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1.
Methods Mol Biol ; 2582: 309-321, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36370359

RESUMO

Approximately 45% of the deaths in the developed world result from conditions with a fibrotic component. Although no specific, focused anti-fibrotic therapies have been approved for clinical use, a long-standing concept is that targeting CCN proteins may be useful to treat fibrosis. Herein, we summarize current data supporting the concept that targeting CCN2 may be a viable anti-fibrotic approach to treat scleroderma. Testing this hypothesis has been made possible by using a mouse model of inflammation-driven skin and lung fibrosis.


Assuntos
Fibrose Pulmonar , Escleroderma Sistêmico , Animais , Bleomicina/efeitos adversos , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibrose , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Pele/metabolismo , Modelos Animais de Doenças , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo
2.
Toxicol Lett ; 372: 36-44, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36309172

RESUMO

Silicosis is a fibrotic lung disease caused by the inhalation of free crystalline silica. Its pathogenesis is extremely complex and involves a variety of cells. Exosomes emerge as a favorable candidate for communication between cells. LncRNA is a major component transported by exosomes in many inflammatory diseases. However, the role of exosomal lncRNA in the pathogenesis of silicosis is still unclear. In this study, the decreased expression of a novel exosomal lncRNA MSTRG.91634.7 in silicosis patients was identified according to high-throughput sequencing. Then, this macrophage-derived exosomal lncRNA MSTRG.91634.7 could regulate the fibroblast's activation by targeting PINK1 in a co-culture system of THP-1 and MRC-5. Finally, the mouse was exposed to 3 mg/50 µL silica to set up the silicosis model. AAV-ov-Pink1 was intratracheally injected to overexpress PINK1 in mice lungs. Our results suggested that PINK1, the target protein of lncRNA MSTRG.91634.7, participated in restricting the silica-induced lung inflammation and fibrosis in mice.


Assuntos
Fibrose Pulmonar , RNA Longo não Codificante , Silicose , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Dióxido de Silício/toxicidade , Silicose/metabolismo , Macrófagos/metabolismo , Fibroblastos/metabolismo , Proteínas Quinases , Pulmão/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
3.
Cytokine ; 161: 156060, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36219898

RESUMO

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.


Assuntos
Insuficiência Cardíaca , Fibrose Pulmonar , Ratos , Animais , Receptores CCR2/metabolismo , Monócitos/metabolismo , Fibrose Pulmonar/metabolismo , Estudos Transversais , Quimiocina CCL2/metabolismo , Pulmão/metabolismo , Proteínas Quimioatraentes de Monócitos/metabolismo , Insuficiência Cardíaca/patologia , Dispneia
5.
BMC Pulm Med ; 22(1): 458, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456932

RESUMO

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fatores de Risco
6.
Int Immunopharmacol ; 113(Pt A): 109409, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36461602

RESUMO

Nintedanib is an effective treatment for pulmonary fibrosis (PF), but the exact mechanism by which this agent works to delay the progression of PF remains unclear. In this study, we explored whether nintedanib alleviates PF at least partially by inhibiting the focal adhesion kinase (FAK)/ERK/S100A4 signalling pathway. Bleomycin (BLM) was used to induce PF in a mouse model, and human fetal lung fibroblast 1 (HFL-1) cells were exposed to transforming growth factor-ß 1 (TGF-ß1) to create an in vitro model of PF. In both models, nintedanib was administered either alone or in conjunction with a FAK vector. In mouse lung tissues, histopathology, inflammatory factor levels, and collagen content were assessed; in HFL-1 cells, HFL-1 activity was assessed, along with collagen I, collagen III, and α-SMA levels. Both mouse tissue and HFL-1 cells were examined for levels of indices associated with extracellular matrix and the FAK/ERK/S100A4 signalling pathway. In mice exposed to BLM, lung inflammation and extracellular matrix deposition were significantly increased. These factors were alleviated by nintedanib treatment but were aggravated by overexpression of FAK. In HFL-1 cells, nintedanib inhibited HFL-1 activity and collagen I, collagen III, and α-SMA levels, whereas overexpression of FAK produced the opposite effect. In both tissues and cells, the FAK/ERK/S100A4 signalling pathway was activated, but nintedanib was able to suppress this pathway. These results suggest that nintedanib alleviates PF by inhibiting the FAK/ERK/S100A4 signalling pathway both in vivo and in vitro.


Assuntos
Fibrose Pulmonar , Humanos , Camundongos , Animais , Proteína-Tirosina Quinases de Adesão Focal , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Indóis/farmacologia , Indóis/uso terapêutico , Sistema de Sinalização das MAP Quinases , Bleomicina , Colágeno Tipo I , Proteína A4 de Ligação a Cálcio da Família S100
7.
RMD Open ; 8(2)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36328401

RESUMO

OBJECTIVES: Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. METHODS: Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. RESULTS: Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. CONCLUSION: Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.


Assuntos
Fibrose Pulmonar , Escleroderma Sistêmico , Humanos , Estados Unidos , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/complicações , Pontuação de Propensão , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos
8.
Front Immunol ; 13: 1021102, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341363

RESUMO

Acute lung injury (ALI) is significantly associated with morbidity and mortality in patients with critical diseases. In recent years, studies have identified that mesenchymal stem/stromal cells (MSCs) ameliorate ALI and pulmonary fibrosis. However, the mechanism underlying this outcome in ALI has not yet been investigated. In this study, RNA sequencing technology was used to analyze the gene expression profile of lung tissue in lipopolysaccharide (LPS)-induced ALI rats following treatment with human umbilical cord MSC (HUCMSC). Differential expression analyses, gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, protein-protein interaction network identification, and hub gene analysis were also performed. HUCMSC treatment decreased inflammatory factor production and alveolar exudates, and attenuated lung damage in LPS-induced ALI rats. The RNA-Seq data indicated that HUCMSC treatment activated the IL-17, JAK-STAT, NF-κB, and TNF-α signaling pathways, increased oxygen transport, and decreased extracellular matrix organization. HUCMSC exert beneficial effects on ALI via these signaling pathways by reducing inflammation, inhibiting pulmonary fibrosis, and improving lung ventilation. Moreover, our study further revealed the hub genes (Tbx2, Nkx2-1, and Atf5) and signaling pathways involved in HUCMSC treatment, thus providing novel perspectives for future research into the molecular mechanisms underlying cell treatment of ALI. HUCMSC can regulate multiple genes and signaling pathways, which can prevent LPS-induced lung damage in an ALI rat model.


Assuntos
Lesão Pulmonar Aguda , Células-Tronco Mesenquimais , Fibrose Pulmonar , Humanos , Ratos , Animais , Lipopolissacarídeos/efeitos adversos , Fibrose Pulmonar/metabolismo , Cordão Umbilical , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Células-Tronco Mesenquimais/metabolismo , Análise de Sequência de RNA , RNA/metabolismo
9.
J Transl Med ; 20(1): 523, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371191

RESUMO

BACKGROUND: Pulmonary fibrosis is a chronic progressive fibrotic interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition caused by activated fibroblasts. Increasing evidence shows that matrix stiffness is essential in promoting fibroblast activation and profibrotic changes. Here, we investigated the expression and function of matrix stiffness-regulated ZNF416 in pulmonary fibrotic lung fibroblasts. METHODS: 1 kappa (soft), 60 kappa (stiff) gel-coated coverslips, or transforming growth factor-beta 1 (TGF-ß1)-cultured lung fibroblasts and the gain- or loss- of the ZNF416 function assays were performed in vitro. We also established two experimental pulmonary fibrosis mouse models by a single intratracheal instillation with 50 mg/kg silica or 6 mg/kg bleomycin (BLM). ZNF416 siRNA-loaded liposomes and TGF-ß1 receptor inhibitor SB431542 were administrated in vivo. RESULTS: Our study identified that ZNF416 could regulate fibroblast differentiation, proliferation, and contraction by promoting the nuclear accumulation of p-Smad2/3. Besides, ZNF416 siRNA-loaded liposome delivery by tail-vein could passively target the fibrotic area in the lung, and co-administration of ZNF416 siRNA-loaded liposomes and SB431542 significantly protects mice against silica or BLM-induced lung injury and fibrosis. CONCLUSION: In this study, our results indicate that mechanosensitive ZNF416 is a potential molecular target for the treatment of pulmonary fibrosis. Strategies aimed at silencing ZNF416 could be a promising approach to fight against pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Animais , Camundongos , Bleomicina , Fibroblastos/metabolismo , Lipossomos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/tratamento farmacológico , RNA Interferente Pequeno/metabolismo , Dióxido de Silício/efeitos adversos , Fator de Crescimento Transformador beta1/metabolismo
10.
Nat Commun ; 13(1): 7114, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402779

RESUMO

Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1-/- fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.


Assuntos
Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Camundongos Endogâmicos C57BL , Fibroblastos/metabolismo , Matriz Extracelular/metabolismo , Bleomicina/toxicidade
11.
Int Immunopharmacol ; 113(Pt B): 109465, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36410185

RESUMO

BACKGROUND: DXM is widely used as an antifibrotic agent due to its protection of the lungs against fibrosis by inhibiting the production of inflammatory mediators. Many studies clearly indicated that the time point at which DXM treatment started, the dose and the duration of intervention are critical for exerting its antifibrotic effect. Exploring the role of DXM in the occurrence and development of PF at different stages is the fundamental purpose of this article. METHODS: Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (5 mg/kg) injection. This experiment was divided into two animal experiments and treated with DXM following or after bleomycin administration respectively. The biochemical, histopathological and molecular alterations were studied in the lung tissues. RESULTS: A long course of low-dose DXM had the ability to ameliorate PF induced by BLM via decreasing inflammation and improving oxidative stress through modulation of TGF-ß/Smad, PI3K/Akt/mTOR and NF-κB signaling pathway. CONCLUSION: Long course of low-dose DXM intake following or after bleomycin administration both had therapeutic effects on pulmonary fibrosis.


Assuntos
Bleomicina , Fibrose Pulmonar , Ratos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Ratos Sprague-Dawley , Fosfatidilinositol 3-Quinases , Dexametasona
12.
Vet Ital ; 58(1): 87-101, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36398675

RESUMO

Pulmonary fibrosis is the end­stage manifestation of wide range of respiratory diseases and during pulmonary fibrosis, pulmonary inflammation and epithelial­mesenchymal transition (EMT) play important roles. Salvianolic acid B (SAB) from the herb Salviae miltiorrhiza has been reported to possess an excellent anti­inflammatory, antifibrotic and antioxidant activity. The present study aimed to investigate the ameliorative effect of SAB on bleomycin induced pulmonary fibrosis in mice. Adult albino mice were divided as SHAM/control group (saline alone), BLM group (bleomycin @ 1mg/kg intratracheally once) and SAB groups (BLM challenged once and SAB administration in three dosages @ 5, 10 and 15 mg/kg intraperitoneally daily for 30 days). Lungs wet/dry ratio and protein concentration in bronchoalveolar lavage fluid, MPO activity, oxidative stress markers, hydroxyproline assay, levels of inflammatory cytokines (TNF­α, IL­6 and TGF­ß1), NF­κB activity, histopathology, immunostaining (E­cadherin, vimentin and alpha ­smooth muscle actin) and ultrastructural changes were studied. SAB showed anti­inflammatory and anti­fibrotic effects through inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition and the expression of several fibrogenic cytokines. SAB also up­regulate E­cadherin and down­regulated vimentin and alpha­smooth muscle actin expression. In conclusion, Salvianolic acid B is effective in alleviating the BLM induced lung fibrosis through suppression of oxidative stress, inflammation, histological, ultrastructural changes and EMT.


Assuntos
Fibrose Pulmonar , Doenças dos Roedores , Camundongos , Animais , Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/veterinária , Vimentina/uso terapêutico , Actinas , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Citocinas/uso terapêutico , Caderinas/uso terapêutico
13.
Ecotoxicol Environ Saf ; 247: 114173, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36326553

RESUMO

The occupational and environmental health safety of rare earths has attracted considerable attention. In China, the rare earth neodymium oxide (Nd2O3) is extensively refined and utilized. However, the mechanisms of Nd2O3-induced lung injury are elusive. In the present study, we found that exposure of mice to Nd2O3 caused an inflammatory reaction and fibrosis in lung tissues, which was in relation to the Nd2O3-induced higher levels of the lncRNA H19 (H19), tumor necrosis factor receptor 1 (TNFRSF1A), p-p65, and p-IKKß and lower levels of miR-29a-3p. Further, in mouse monocyte macrophage leukemia cells (RAW264.7), Nd2O3 induced an inflammatory reaction, increases of H19 and TNFRSF1A levels, decreases of miR-29a-3p levels, and activation of the nuclear factor (NF)-κB signaling pathway. Further, we established that miR-29a-3p regulates TNFRSF1A expression. Up-regulation of miR-29a-3p and down-regulation of H19 blocked the Nd2O3-induced secretion of TNF-α, MIP-1α, and IL-6; the increases of TNFRSF1A levels; and activation of the NF-κB signaling pathway in RAW264.7 cells. Further, in Nd2O3-treated RAW26.4 cells, H19 inhibited the expression of miR-29a-3p, which targets TNFRSF1A, and activated the NF-κB signaling pathway to enhance the expression of TNF-α, MIP-1α, and IL-6. Moreover, for mice, up-regulation of miR-29a-3p reversed lung tissue inflammation, pulmonary fibrosis, and activation of the NF-κB signaling pathway induced by Nd2O3. In sum, the present investigation shows that H19 via miR-29a-3p is involved in lung inflammation and pulmonary fibrosis induced by Nd2O3, which is a mechanism for the Nd2O3-induced lung inflammatory response and pulmonary fibrosis. This information is useful for development of a biomarker of Nd2O3-induced lung injury.


Assuntos
Lesão Pulmonar , MicroRNAs , Pneumonia , Fibrose Pulmonar , RNA Longo não Codificante , Animais , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , RNA Longo não Codificante/genética , NF-kappa B , Quimiocina CCL3 , Fator de Necrose Tumoral alfa , Interleucina-6 , Inflamação/induzido quimicamente , Inflamação/genética , MicroRNAs/genética
14.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361827

RESUMO

Pulmonary fibrosis is becoming an increasingly common pathology worldwide. Unfortunately, this disorder is characterized by a bad prognosis: no treatment is known, and the survival rate is dramatically low. One of the most frequent reasons for pulmonary fibrosis is hypersensitivity pneumonitis (HP). As the main mechanism of pulmonary fibrosis is a pathology of the repair of wounded pulmonary epithelium with a pivotal role in epithelial-mesenchymal transition (EMT), we assumed that EMT silencing could prevent disease development. Because of several biological features including wound healing promotion, an ideal candidate for use in the treatment of pulmonary fibrosis seems to be cathelicidin. The aim of the studies was to understand the influence of cathelicidin on the EMT process occurring during lung fibrosis development in the course of HP. Cathelicidin's impact on EMT was examined in a murine model of HP, wherein lung fibrosis was induced by chronic exposure to extract of Pantoea agglomerans (SE-PA) by real-time PCR and Western blotting. Studies revealed that mouse exposure to cathelicidin did not cause any side changes in the expression of investigated genes/proteins. Simultaneously, cathelicidin administered together or after SE-PA decreased the elevated level of myofibroblast markers (Acta2/α-smooth muscle actin, Cdh2/N-cadherin, Fn1/Fibronectin, Vim/vimentin) and increased the lowered level of epithelial markers (Cdh1/E-cadherin, Ocln/occludin). Cathelicidin provided with SE-PA or after cessation of SE-PA inhalations reduced the expression of EMT-associated factors (Ctnnd1/ß-catenin, Nfkb1/NFκB, Snail1/Snail, Tgfb1/TGFß1 Zeb1/ZEB1, Zeb2/ZEB2) elevated by P. agglomerans. Cathelicidin's beneficial impact on the expression of genes/proteins involved in EMT was observed during and after the HP development; however, cathelicidin was not able to completely neutralize the negative changes. Nevertheless, significant EMT silencing in response to cathelicidin suggested the possibility of its use in the prevention/treatment of pulmonary fibrosis.


Assuntos
Alveolite Alérgica Extrínseca , Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/patologia , Transição Epitelial-Mesenquimal/fisiologia , Modelos Animais de Doenças , Alveolite Alérgica Extrínseca/patologia , Pulmão/patologia
15.
Int J Mol Sci ; 23(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36362112

RESUMO

Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment. The present investigation explored the action of MRS5980, a new, highly potent and selective A3AR agonist, in an established murine model of lung fibrosis. The effects of either vehicle or MRS5980 were studied in mice following intratracheal bleomycin administration. We evaluated the role of the A3AR agonist on lung stiffness, studying the airway resistance to inflation, oxidative stress (8-OHdG and MDA), inflammation, pro- and anti-inflammatory marker levels (IL-1ß, IL-6, TNF-α, IL-10 and IL-17A) and fibrosis establishment, evaluating transforming growth factor (TGF)-ß expression and α-smooth muscle actin (α-SMA) deposition in lungs. Bleomycin administration increased lung stiffness, TGF-ß levels, α-SMA deposition, and inflammatory and oxidative stress markers. The treatment with MRS5980 attenuated all the analyzed functional, biochemical and histopathological markers in a dose-dependent manner. Our findings support the therapeutic potential of A3AR agonists in lung fibrosis by demonstrating reduced disease progression, as indicated by decreased inflammation, TGF-ß expression and fibrotic remodeling.


Assuntos
Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Bleomicina/farmacologia , Camundongos Endogâmicos C57BL , Pulmão/patologia , Fator de Crescimento Transformador beta/metabolismo , Fibroblastos/metabolismo , Fibrose , Inflamação/patologia , Receptores Purinérgicos P1/metabolismo , Adenosina/metabolismo
17.
Pharmacol Res Perspect ; 10(6): e01028, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36426895

RESUMO

Bleomycin-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality in chemotherapy patients. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50 s of 4 and 15 µM, respectively. The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of bleomycin-induced lung fibrosis. Animals were given intraperitoneal bleomycin for 4 weeks and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib) or the clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG-257081 gained weight vs. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. In contrast, prednisolone led to marked increases in lung fibrosis by all metrics. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent bleomycin-induced lung fibrosis in a clinically relevant model of the disease.


Assuntos
Bleomicina , Fibrose Pulmonar , Humanos , Animais , Camundongos , Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Inflamação , Fibroblastos , Prednisolona
18.
Clin Transl Med ; 12(11): e1099, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36336784

RESUMO

BACKGROUND: Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. METHODS: Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin-exposed conditional Ptx3-deficient and PTX3-neutralizing antibody (αPTX3i)-treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44-involved PTX3-induced fibrosis in HFL1 and primary mouse fibroblasts. RESULTS: PTX3 was upregulated in the lungs and plasma of bleomycin-exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin-exposed conditional Ptx3-deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen-expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K-AKT1, NF-κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic-based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin-induced pulmonary fibrosis. CONCLUSIONS: The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.


Assuntos
Lesão Pulmonar , Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Bleomicina/efeitos adversos , Fibrose , Colágeno/efeitos adversos , Colágeno/metabolismo
19.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36430808

RESUMO

Although pulmonary fibrosis (PF) is considered a rare disease, the incidence thereof has increased steadily in recent years, while a safe and effective cure remains beyond reach. In this study, the potential of tocotrienol-rich fractions (TRF) and carotene to alleviate PF was explored. PF was induced in Sprague-Dawley rats via a single intratracheal bleomycin (BLM) (5 mg/kg) instillation. These rats were subsequently treated with TRF, carotene, pirfenidone (Pir) and nintedanib (Nin) for 28 days via gavage administration, whereafter histopathological performance, biochemical functions and molecular alterations were studied in the lung tissues. Our results showed that TRF, carotene, Nin and Pir all ameliorated PF by reducing inflammation and resisting oxidative stress to varying degrees. The related mechanisms involved the TGF-ß1/Smad, PI3K/Akt and NF-κB signaling pathways. Ultimately, our findings revealed that, when combined with TRF, the therapeutic effects of Nin and Pir on PF were enhanced, indicating that TRF may, indeed, provide promising potential for use in combination therapy in the treatment of PF.


Assuntos
Fibrose Pulmonar , Tocotrienóis , Ratos , Animais , Fibrose Pulmonar/metabolismo , Tocotrienóis/farmacologia , Tocotrienóis/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , Carotenoides/uso terapêutico
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(11): 1011-1017, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36328432

RESUMO

Objective To observe the role of connective tissue growth factor (CTGF) and collagen synthesis in anti-pulmonary fibrosis (PF) by Kiwi fruit essence(unsaturated fatty acid of actinidia chinesis planch seed oil)in rats. Methods Sixty male SD rats were randomly divided into control group, model group, Kiwi fruit essence (60, 120, 240 mg/kg) treatment groups, and 5 mg/kg prednisone acetate group, with 10 animals in each group. Rats in control group were intratracheally administered with 9 g/L sodium chloride solution, and animals in other groups were intratracheally administered with bleomycin A5 to establish PF model. From the second day on, rats in the latter 4 groups were intragastrically treated with Kiwi fruit essence of 60, 120 and 240 mg/kg and prednisone acetate of 5 mg/kg, respectively. Rats in control and model groups were treated with 9 g/L sodium chloride solution once a day. All rats were sacrificed on day 28, and then pulmonary tissues were removed. The extent of PF lesions were evaluated using HE and Masson staining. The contents of hydroxyproline (HYP) were measured by a commercial kit. The mRNA expressions of CTGF and α-smooth muscle actin (α-SMA) in pulmonary tissues was detected by quantitative real-time PCR. The protein expressions of CTGF, α-SMA, collagen type 1 (Col1) and Col3 were measured by Western blotting. The protein levels of CTGF were analyzed using immunohistochemical staining. Results Compared with the model group, the alveolitis and PF extent in 60, 120, 240 mg/kg Kiwi fruit essence treatment groups as well as 5 mg/kg prednisone acetate group were significantly alleviated, and the content of HYP and the expression of CTGF, α-SMA, Col1 and Col3 decreased. The changes of above indicators were dose-dependent among the (60, 120, 240) mg/kg Kiwi fruit essence treatment groups. Moreover, the above indicators were found higher in (60, 120) mg/kg Kiwi fruit essence treatment groups than those in 5 mg/kg prednisone acetate group, which, however, showed no significantly difference between 240 mg/kg Kiwi fruit essence treatment group and 5 mg/kg prednisone acetate group. Conclusion Kiwi fruit essence down-regulates CTGF expression and decreases the levels of α-SMA, leading to inhibition of Col1 and Col3 synthesis and alleviation of PF.


Assuntos
Actinidia , Óleos Voláteis , Fibrose Pulmonar , Ratos , Masculino , Animais , Actinidia/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Prednisona , Cloreto de Sódio , Ratos Sprague-Dawley , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Fibrose Pulmonar/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ácidos Graxos Insaturados , Óleos Vegetais/farmacologia , Acetatos
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