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Objective: To systematically study the anti-fibrotic effect of N-acetyl-seryl-as partyl-lysyl-proline (Ac-SDKP) on pulmonary fibrosis. Methods: In May 2021, a computer search was performed on CNKI, Wanfang Knowledge Service Platform, VIP.com, China Biomedical Literature Database, Pubmed, OVID and other databases. The retrieval time was from January 2008 to May 2021. Randomized controlled experiments on the inhibition of pulmonary fibrosis by Ac-SDKP were screened. The control group was the pulmonary fibrosis model group and the experimental group was the Ac-SDKP treatment group. The quality of the literature was assessed using the syrcle risk of bias assessment tool, and data were extracted. Data analysis was Performed using revman 5.4 software. Results: 18 papers were included, with a total of 428 animal models. The results of meta analysis showed that the contents of α-smooth muscle actin (α-SMA), type I collagen, type Ⅲ collagen, transforming growth factor-β (TGF-β) and Nodule area in the exPerimental group were lower than those in the control grouP. [SMD=-2.44, 95%CI (-3.71--1.17), P=0.000][SMD=-5.36, 95%CI (-7.13--3.59), P=0.000] [SMD=-3.07, 95%CI (-4.13--2.02), P<0.000][SMD=-2.88, 95%CI (-3.63--2.14), P=0.000] [SMD=-1.80, 95%CI (-2.42--1.18), P=0.000], the content of hydroxy proline in the experimental group was higher than that in the control group [SMD=7.62, 95%CI (4.90-10.33), P=0.000], all indexes included in the literature were statistically significant. Conclusion: Ac-SDKP has obvious inhibitory effect on the process of pulmonary fibrosis, and may become a new clinical drug for the treatment of pulmonary fibrosis.
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Rats , Animals , Pulmonary Fibrosis , Rats, Wistar , Fibrosis , Disease Models, Animal , ProlineABSTRACT
Objective: To study the effect of anti-fibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on phosphorylated heat shock protein 27 (P-HSP27) and zinc finger family transcriptional repressor 1 (SNAI1) expression to explore the anti-silicosis fibrosis effect of Ac-SDKP. Methods: In December 2014, the rat silicosis animal model was prepared by one-time bronchial infusion of silicon dioxide (SiO(2)) dust. 80 SPF healthy adult Wistar rats were selected, and the rats were divided into 8 groups according to the random number table method, 10 in each group. Model control group for 4 weeks (feeding for 4 weeks) , model control group for 8 weeks (feeding for 8 weeks) : bronchial perfusion with normal saline 1.0 ml per animal. Silicosis model group for 4 weeks (feeding for 4 weeks) and silicosis model group for 8 weeks (feeding for 8 weeks) : bronchial perfusion of 50 mg/ml SiO(2) suspension 1.0 ml per animal. Ac-SDKP administration group for 4 weeks (feeding for 4 weeks) , Ac-SDKP administration group for 8 weeks (feeding for 8 weeks) : Ac-SDKP 800 μg·kg(-1)·d(-1) was administered by intraperitoneal pump. Ac-SDKP preventive treatment group: 48 h after Ac-SDKP 800 μg·kg(-1)·d(-1) administration, bronchial perfusion of SiO(2) suspension 1.0 ml per animal, raised for 8 weeks. Ac-SDKP anti-fibrosis treatment group: after bronchial perfusion of 1.0 ml of SiO(2) suspension for 4 weeks, Ac-SDKP 800 μg·kg(-1)·d(-1) was administered for 4 weeks. Western blotting was used to detect the expression of P-HSP27, SNAI1, α-smooth muscle actin (α-SMA) , and collage typeⅠ and Ⅲ in each group. The expression of P-HSP27 and SNAI1 was detected by immunohistochemistry, and the co-localized expression of P-HSP27 and α-SMA was detected by laser confocal microscopy. Results: Compared with the model control group, the expressions of P-HSP27, SNAI1, α-SMA, and collage typeⅠ and Ⅲ in the silicosis fibrosis area of the rats in the silicosis model group were enhanced, and the differences were statistically significant (P<0.05) . After Ac-SDKP intervention, compared with silicosis model group for 8 weeks, the expressions of P-HSP27, SNAI1 α-SMA, and collage typeⅠ and Ⅲ in the Ac-SDKP preventive and anti-fibrosis treatment groups were significantly decreased, and the differences were statistically significant (P<0.05) . However, the expressions of P-HSP27 SNAI1, and collage typeⅠ and Ⅲ between the Ac-SDKP administration group and the model control group did not change significantly, and the differences were not statistically significant (P>0.05) . Laser confocal results showed that the positive cells expressing P-HSP27 and α-SMA in the lung tissue of the silicosis model group were more than those in the model control group. Compared with the silicosis model group, the Ac-SDKP prevention and anti-fibrosis treatment groups expressing the positive cells of P-HSP27 and α-SMA decreased. Compared with the model control group for 8 weeks, there were some double-positive cells expressing P-HSP27 and α-SMA in the nodules of the silicosis model group for 8 weeks. Conclusion: Ac-SDKP may play an anti-silicic fibrosis effect by regulating the P-HSP27/SNAI1 pathway.
Subject(s)
Animals , Rats , HSP27 Heat-Shock Proteins , Oligopeptides , Rats, Wistar , Silicon Dioxide , Silicosis/metabolismABSTRACT
Objective: To explore whether N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits the formation of silica nodules and the deposition of collagen by inhibiting the expressions of inflammatory factor myeloid-related protein14 (MRP-14) and collagen in silicosis rats. Methods:The silicosis model of rats was established by one-off bronchial instillation of silicon (SiO2) dust. Sixty healthy adult rats of SPF grade were randomly divided into six groups: control 4-week group, control 8-week group, silicosis model 4-week group, silicosis model 8-week group, Ac-SDKP prevention treatment group, and Ac-SDKP anti-fibrosis treatment group, with ten rats in each group. Immunohistochemical method was used to detect the expression of MRP-14 protein in silicosis model tissues. Western blot method was used to detect the expressions of MRP-14 and collagen protein in silicosis model tissues. Results: Compared with those in the corresponding control group, the expressions of MRP-14 and collagen in silicosis fibrosis areas were significantly increased in the dust-exposed group (P<0.05). Compared with those in the silicosis model 8-week group, the expressions of MRP-14 and collagen were significantly decreased after Ac-SDKP intervention (P<0.05). Conclusion: Ac-SDKP can inhibit silicosis in rats by inhibiting the regulation of MRP-14 expression.
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ABSTRACT:Objective To observe whether N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)can inhibit rat silicotic fibrosis by regulating stimulatory G proteinα(Gαs)/inhibitory G proteinα(Gαi)signal.Methods Male Wistar rats were randomly divided into three groups (n=1 0 ):control 1 6-w group,silicosis 1 6-w group,and Ac-SDKP pre-treatment group.The pathological changes of the lung tissue was observed by HE staining;the expressions ofα-smooth muscle actin (α-SMA),Collagen Ⅰ,fibronectin (Fn),Gαs,Gαi2 ,Gαi3 and cAMP were detected by Western blot.Immunofluorescence was performed on lung tissue sections to detect the coexpression ofα-SMA/Gαi3 . Results Within silicosis 16-w group,HE staining showed that the silicotic nodule volume increased,nodule fusion and the formation of interstitial fibrosis could be seen,and cell fibrous nodules were visible.Immunofluorescence staining showed the enhanced coexpression ofα-SMA/Gαi3 in fibrosis area.Compared with those in control group, the expressions ofα-SMA,Collagen Ⅰ,Fn,Gαi2 and Gαi3 significantly increased in silicosis 1 6-w group,but the expressions of Gαs and cAMP decreased.Compared with silicosis 1 6-w group,Ac-SDKP pre-treatment group had alleviated lung injury and decreased coexpression ofα-SMA/Gαi3 .The expressions ofα-SMA,Collagen Ⅰ,Fn,Gαi2 and Gαi3 protein significantly decreased in Ac-SDKP pre-treatment group,while the expressions of Gαs and cAMP increased obviously.Conclusion Ac-SDKP can regulate the expressions of Gαs and Gαi and promote the formation of cAMP,thus playing an effective role against silicotic fibrosis.
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Objective To observe the function of Ac-SDKP on p-CREB,p-Smad2/3 signal and restraining silicotic fibrosis.Methods Wistar rats were randomly divided into:control group;silicosis group;Ac-SDKP post-treatment group;Ac-SDKP pre-treatment group.The morphology of lung tissue was observed by Van Gieson stain-ing.The expression of α-SMA,cAMP,PKA,p-CREB and p-Smad2/3 protein were assessed by Western blot.The colocalization of p-Smad2/3 and α-SMA were detected by immuno-fluorescence. Results In silicosis group,the deposition of collagen were visible in the fibrotic area,the expression of α-SMA and p-Smad2/3 increased signifi-cantly,and the expression of cAMP,PKA and p-CREB decreased significantly. After Ac-SDKP treatment,the expression of cAMP,PKA and p-CREB were significantly up-regulated,the expression of -SMA and p-Smad2/3 protein were significantly down-regulated,lung tissue damage and collagen deposition decreased. Conclusion By activating the signal of cAMP/PKA/p-CREB,Ac-SDKP was capable of restraining the expression of p-Smad2/3,so as to restrain silicotic fibrosis.
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Objective To investigate the changes of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) and angiotensin converting enzyme (ACE)/angiotensin II(Ang II)/angiotensin II type 1 receptor (AT1R) axis and their impact on the development and progression of silicotic fibrosis. MethodsSixty male Wistar rats were randomly divided into 6 groups (n=10). The rats inhaled dust for 0, 2, 4, 8, 12, and 16 weeks (w) respectively to reproduce silicosis model. HE staining was performed to observe the pathological changes of the lung tissue. The expression of α smooth muscle actin (α-SMA), collagen I (Col I), fibronectin (Fn), ACE and AT1R were measured by Western blotting. The levels of Ac-SDKP and Ang II in lung tissue were detected by ELISA. ResultsMacrophage infiltration and widened alveolar wall were observed by HE staining in the silicosis 2-w group. Isolated cell lesions which composed of macrophages were seen in silicosis 4-w group. The alveolar wall widened obviously and the number of silicotic nodules increased at 8w and 12w. The fusion of silicotic lesions, interstitial fibrosis and fibrous lesions were observed at 16w. Compared with control group, the expressions of α-SMA, Col I and Fn protein in silicosis 4-, 8-, 12-, and 16-w group increased gradually. In silicosis 2-, 4-, 8-, 12-, 16-w group, the expressions of ACE, Ang II and AT1R gradually increased compared to the control. The level of Ac-SDKP in the lung tissue of silicosis 2-w group was significantly higher than that in control group, and then decreased gradually, and significantly lower in the silicosis 12- and 16-w group than the control (P<0.05). ConclusionAlong with the development and progression of silicosis, ACE, Ang II, and AT1R expressions gradually increase in local lung tissue, while the expression of Ac-SDKP gradually decreases. Ac-SDKP and Ang II signal would participate the silicotic fibrosis process in rats.
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AIM: To detect whether N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits epithelial-mes-enchymal transition in A549 cells induced by TGF-β1 through suppressing the expression of heat shock protein 27 (HSP27) and zinc finger proteins Snail (including SNAI1and SNAI2) which ultimately inhibited the deposition of type I and type III collagens.METHODS:The colocalizations of HSP27 and SNAI1/SNAI2 respectively on A549 alveolar epi-thelial cells induced by TGF-β1 were measured by confocal microscopy .The expression of HSP27, SNAI1 and SNAI2 at mRNA level was detected by real-time PCR.Western blotting analysis was used to detect the expression of HSP 27, SNAI1 and SNAI2 on epithelial-mesenchymal transition in A549 cells induced by TGF-β1 and also the deposition of type I and type III collagens in A549 cells transfected with HSP27shRNA prior to TGF-β1 stimulation.RESULTS: Compared with control group, TGF-β1 increased the expression of HSP27, SNAI1, SNAI2, type I and type III collagen, which decreased significantly followed by Ac-SDKP intervention.The expression of SNAI1, type I and type III collagen decreased signifi-cantly after transfected with HSP27shRNA in A549 cells, which had the similar effect on Ac-SDKP intervention.CON-CLUSION:Ac-SDKP inhibits the transition of cultured A 549 cells to myofibroblasts and attenuates collagen synthesis by suppressing the expression of HSP 27 and zinc finger proteins SNAI 1 and SNAI2.
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[Abstract ] Objective Silicosis is one of the most serious occupational diseases in China .In this study,we explored the reg -ulatory effect of N-acetyl-seryl-aspartyl-lysyl-proline ( Ac-SDKP ) on angiotensin ( Ang ) Ⅱ-induced extracellular signal-regulated ki-nase ( ERK1/2) and Jun N-terminal kinase ( JNK) signals and its inhibitory effect on the differentiation of human embryonic lung MRC-5 fibroblasts to myofibroblasts via Ang Ⅱ-induced ERK1/2 and JNK signals . Methods Human embryonic lung MRC-5 fibro-blasts were induced by Ang Ⅱand pre-treated with the JNK signal inhibitor ( SP600125 ) , the ERK1/2 signal inhibitor ( PD98059 ) or Ac-SDKP.The proliferation of the cells was measured by MTT assay .The expressions of αS-MA, SRF, p-ERK1/2 and p-JNK were determined by immunocytochemical staining , and the expression levels of these proteins and collagen Ⅰwere detected by Western blot .Results The A value of Ang Ⅱ group (0.56 ±0.08) measured by MMT assay was 2.07 fold as control group ( 0.27 ±0.05 ). Pretreatment with SP600125 , PD98059 and Ac-SDKP, the A value were (0.39 ±0.02), (0.40 ±0.03) and (0.36 ±0 0.5) that had a statistical significance with Ang Ⅱgroup.The up-regulation of colla-gen type Ⅰ,α-SMA, SRF were induced by Ang Ⅱ by 4.50, 3.50 and 3.00 fold compared with control group.Moreover, the expression of p-ERK1/2 and p-JNK were increased as 6.71 and 7.90 fold as control. Pre-treatment with Ac-SDKP could inhibit p-JNK and p-ERK1/2 to 29.79% and 46.84% compared with AngⅡ group. Conclusion Ac -SDKP can inhibit the differentiation of human embryonic lung MRC-5 fibroblasts to myofibroblasts by regulating AngⅡ-induced JNK and ERK1/2 signals.
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Objective To investigate the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on the synthesis of collagen and the expression of NF-κB p65 in lung of rats with silicosis fibrosis .Methods Rats were divided into 3 groups randomly :the control group(each rat was intratracheally instilled with 1 mL normal saline and killed after 8 weeks ,the silicotic model group(each rat was intratracheally instilled with 1 mL silica suspension and killed after 8 weeks ,the AcSDKP treated group(each rat was intra-tracheally instilled with 1 mL silica suspension and AcSDKP (800 μg · kg -1 · d-1 ) was administered into every rat ,then rats were killed after 8 weeks .Lung fibrosis in morphology and collagen content was observed by HE and vg staining and hydroxyproline as-say .The expression of NF-κB p65 was detected with the immunohistochemistry and Western blot .Results Compared with the con-trol group ,the quantity of silicon nodules ,collagen content and the expression of NF-κB p65were increased in the silicotic model group .Compared with the silicotic model group ,the quantity of silicon nodules ,collagen content and the expression of NF-κB p65 were decreased in the AcSDKP-treated group .Conclusion AcSDKP could inhibit the activity and expression of NF-κB p65 by strengthening the stability of I-κB ,which may influence the progress of alveolar inflammation and silicosis fibrosis .