) were detected by enzyme-linked immunosorbent assay. The mRNA expression of ACE and ACE2, and protein expression of the renin-angiotensin system (RAS) components and EMT indicators were studied by qRT-PCR and Western blot, respectively. Results: DIZE treatment and overexpression of ACE2 markedly inhibited the formation of silica-induced lung fibrosis and increased the level of E-cadherin, with concomitant downregulation of pro-collagen, vimentin, and α-SMA via RAS signaling. Furthermore, DIZE and Ang-(1-7) attenuated the EMT and collagen deposition induced by silica in MLE-12 cells. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 (a specific Mas receptor blocker). Conclusion: The overexpression of ACE2 and treatment with DIZE can ameliorate EMT in silicotic mice via activation of the ACE2-Ang-(1-7)-Mas receptor axis, and these changes are accompanied by suppression of the ACE-Ang II-AT1 receptor axis.

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“…The rats were provided with free access to water and food and housed in a temperature-controlled chamber at 22°C–24°C with a 12-h light/12-h dark cycle. We established the silicotic model using a HOPE MED 8050 exposure control apparatus (HOPE Industry and Trade, Tianjin, China) as reported previously 22 . The rats were placed in the apparatus suffused with SiO 2 (s5631, Sigma-Aldrich, St. Louis, MO, USA; ground and then heated at 180°C for 6 h).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Mice by Regulating Meprin α

Chen

Yao

et al. 2020

Molecular Therapy - Nucleic Acids

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Silicosis is a fatal profession-related disease linked to longterm inhalation of silica. The present study aimed to determine whether meprin a, a master regulator of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicotic and control lung macrophages and fibroblasts upon activation. NR8383 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin a and miR-155-5p. In vitro meprin a manipulation was performed by recombinant mouse meprin a protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin a and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin a level was stably repressed in silicotic rats. In vitro, silica decreased meprin a, and exogenous meprin a reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mep1a by binding to the 3 0 untranslated region. Treatment with anti-miR-155-5p elevated meprin a, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin a and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/ meprin a are two of the major regulators of silicosis.

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Ac-SDKP increases α-TAT 1 and promotes the apoptosis in lung fibroblasts and epithelial cells double-stimulated with TGF-β1 and silica

Cited by 32 publications

References 24 publications

Role of Nephronectin in Pathophysiology of Silicosis

Role of Nephronectin in Pathophysiology of Silicosis

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Mice by Regulating Meprin α

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