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1.
Nihon Hoshasen Gijutsu Gakkai Zasshi ; 77(11): 1288-1297, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34803109

RESUMO

PURPOSE: This study aimed to perform longitudinal observation using 4D-computed tomography (CT) and compare images acquired by 3D-CT and 3D-ultrashort echo time (UTE) for evaluation of bleomycin-induced lung fibrosis model. METHOD: The pulmonary fibrosis model was induced by instilling intratracheally with 50 µl of bleomycin. 4D-CT images were classified into four phases after acquisition and analyzed. To study the effects of respiratory gating, we aquired 3D-CT and 3D-UTE images with and without respiratory gating. For comparison between CT and UTE images, we performed no-triggerd 3D-CT and 3D-UTE under free-breathing. MR signal intensity ratio and CT values were measured in three regions of the upper, middle, and lower lung. RESULTS: At 4DCT, total lung volume at maximum inspiration (4th phase) decreased significantly compared with control mouse and the ratio of lung volume at inspiration to expiration also showed a significant decrease. In comparison of the images between with and without respiratory gating, clearer images were obtained by respiratory gating. However, there was no significant difference between both. In comparison between CT and UTE images, magnetic resonance (MR) signal intensity ratio and CT value were significantly correlated, but 3D-UTE images showed poor delineation of the lower lung and that near the diaphragm compared with 3D-CT images. CONCLUSION: 4D micro-CT and nontriggered 3D UTE-magnetic resonance imaging (MRI) under free breathing can be useful to evaluate bleomycininduced lung fibrosis model mouse.


Assuntos
Bleomicina , Fibrose Pulmonar , Animais , Imageamento Tridimensional , Pulmão/diagnóstico por imagem , Imageamento por Ressonância Magnética , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Microtomografia por Raio-X
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 454-459, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816650

RESUMO

Objective: To investigate the effects of simvastatin (SIM) on pulmonary fibrosis and the expression of VE-cadherin(VE-cad),vimentin(VIM) and alpha-smooth muscle actin(α-SMA)in the pulmonary fibrosis tissue of rats. Methods: Sixty healthy male SD rats were randomly divided into control group(group A), bleomycin group(group B), 5 mg SIM group (group C) and 10 mg SIM group (group D),15 rats in each group. The model of rat pulmonary fibrosis was established by itraperitoneal injection of bleomycin(5 mg/kg). Since the first day of modeling, the rats of group C and D were treated with simvastatin suspension 5 mg/(kg·d) and 10 mg/(kg·d) by intragastric administration everyday, and the rats of group A and B were treated with equal volume of saline 10 ml/(kg·d) everyday. Five rats of each group were sacrificed randomly at the 7th, 14th and 28th day. Masson staining was used to observe the morphological changes of lung tissue in rats. The degree of fibrosis in lung tissues of each group was evaluated by the content of hydroxyproline (HYP) . The microvessel density (MVD) was analyzed by immunohistochemistry,The expressions of protein and mRNA of VE-cad, VIM and α-SMA were determined by immunohistochemistry and RT-PCR. Results: ①Compared with group A, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in lung tissues of groups B, C and D were increased significantly at the 7th, 14th and 28th day(all P<0.05), which reached highest level at the 28th day. However, the mRNA and protein expression levels of VE-CAD were decreased significantly at the corresponding time (P<0.05), which reached lowest level at 28th day. ②Compared with group B, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in groups C and D were decreased at the 7th, 14th and 28th day (all P<0.05), which were decreased more obviously in group D at the 28th day. However, the mRNA and protein expression levels of VE-CAD were increased at the corresponding time (all P<0.05), which were increased more obviously in group D at the 28th day. Conclusion: Simvastatin can reduce the degree of pulmonary fibrosis in rats through inhibiting the process of EnMT, which can enhance the expression of VE-cad and reduce the expression of VIM and α-SMA.


Assuntos
Fibrose Pulmonar , Sinvastatina , Animais , Bleomicina , Pulmão , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(6): 577-583, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34821087

RESUMO

Objective: To study the role of Notch-1/Twist-1 axis in the process of epithelial-mesenchymal transition (EMT) of type II alveolar epithelial cells in pulmonary fibrosis (PF) and hope to provide a new theoretical basis for the pathogenesis of PF. Methods: Thirty rats were randomly divided into control group and bleomycin (BLM) group, 15 rats in each group. The PF rat model was induced by intratracheal injection of BLM (7 500 U/kg). Excised inferior lobe of left lung was fixed in 10% formalin for HE staining, Masson staining and transforming growth factor-beta 1 (TGF-ß1) immunohistochemistry staining after BLM injection for 28 days. The cultured type II alveolar epithelial cells (RLE-6TN) were divided into 4 groups (Control group, transforming growth factor-beta 1 (TGF-ß1) group, Notch-1 negative control siRNA (NC siRNA, 100 pmol/L) group and Notch-1 siRNA (100 pmol/L) group), each group was established nine holes. The cells were treated with TGF-ß1 (5.0 ng/ml) for 24 h following NC siRNA or Notch-1 siRNA for 48 h. The mRNA and (or) proteins levels of TGF-ß1, collagen I, collagen III, E-Cadherin, zonula occludens-1 (ZO-1), Vimentin, E-Cadherin, Notch-1, Notch-1 intracellular domain (NICD), Hes-1 and Twist-1 were detected in lung tissue and type II alveolar epithelial cells. Results: In vivo, compared with the control group, the alveolar atrophy, collapse and fusion occurred, alveolar septum widened significantly, and a large number of inflammatory cells infiltrated in the pulmonary interstitial of the rats in the BLM group. And compared with control group, BLM obviously increased collagen deposition and collagen I and collagen III expressions, while the expressions of ZO-1 and E-cadherin were decreased, and the expressions of Vimentin and N-cadherin were increased, and concomitantly with increasing Notch-1, NICD, Hes-1 and Twist-1 expression in lung tissues of rats (P<0.01). In vitro, compared with control group, TGF-ß1 treatment obviously induced collagen I, collagen III, Notch-1, NICD, Hes-1 and Twist-1 expressions, and the expressions of E-cadherin and ZO-1 were decreased and the expressions of Vimentin and N-cadherin were increased(P<0.01). Compared with TGF-ß1 group, Notch-1 siRNA treatment significantly inhibited the expressions of Notch-1, NICD, Hes-1 and Twist-1, and the expressions of E-cadherin and ZO-1 were increased and the expressions of Vimentin and N-cadherin were decreased, and also obviously reduced the expressions of collagen I and collagen III induced by TGF-ß1 (P<0.05 or P<0.01). Conclusion: Notch-1/Twist-1 axis is involved in the EMT process of type II alveolar epithelial cells, suggesting that Notch-1/Twist-1 signaling may be involved in the development of pulmonary fibrosis.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose Pulmonar , Células Epiteliais Alveolares , Animais , Bleomicina , Pulmão , Fibrose Pulmonar/induzido quimicamente , Ratos , Fator de Crescimento Transformador beta1
4.
In Vivo ; 35(6): 3053-3066, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697137

RESUMO

BACKGROUND/AIM: The role of senescence and bone marrow-derived cells in silica-induced pulmonary fibrosis is unknown. MATERIALS AND METHODS: C57BL/6HNsd, p16+/LUC, and tdTOMp16+ mice were intratracheally injected with 200 mg/kg crystalline silica or irradiated (20 Gy) to the thoracic cavity and followed for the development of lung fibrosis. RESULTS: The p16+/LUC mice demonstrated senescence by day 7 after silica exposure. C57BL/6 mice exposed to silica demonstrated upregulation of p16, p21, and tyrosine kinase Fgr by day 7, whereas thoracic irradiation induced p21 and Fgr by day 50 and p16 by day 110. Silica exposed GFP+ bone marrow chimeric C57BL/6 mice demonstrated senescent cells and gfp+/Fgr+ monocyte/macrophages in the lungs on day 21. The Fgr inhibitor TL02-59 abrogated monocyte/macrophages recruitment in in vitro transwell experiments. CONCLUSION: Both silica and radiation exposure induce senescence and upregulate tyrosine kinase Fgr for the recruitment of bone marrow-derived monocyte/macrophages and the development of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Dióxido de Silício , Animais , Medula Óssea , Senescência Celular , Pulmão , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos , Fibrose Pulmonar/induzido quimicamente , Dióxido de Silício/toxicidade
5.
Eur J Pharm Sci ; 167: 106009, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34537373

RESUMO

Pulmonary fibrosis is a chronic progressive lung disease that lacks effective treatments in clinic. It is characterized by repair disorder of epithelial cells, formation of fibroblast foci as well as destruction of alveolar structure. Previously we first determined that parent peptide DR8 (DHNNPQIR-NH2) has anti-fibrotic activity in bleomycin-induced mice. In order to further improve the druggability of DR8, including anti-fibrotic activity, stability and security, the structure-activity relationship was investigated using a series of D-amino acid and alanine scanning analogs of DR8. The results indicated that peptides DR8-3D and DR8-8A exhibited potent anti-fibrotic activity and better stability. Further mechanism research revealed that DR8-3D and DR8-8A ameliorated lung fibrosis by inhibiting TGF-ß1 mediated epithelial-mesenchymal transition process and ERK1/2 signaling pathway in vitro and in vivo. Moreover, we found that anti-fibrotic activity of DR8 was closely related to the residues aspartic acid (Asp)1, histidine (His)2, proline (Pro)5 and glutamine (Gln)6, which suggested that the position of residues asparagine (Asn)3, asparagine (Asn)4, isoleucine (Ile)7 and arginine (Arg)8 could be further modified to optimized its anti-fibrotic effect. Therefore, we consider that DR8-3D and DR8-8A not only could be used as a potential leading compound for the treatment of bleomycin-induced lung fibrosis but also laid a foundation for the development of new anti-fibrotic drugs.


Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Animais , Bleomicina , Transição Epitelial-Mesenquimal , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo
6.
Chin Med J (Engl) ; 134(18): 2175-2185, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34483252

RESUMO

BACKGROUND: Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis, partially by activating lung fibroblasts. However, how macrophages communicate with lung fibroblasts is largely unexplored. Exosomes can mediate intercellular communication, whereas its role in lung fibrogenesis is unclear. Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis. METHODS: In vivo, bleomycin (BLM)-induced lung fibrosis model was established and macrophages infiltration was examined. The effects of GW4869, an exosomes inhibitor, on lung fibrosis were assessed. Moreover, macrophage exosomes were injected into mice to observe its pro-fibrotic effects. In vitro, exosomes derived from angiotensin II (Ang II)-stimulated macrophages were collected. Then, lung fibroblasts were treated with the exosomes. Twenty-four hours later, protein levels of α-collagen I, angiotensin II type 1 receptor (AT1R), transforming growth factor-ß (TGF-ß), and phospho-Smad2/3 (p-Smad2/3) in lung fibroblasts were examined. The Student's t test or analysis of variance were used for statistical analysis. RESULTS: In vivo, BLM-treated mice showed enhanced infiltration of macrophages, increased fibrotic alterations, and higher levels of Ang II and AT1R. GW4869 attenuated BLM-induced pulmonary fibrosis. Mice with exosomes injection showed fibrotic features with higher levels of Ang II and AT1R, which was reversed by irbesartan. In vitro, we found that macrophages secreted a great number of exosomes. The exosomes were taken by fibroblasts and resulted in higher levels of AT1R (0.22 ±â€Š0.02 vs. 0.07 ±â€Š0.02, t = 8.66, P = 0.001), TGF-ß (0.54 ±â€Š0.05 vs. 0.09 ±â€Š0.06, t = 10.00, P < 0.001), p-Smad2/3 (0.58 ±â€Š0.06 vs. 0.07 ±â€Š0.03, t = 12.86, P < 0.001) and α-collagen I (0.27 ±â€Š0.02 vs. 0.16 ±â€Š0.01, t = 7.01, P = 0.002), and increased Ang II secretion (62.27 ±â€Š7.32 vs. 9.56 ±â€Š1.68, t = 12.16, P < 0.001). Interestingly, Ang II increased the number of macrophage exosomes, and the protein levels of Alix (1.45 ±â€Š0.15 vs. 1.00 ±â€Š0.10, t = 4.32, P = 0.012), AT1R (4.05 ±â€Š0.64 vs. 1.00 ±â€Š0.09, t = 8.17, P = 0.001), and glyceraldehyde-3-phosphate dehydrogenase (2.13 ±â€Š0.36 vs. 1.00 ±â€Š0.10, t = 5.28, P = 0.006) were increased in exosomes secreted by the same number of macrophages, indicating a positive loop between Ang II and exosomes production. CONCLUSIONS: Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.


Assuntos
Exossomos , Fibrose Pulmonar , Angiotensina II , Animais , Bleomicina/toxicidade , Fibroblastos , Pulmão , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Receptor Tipo 1 de Angiotensina
7.
Ecotoxicol Environ Saf ; 225: 112757, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34509164

RESUMO

Environmental pollutant cadmium (Cd) can cause macrophage dysfunction, and the imbalance of M1/M2 is involved in the process of tissue fibrosis. In order to explore the effect of subacute CdCl2 exposure on pig lung tissue fibers and its mechanism, based on the establishment of this model, ICP-MS, H&E staining, Masson staining, Immunofluorescence, RT-PCR, and Western Blot methods were used to detect related indicators. The results found that lung tissue fibrosis, Cd content significantly increased, lung tissue ion disturbance, miR-20a-3p down-regulation, M1/M2 imbalance, LXA4/FPR2 content decreased, MDA content increased, NF-κB/NLRP3, TGFß pathway, PPARγ/Wnt pathway activated, and the expression of fibrosis-related factors increased. The above results indicate that subacute CdCl2 exposure increase Cd content in the pig lungs, which leads to M1/M2 imbalance and down-regulates the content of LXA4/FPR2, further activates the oxidative stress/NF-κB/NLRP3 pathway, thereby activating the TGFß and PPARγ/Wnt pathways to induce fibrosis. This study aims to reveal the toxic effects of CdCl2 and will provide new insights into the toxicology of Cd.


Assuntos
NF-kappa B , Fibrose Pulmonar , Animais , Regulação para Baixo , Fibrose , Macrófagos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fibrose Pulmonar/induzido quimicamente , Suínos
8.
Carbohydr Polym ; 273: 118567, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560978

RESUMO

Diffuse alveolar injury and pulmonary fibrosis (PF) are the main causes of death of Covid-19 cases. In this study a low molecular weight fucoidan (LMWF) with unique structural was obtained from Laminaria japonica, and its anti- PF and anti-epithelial-mesenchymal transition (EMT) bioactivity were investigated both in vivo and in vitro. After LWMF treatment the fibrosis and inflammatory factors stimulated by Bleomycin (BLM) were in lung tissue. Immunohistochemical and Western-blot results found the expression of COL2A1, ß-catenin, TGF-ß, TNF-α and IL-6 were declined in mice lung tissue. Besides, the phosphorylation of PI3K and Akt were inhibited by LMWF. In addition, the progression of EMT induced by TGF-ß1 was inhibited by LMWF through down-regulated both TGF-ß/Smad and PI3K/AKT signaling pathways. These data indicate that unique LMWF can protect the lung from fibrosis by weakening the process of inflammation and EMT, and it is a promising therapeutic option for the treatment of PF.


Assuntos
COVID-19/complicações , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Fibrose Pulmonar/complicações , Fibrose Pulmonar/tratamento farmacológico , SARS-CoV-2 , Células A549 , Animais , Bleomicina/efeitos adversos , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/mortalidade , Transdução de Sinais/efeitos dos fármacos
9.
Sci Rep ; 11(1): 18513, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531421

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.


Assuntos
Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Animais , Bleomicina , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Indóis/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/patologia , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia
10.
Arthritis Res Ther ; 23(1): 234, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488870

RESUMO

BACKGROUND: The TßRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFß signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype. METHODS: PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored. RESULTS: Gene expression data were consistent with the downregulation of the PPAR pathway in the TßRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure. CONCLUSIONS: In the TßRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications.


Assuntos
Fibrose Pulmonar , Escleroderma Sistêmico , Animais , Benzotiazóis , Camundongos , Camundongos Transgênicos , PPAR gama , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Transdução de Sinais , Sulfonamidas , Fator de Crescimento Transformador beta
11.
Stem Cell Res Ther ; 12(1): 506, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530920

RESUMO

BACKGROUND: Mesenchymal stromal cells (MSCs) are a potential therapeutic tool for pulmonary fibrosis. However, ex vivo MSC expansion using serum poses risks of harmful immune responses or unknown pathogen infections in the recipients. Therefore, MSCs cultured in serum-free media (SF-MSCs) are ideal for clinical settings; however, their efficacy in pulmonary fibrosis is unknown. Here, we investigated the effects of SF-MSCs on bleomycin-induced pulmonary inflammation and fibrosis compared to those of MSCs cultured in serum-containing media (S-MSCs). METHODS: SF-MSCs and S-MSCs were characterized in vitro using RNA sequence analysis. The in vivo kinetics and efficacy of SF-MSC therapy were investigated using a murine model of bleomycin-induced pulmonary fibrosis. For normally distributed data, Student's t test and one-way repeated measures analysis of variance followed by post hoc Tukey's test were used for comparison between two groups and multiple groups, respectively. For non-normally distributed data, Kruskal-Wallis and Mann-Whitney U tests were used for comparison between groups, using e Bonferroni's correction for multiple comparisons. All tests were two-sided, and P < 0.05 was considered statistically significant. RESULTS: Serum-free media promoted human bone marrow-derived MSC expansion and improved lung engraftment of intravenously administered MSCs in recipient mice. SF-MSCs inhibited the reduction in serum transforming growth factor-ß1 and the increase of interleukin-6 in both the serum and the bronchoalveolar lavage fluid during bleomycin-induced pulmonary fibrosis. SF-MSC administration increased the numbers of regulatory T cells (Tregs) in the blood and lungs more strongly than in S-MSC administration. Furthermore, SF-MSCs demonstrated enhanced antifibrotic effects on bleomycin-induced pulmonary fibrosis, which were diminished by antibody-mediated Treg depletion. CONCLUSIONS: SF-MSCs significantly suppressed BLM-induced pulmonary inflammation and fibrosis through enhanced induction of Tregs into the lungs and corrected the dysregulated cytokine balance. Therefore, SF-MSCs could be a useful tool for preventing pulmonary fibrosis progression without the demerits of serum use.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Medula Óssea , Células Cultivadas , Meios de Cultura Livres de Soro , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/terapia , Linfócitos T Reguladores
12.
PLoS One ; 16(9): e0256756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34492061

RESUMO

There have been no studies on the effects of polyhexamethylene guanidine phosphate (PHMG) after a long period of exposure in the rodent model. We aimed to evaluate long-term lung damage after PHMG exposure using conventional chest computed tomography (CT) and histopathologic analysis in a rat model. A PHMG solution was intratracheally administrated to 24 male rats. At 8, 26, and 52 weeks after PHMG instillation, conventional chest CT was performed in all rats and both lungs were extracted for histopathologic evaluation. At 52 weeks after PHMG instillation, four carcinomas had developed in three of the eight rats (37.5%). Bronchiolo-alveolar hyperplasia and adenoma were found in rats at 8, 26, and 52 weeks post-instillation. The number of bronchiolo-alveolar hyperplasia significantly increased over time (P-value for trend< 0.001). The severity of lung fibrosis and fibrosis scores significantly increased over time (P-values for trend = 0.002 and 0.023, respectively). Conventional chest CT analysis showed that bronchiectasis and linear density scores suggestive of fibrosis significantly increased over time (P-value for trend < 0.001). Our study revealed that one instillation of PHMG in a rat model resulted in lung carcinomas and progressive and irreversible fibrosis one year later based on conventional chest CT and histopathologic analysis. PHMG may be a lung carcinogen in the rat model.


Assuntos
Guanidinas/farmacologia , Pneumopatias/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/diagnóstico , Animais , Modelos Animais de Doenças , Guanidinas/toxicidade , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/induzido quimicamente , Pneumopatias/diagnóstico , Pneumopatias/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Ratos , Tórax/diagnóstico por imagem , Tórax/efeitos dos fármacos , Tórax/patologia , Tomografia Computadorizada por Raios X
13.
J Transl Med ; 19(1): 349, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399790

RESUMO

BACKGROUND: Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. METHODS: The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-ß1)-induced differentiated lung fibroblasts were used for in vitro models. RESULTS: At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2-10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-ß1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. CONCLUSIONS: In this study, we identified that metformin might be a potential drug for silicosis treatment.


Assuntos
Metformina , Fibrose Pulmonar , Proteínas Quinases Ativadas por AMP , Animais , Transição Epitelial-Mesenquimal , Fibroblastos , Humanos , Pulmão , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Dióxido de Silício/toxicidade , Fator de Crescimento Transformador beta1
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 308-312, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374245

RESUMO

Objective: To investigate the effects of interleukin 11 (IL-11) antagonist on bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: C57BL/6 mice were randomly divided into the control group, IL-11 antagonist group, BLM group, and BLM + IL-11 antagonist group (30 in each group). Mice in the BLM group and BLM + IL-11 antagonist group were injected with BLM at the dose of 1.5 mg/kg to induce pulmonary fibrosis. The IL-11 antagonist IL-11 Rα FC (2.5 mg/kg) was administered via the tail vein to the mice in the IL-11 antagonist group and BLM + IL-11 antagonist group every 3 days from the BLM injection. The survival status of the mice was observed. On the 21st day after modeling, HE staining, Masson staining, and Ashcroft score were used to evaluate the degree of pulmonary fibrosis. The content of hydroxyproline (HYP) in lung tissue was determined by the alkaline hydrolysis method. The gene and protein expressions of Collagen I, Collagen III, and α-SMA in lung tissues were detected by real-time PCR and Western blot, respectively. TGF-ß1 content in lung tissue was determined by enzyme-linked immunosorbent assay. Results: Compared with the control group, BLM reduced the survival rate, destructed the lung tissue, and increased the gene and protein expressions of Collagen I, Collagen III, α-SMA, and the content of TGF-ß1 in lung tissue. While, IL-11 Rα Fc treatment improved the survival rate of BLM-induced pulmonary mice, reduced pathological changes, and hydroxyproline content in lung tissue. IL-11 Rα Fc also reduced Collagen I, Collagen III, and α-SMA mRNA and protein expression in the lungs of BLM-treated mice, as well as TGF-ß1 content. Conclusion: The IL-11 antagonist alleviates BLM-induced pulmonary fibrosis in mice, which provides a new idea for the clinical treatment of pulmonary fibrosis.


Assuntos
Interleucina-11 , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1
15.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445540

RESUMO

Exposure to hydrochloric acid (HCl) represents a threat to public health. Children may inhale higher doses and develop greater injury because of their smaller airways and faster respiratory rate. We have developed a mouse model of pediatric exposure to HCl by intratracheally instilling p24 mice (mice 24 days old; 8-10 g) with 2 µL/g 0.1 N HCl, and compared the profile of lung injury to that in HCl-instilled adults (10 weeks old; 25-30 g) and their age-matched saline controls. After 30 days, alveolar inflammation was observed with increased proteinosis and mononuclear cells in the bronchoalveolar lavage fluid (BALF) in both HCl-instilled groups. Young p24 animals-but not adults-exhibited higher NLR family pyrin domain containing 3 (NLRP3) inflammasome levels. Increased amounts of Transforming Growth Factor-ß (TGF-ß) mRNA and its intracellular canonical and non-canonical pathways (p-Smad2 and p-ERK) were found in the lungs of both young and adult HCl-instilled mice. Constitutive age-related differences were observed in the levels of heat shock protein family (HSP70 and HSP90). HCl equally provoked the deposition of collagen and fibronectin; however, significant age-dependent differences were observed in the increase in elastin and tenascin C mRNA. HCl induced pulmonary fibrosis with an increased Ashcroft score, which was higher in adults, and a reduction in alveolar Mean Alveolar Linear Intercept (MALI). Young mice developed increased Newtonian resistance (Rn) and lower PV loops, while adults showed a higher respiratory system resistance and elastance. This data indicate that young p24 mice can suffer long-term complications from a single exposure to HCl, and can develop chronic lung injury characterized by a stronger persistent inflammation and lesser fibrotic pattern, mostly in the airways, differently from adults. Further data are required to characterize HCl time- and dose-dependent injury in young animals and to identify new key-molecular targets.


Assuntos
Lesão Pulmonar Aguda/patologia , Envelhecimento , Líquido da Lavagem Broncoalveolar/química , Ácido Clorídrico/toxicidade , Inflamação/patologia , Fibrose Pulmonar/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente
16.
Stem Cell Res Ther ; 12(1): 471, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425896

RESUMO

BACKGROUND: Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair. However, little is known about lung-resident ALDHbr. This study was performed to clarify the characteristics of lung-resident ALDHbr cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis. METHODS: The characteristics of lung-resident/nonhematopoietic (CD45-) ALDHbr cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45-/ALDHbr for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45-/ALDHbr cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice. RESULTS: Lung CD45-/ALDHbr showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45-/ALDHbr cell population, and especially its CD45-/ALDHbr/PDGFRα+ subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45-/ALDHbr cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45-/ALDHbr/PDGFRα+ population was more remarkable in aged mice than in young mice. CONCLUSIONS: Our results strongly suggest that the lung expression of ALDH and lung-resident CD45-/ALDHbr cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45-/ALDHbr cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment.


Assuntos
Fibrose Pulmonar , Células-Tronco , Aldeído Desidrogenase , Animais , Bleomicina/toxicidade , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/terapia
17.
Sci Rep ; 11(1): 16525, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400742

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-ß and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-ß induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-ß and angiotensin II synergistically induced TGF-ß, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.


Assuntos
Ergocalciferóis/uso terapêutico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Vitamina D/uso terapêutico , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensinogênio/metabolismo , Animais , Bleomicina , Modelos Animais de Doenças , Ergocalciferóis/farmacologia , Losartan/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Vitamina D/farmacologia
18.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445094

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-ß and epithelial-mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-ß-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-ß1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-ß signaling pathways and may be a novel drug candidate for pulmonary fibrosis.


Assuntos
Flavonoides/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Bleomicina , Linhagem Celular , Transição Epitelial-Mesenquimal , Flavonoides/farmacologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
19.
Pulm Pharmacol Ther ; 70: 102057, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34425215

RESUMO

Pulmonary fibrosis is a progressive disease with poor prognosis and limited therapeutic options. In this study, we evaluated the potential therapeutic effects of CG223, a novel inhibitor of bromodomain and extra-terminal motif (BET) proteins, on pulmonary fibrosis by focusing on the transforming growth factor-ß1 (TGF-ß1) pathway. In a murine model of bleomycin-induced pulmonary fibrosis, CG223 attenuated fibrosis while reducing the infiltration of inflammatory cells into the lungs. Fibroblasts expressing BRD4, a member of the BET protein family, were enriched in the tissue regions corresponding to bleomycin-induced fibrotic lesions. Additionally, pulmonary fibroblasts isolated from bleomycin-instilled mice showed a significantly increased association of BRD4 with the promoters of two pro-fibrotic genes linked to the entry into the TGF-ß1 autocrine/paracrine loop, thrombospondin 1 (Thbs1) and integrin ß3 (Itgb3), as well as with the promoter of a myofibroblast marker gene, actin alpha 2 (Acta2). Subsequent in vitro studies with murine primary lung fibroblasts showed that the mRNA induction of Thbs1, Itgb3, and Acta2 by TGF-ß1 can be inhibited by CG223 in a dose-dependent manner. Taken together, CG223-induced BRD4 inhibition suppressed lung fibrogenesis by affecting multiple genes, including those involved in the triggering of the TGF-ß1 autocrine/paracrine loop.


Assuntos
Bleomicina , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Fibroblastos , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fatores de Transcrição , Fator de Crescimento Transformador beta1/genética
20.
Stem Cell Res Ther ; 12(1): 397, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256845

RESUMO

BACKGROUND: Pulmonary fibrosis (PF) is a growing clinical problem with limited therapeutic options. Human umbilical cord mesenchymal stromal cell (hucMSC) therapy is being investigated in clinical trials for the treatment of PF patients. However, little is known about the underlying molecular and cellular mechanisms of hucMSC therapy on PF. In this study, the molecular and cellular behavior of hucMSC was investigated in a bleomycin-induced mouse PF model. METHODS: The effect of hucMSCs on mouse lung regeneration was determined by detecting Ki67 expression and EdU incorporation in alveolar type 2 (AT2) and lung fibroblast cells. hucMSCs were transfected to express the membrane localized GFP before transplant into the mouse lung. The cellular behavior of hucMSCs in mouse lung was tracked by GFP staining. Single cell RNA sequencing was performed to investigate the effects of hucMSCs on gene expression profiles of macrophages after bleomycin treatment. RESULTS: hucMSCs could alleviate collagen accumulation in lung and decrease the mortality of mouse induced by bleomycin. hucMSC transplantation promoted AT2 cell proliferation and inhibited lung fibroblast cell proliferation. By using single cell RNA sequencing, a subcluster of interferon-sensitive macrophages (IFNSMs) were identified after hucMSC infusion. These IFNSMs elevate the secretion of CXCL9 and CXCL10 following hucMSC infusion and recruit more Treg cells to the injured lung. CONCLUSIONS: Our study establishes a link between hucMSCs, macrophage, Treg, and PF. It provides new insights into how hucMSCs interact with macrophage during the repair process of bleomycin-induced PF and play its immunoregulation function.


Assuntos
Células-Tronco Mesenquimais , Fibrose Pulmonar , Animais , Humanos , Macrófagos , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/terapia , Linfócitos T Reguladores , Cordão Umbilical
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