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1.
Sci Adv ; 10(24): eado4791, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38865465

RESUMO

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.


Assuntos
Bleomicina , Muco , Nanopartículas , Animais , Nanopartículas/química , Camundongos , Muco/metabolismo , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Modelos Animais de Doenças , Administração por Inalação , Lipídeos/química , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Humanos , Lipossomos
2.
JCI Insight ; 9(11)2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38855869

RESUMO

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.


Assuntos
Biomarcadores , Progressão da Doença , Vesículas Extracelulares , Fibrose Pulmonar , Proteína B Associada a Surfactante Pulmonar , Vesículas Extracelulares/metabolismo , Humanos , Animais , Biomarcadores/sangue , Camundongos , Masculino , Feminino , Fibrose Pulmonar/sangue , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Proteína B Associada a Surfactante Pulmonar/sangue , Proteína B Associada a Surfactante Pulmonar/metabolismo , Pessoa de Meia-Idade , Idoso , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/patologia , Pulmão/metabolismo , Proteômica/métodos , Modelos Animais de Doenças , Prognóstico , Precursores de Proteínas , Proteínas Associadas a Surfactantes Pulmonares
3.
Cells ; 13(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38891078

RESUMO

Pulmonary fibrosis is a chronic, progressive, irreversible lung disease characterized by fibrotic scarring in the lung parenchyma. This condition involves the excessive accumulation of extracellular matrix (ECM) due to the aberrant activation of myofibroblasts in the alveolar environment. Transforming growth factor beta (TGF-ß) signaling is a crucial driver of fibrogenesis because it promotes excessive ECM deposition, thereby leading to scar formation and lung damage. A primary target of TGF-ß signaling in fibrosis is Collagen Triple Helix Repeat Containing 1 (CTHRC1), a secreted glycoprotein that plays a pivotal role in ECM deposition and wound repair. TGF-ß transcriptionally regulates CTHRC1 in response to tissue injury and controls the wound healing response through functional activity. CTHRC1 may also play an essential role in re-establishing and maintaining tissue homeostasis after wound closure by modulating both the TGF-ß and canonical Wnt signaling pathways. This dual function suggests that CTHRC1 regulates tissue remodeling and homeostasis. However, deregulated CTHRC1 expression in pathogenic fibroblasts has recently emerged as a hallmark of fibrosis in multiple organs and tissues. This review highlights recent studies suggesting that CTHRC1 can serve as a diagnostic and prognostic biomarker for fibrosis in idiopathic pulmonary fibrosis, systemic sclerosis, and post-COVID-19 lung fibrosis. Notably, CTHRC1 expression is responsive to antifibrotic drugs that target the TGF-ß pathway, such as pirfenidone and bexotegrast, indicating its potential as a biomarker of treatment success. These findings suggest that CTHRC1 may present new opportunities for diagnosing and treating patients with lung fibrosis.


Assuntos
Proteínas da Matriz Extracelular , Fibroblastos , Fibrose Pulmonar , Humanos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas da Matriz Extracelular/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Animais , Fator de Crescimento Transformador beta/metabolismo , Matriz Extracelular/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo
4.
Int J Mol Sci ; 25(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38892317

RESUMO

The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.


Assuntos
Modelos Animais de Doenças , Camundongos Knockout , Escleroderma Sistêmico , Receptor 7 Toll-Like , Receptor Toll-Like 9 , Animais , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/genética , Receptor Toll-Like 9/metabolismo , Receptor Toll-Like 9/genética , Camundongos , Bleomicina/efeitos adversos , Camundongos Endogâmicos BALB C , Citocinas/metabolismo , Pele/patologia , Pele/metabolismo , Pele/imunologia , Fibrose , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/etiologia , Glicoproteínas de Membrana
5.
PLoS One ; 19(6): e0305409, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38875245

RESUMO

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis caused by lung injury is accompanied by varying degrees of inflammation, and diazepam can reduce the levels of inflammatory factors. Therefore, the purpose of this study was to determine whether diazepam can inhibit inflammation and ameliorate pulmonary fibrosis by regulating the let-7a-5p/myeloid differentiation factor 88 (MYD88) axis. METHODS: Lipopolysaccharide (LPS) was used to induce cell pyroptosis in an animal model of pulmonary fibrosis. After treatment with diazepam, changes in cell proliferation and apoptosis were observed, and the occurrence of inflammation and pulmonary fibrosis in the mice was detected. RESULTS: The results showed that LPS can successfully induce cell pyroptosis and inflammatory responses and cause lung fibrosis in mice. Diazepam inhibits the expression of pyroptosis-related factors and inflammatory factors; moreover, it attenuates the occurrence of pulmonary fibrosis in mice. Mechanistically, diazepam can upregulate the expression of let-7a-5p, inhibit the expression of MYD88, and reduce inflammation and inhibit pulmonary fibrosis by regulating the let-7a-5p/MYD88 axis. CONCLUSION: Our findings indicated that diazepam can inhibit LPS-induced pyroptosis and inflammatory responses and alleviate pulmonary fibrosis in mice by regulating the let-7a-5p/MYD88 axis.


Assuntos
Diazepam , Inflamação , Lipopolissacarídeos , MicroRNAs , Fator 88 de Diferenciação Mieloide , Fibrose Pulmonar , Piroptose , Animais , Piroptose/efeitos dos fármacos , Camundongos , Diazepam/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos
6.
Respir Res ; 25(1): 242, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877465

RESUMO

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.


Assuntos
Alcaloides , Diferenciação Celular , Fibroblastos , Camundongos Endogâmicos C57BL , Miofibroblastos , Fibrose Pulmonar , Dióxido de Silício , Silicose , Animais , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Alcaloides/farmacologia , Dióxido de Silício/toxicidade , Camundongos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Diferenciação Celular/efeitos dos fármacos , Silicose/patologia , Silicose/metabolismo , Silicose/tratamento farmacológico , Masculino
7.
Biomed Pharmacother ; 176: 116823, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38834008

RESUMO

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-ß1/SMAD pathway.


Assuntos
Bleomicina , Extratos Vegetais , Fibrose Pulmonar , Transdução de Sinais , Proteínas Smad , Espectrometria de Massas em Tandem , Fator de Crescimento Transformador beta1 , Ziziphus , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Masculino , Ziziphus/química , Camundongos , Extratos Vegetais/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Smad/metabolismo , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Transdução de Sinais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Metabolômica/métodos , Anti-Inflamatórios/farmacologia , Espectrometria de Massa com Cromatografia Líquida
8.
BMC Pulm Med ; 24(1): 271, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844923

RESUMO

BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.


Assuntos
Análise da Randomização Mendeliana , Metabolômica , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Canadá/epidemiologia , Estudo de Associação Genômica Ampla , Biomarcadores/metabolismo , Biomarcadores/sangue , Progressão da Doença , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Feminino
9.
Front Endocrinol (Lausanne) ; 15: 1379521, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38854692

RESUMO

At present, pulmonary fibrosis (PF) is a prevalent and irreversible lung disease with limited treatment options, and idiopathic pulmonary fibrosis (IPF) is one of its most common forms. Recent research has highlighted PF as a metabolic-related disease, including dysregulated iron, mitochondria, lipid, and glucose homeostasis. Systematic reports on the regulatory roles of glucose metabolism in PF are rare. This study explores the intricate relationships and signaling pathways between glucose metabolic processes and PF, delving into how key factors involved in glucose metabolism regulate PF progression, and the interplay between them. Specifically, we examined various enzymes, such as hexokinase (HK), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), pyruvate kinase (PK), and lactate dehydrogenase (LDH), illustrating their regulatory roles in PF. It highlights the significance of lactate, alongside the role of pyruvate dehydrogenase kinase (PDK) and glucose transporters (GLUTs) in modulating pulmonary fibrosis and glucose metabolism. Additionally, critical regulatory factors such as transforming growth factor-beta (TGF-ß), interleukin-1 beta (IL-1ß), and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were discussed, demonstrating their impact on both PF and glucose metabolic pathways. It underscores the pivotal role of AMP-activated protein kinase (AMPK) in this interplay, drawing connections between diabetes mellitus, insulin, insulin-like growth factors, and peroxisome proliferator-activated receptor gamma (PPARγ) with PF. This study emphasizes the role of key enzymes, regulators, and glucose transporters in fibrogenesis, suggesting the potential of targeting glucose metabolism for the clinical diagnosis and treatment of PF, and proposing new promising avenues for future research and therapeutic development.


Assuntos
Glucose , Glicólise , Fibrose Pulmonar , Humanos , Glucose/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Transdução de Sinais
10.
Sci Rep ; 14(1): 13158, 2024 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849437

RESUMO

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.


Assuntos
Pulmão , Respiração Artificial , Síndrome do Desconforto Respiratório , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/fisiopatologia , Idoso , Pulmão/fisiopatologia , Pulmão/patologia , Elasticidade , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Fibrose Pulmonar/metabolismo , Mecânica Respiratória/fisiologia , Estresse Mecânico , Doenças Pulmonares Intersticiais/fisiopatologia , Modelos Teóricos
11.
Pestic Biochem Physiol ; 202: 105971, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879290

RESUMO

Paraquat (PQ) poisoning leads to irreversible fibrosis in the lungs with high mortality and no known antidote. In this study, we investigated the effect of the SET and MYND domain containing 2 (SMYD2) on PQ-induced pulmonary fibrosis (PF) and its potential mechanisms. We established an in vivo PQ-induced PF mouse model by intraperitoneal injection of PQ (20 mg/kg) and in vitro PQ (25 µM)-injured MLE-12 cell model. On the 15th day of administration, tissue injury, inflammation, and fibrosis in mice were evaluated using various methods including routine blood counts, blood biochemistry, blood gas analysis, western blotting, H&E staining, ELISA, Masson staining, and immunofluorescence. The findings indicated that AZ505 administration mitigated tissue damage, inflammation, and collagen deposition in PQ-poisoned mice. Mechanistically, both in vivo and in vitro experiments revealed that AZ505 treatment suppressed the PQ-induced epithelial-mesenchymal transition (EMT) process by downregulating GLI pathogenesis related 2 (GLIPR2) and ERK/p38 pathway. Further investigations demonstrated that SMYD2 inhibition decreased GLIPR2 methylation and facilitated GLIPR2 ubiquitination, leading to GLIPR2 destabilization in PQ-exposed MLE-12 cells. Moreover, rescue experiments conducted in vitro demonstrated that GLIPR2 overexpression eliminated the inhibitory effect of AZ505 on the ERK/p38 pathway and EMT. Our results reveal that the SMYD2 inhibitor AZ505 may act as a novel therapeutic candidate to suppress the EMT process by modulating the GLIPR2/ERK/p38 axis in PQ-induced PF.


Assuntos
Transição Epitelial-Mesenquimal , Paraquat , Fibrose Pulmonar , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Camundongos , Paraquat/toxicidade , Masculino , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética
12.
J Nanobiotechnology ; 22(1): 331, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867284

RESUMO

BACKGROUND: In the context of increasing exposure to silica nanoparticles (SiNPs) and ensuing respiratory health risks, emerging evidence has suggested that SiNPs can cause a series of pathological lung injuries, including fibrotic lesions. However, the underlying mediators in the lung fibrogenesis caused by SiNPs have not yet been elucidated. RESULTS: The in vivo investigation verified that long-term inhalation exposure to SiNPs induced fibroblast activation and collagen deposition in the rat lungs. In vitro, the uptake of exosomes derived from SiNPs-stimulated lung epithelial cells (BEAS-2B) by fibroblasts (MRC-5) enhanced its proliferation, adhesion, and activation. In particular, the mechanistic investigation revealed SiNPs stimulated an increase of epithelium-secreted exosomal miR-494-3p and thereby disrupted the TGF-ß/BMPR2/Smad pathway in fibroblasts via targeting bone morphogenetic protein receptor 2 (BMPR2), ultimately resulting in fibroblast activation and collagen deposition. Conversely, the inhibitor of exosomes, GW4869, can abolish the induction of upregulated miR-494-3p and fibroblast activation in MRC-5 cells by the SiNPs-treated supernatants of BEAS-2B. Besides, inhibiting miR-494-3p or overexpression of BMPR2 could ameliorate fibroblast activation by interfering with the TGF-ß/BMPR2/Smad pathway. CONCLUSIONS: Our data suggested pulmonary epithelium-derived exosomes serve an essential role in fibroblast activation and collagen deposition in the lungs upon SiNPs stimuli, in particular, attributing to exosomal miR-494-3p targeting BMPR2 to modulate TGF-ß/BMPR2/Smad pathway. Hence, strategies targeting exosomes could be a new avenue in developing therapeutics against lung injury elicited by SiNPs.


Assuntos
Colágeno , Epigênese Genética , Exossomos , Fibroblastos , Pulmão , MicroRNAs , Nanopartículas , Transdução de Sinais , Dióxido de Silício , Fator de Crescimento Transformador beta , Exossomos/metabolismo , Animais , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Dióxido de Silício/química , Transdução de Sinais/efeitos dos fármacos , Ratos , Pulmão/metabolismo , Pulmão/patologia , Colágeno/metabolismo , Humanos , Nanopartículas/química , MicroRNAs/metabolismo , MicroRNAs/genética , Linhagem Celular , Fator de Crescimento Transformador beta/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Masculino , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Ratos Sprague-Dawley , Epitélio/metabolismo , Epitélio/efeitos dos fármacos
13.
Int Immunopharmacol ; 136: 112368, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823175

RESUMO

Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and pulmonary interstitial fibrosis. Currently, there are no effective treatments available. Recent research suggests that the Integrin ß1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin ß1 inhibitor) and BYL-719 (PI3K inhibitor) on silicosis rats at 28 and 56 days after silica exposure. Histopathological analysis of rat lung tissue was performed using H&E staining and Masson staining. Immunohistochemistry, Western blotting, and qRT-PCR were employed to assess the expression of markers associated with epithelial-mesenchymal transition (EMT), fibrosis, and the Integrin ß1/ILK/PI3K pathway in lung tissue. The results showed that Echistatin, BYL 719 or their combination up-regulated the expression of E-cadherin and down-regulated the expression of Vimentin and extracellular matrix (ECM) components, including type I and type III collagen. The increase of Snail, AKT and ß-catenin in the downstream Integrin ß1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinß1 /ILK/PI3K signaling pathway. This indicates that the Integrin ß1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.


Assuntos
Transição Epitelial-Mesenquimal , Integrina beta1 , Fosfatidilinositol 3-Quinases , Proteínas Serina-Treonina Quinases , Fibrose Pulmonar , Transdução de Sinais , Dióxido de Silício , Silicose , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Integrina beta1/metabolismo , Integrina beta1/genética , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Masculino , Dióxido de Silício/toxicidade , Silicose/metabolismo , Silicose/patologia , Silicose/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Ratos Sprague-Dawley
14.
Sci Adv ; 10(25): eadm9817, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38896611

RESUMO

Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated CMKLR1 expression as a transient signature of monocyte-derived macrophages (MDMφ) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMφ as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1-targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high CMKLR1 expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases.


Assuntos
Fibrose Pulmonar Idiopática , Pneumonia , Animais , Humanos , Camundongos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/diagnóstico por imagem , Pneumonia/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Biomarcadores , Modelos Animais de Doenças , Tomografia por Emissão de Pósitrons/métodos , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Bleomicina , Pulmão/patologia , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Masculino , Feminino , Camundongos Endogâmicos C57BL
16.
BMC Pulm Med ; 24(1): 229, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730387

RESUMO

BACKGROUND: Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most prevalent form. In traditional Chinese medicine, various disorders are treated using Sinomenine (SIN). The SIN's strategy for PF defense is unclear. METHODS: Bleomycin (BLM) was used to induce PF, after which inflammatory factors, lung histological alterations, and the TGF-/Smad signaling pathway were assessed. By administering various dosages of SIN and the TGF- receptor inhibitor SB-431,542 to human embryonic lung fibroblasts (HFL-1) and A549 cells, we were able to examine proliferation and migration as well as the signaling molecules implicated in Epithelial-Mesenchymal Transition (EMT) and Extra-Cellular Matrix (ECM). RESULTS: In vivo, SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice. In vitro, SIN inhibited the migration and proliferation by inhibiting TGF-ß1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the myofibroblasts (FMT) of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins. CONCLUSION: SIN attenuated PF by down-regulating TGF-ß/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.


Assuntos
Morfinanos , Proteínas Proto-Oncogênicas c-akt , Fibrose Pulmonar , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Células A549 , Bleomicina , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfinanos/farmacologia , Morfinanos/uso terapêutico , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
Mol Med ; 30(1): 72, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822247

RESUMO

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.


Assuntos
Bleomicina , DNA Glicosilases , Modelos Animais de Doenças , Macrófagos , Mitofagia , Proteínas Quinases , Fibrose Pulmonar , Animais , Mitofagia/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , DNA Glicosilases/metabolismo , DNA Glicosilases/genética , Camundongos , Macrófagos/metabolismo , Proteínas Quinases/metabolismo , Bleomicina/efeitos adversos , Masculino , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ativação de Macrófagos , Humanos , Quinazolinonas
18.
Int J Mol Sci ; 25(10)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38791282

RESUMO

We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of α-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGFß, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.


Assuntos
Actinas , Bleomicina , Fibroblastos , Camundongos Knockout , Fibrose Pulmonar , Proteínas Ativadoras de ras GTPase , Animais , Bleomicina/efeitos adversos , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Actinas/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/genética , Camundongos , Fibroblastos/metabolismo , Fibroblastos/patologia , Pulmão/patologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Polimerização , Modelos Animais de Doenças
19.
Mol Med ; 30(1): 70, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38789926

RESUMO

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.


Assuntos
Bleomicina , Bortezomib , Linfócitos T CD4-Positivos , Quimiocina CXCL16 , Modelos Animais de Doenças , Fibrose Pulmonar , Receptores CXCR6 , Bleomicina/efeitos adversos , Bortezomib/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Animais , Camundongos , Receptores CXCR6/metabolismo , Quimiocina CXCL16/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Quimiotaxia/efeitos dos fármacos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos CD , Lectinas Tipo C
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(4): 644-651, 2024 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-38708496

RESUMO

OBJECTIVE: To observe the effect of Shenqi Chongcao (SQCC) Formula on the ASS1/src/STAT3 signaling pathway in a rat model of lung fibrosis and explore its therapeutic mechanism. METHODS: A total of 120 male SD rats were divided equally into 5 groups, including a blank control group with saline treatment and 4 groups of rat models of idiopathic pulmonary fibrosis induced by intratracheal instillation of bleomycin. One day after modeling, the rat models were treated with daily gavage of 10 mL/kg saline, SQCC decoction (0.423 g/kg), pirfenidone (10 mL/kg), or intraperitoneal injection of arginine deiminase (ADI; 2.25 mg/kg, every 3 days) for 28 days. After the treatments, the lung tissues of the rats were collected for calculating the lung/body weight ratio, observing histopathology using HE and Masson staining, and analyzing the inflammatory cells in BALF using Giemsa staining. Serum chemokine ligand 2 (CCL2) and transforming growth factor-ß1 (TGF-ß1) levels were measured with ELISA. The protein expressions of src, p-srcTry529, STAT3, and p-STAT3Try705 and the mRNA expressions of ASS1, src and STAT3 in the lung tissues were detected using Western blotting and RT-qPCR. RESULTS: The neutrophil, macrophage and lymphocyte counts and serum levels of CCL2 and TGF-ß1 were significantly lower in SQCC, pirfenidone and ADI treatment groups than in the model group at each time point of measurement (P < 0.05). P-srcTry529 and p-STAT3Try705 protein expression levels and ASS1, src, and STAT3 mRNA in the lung tissues were also significantly lower in the 3 treatment groups than in the model group (P < 0.05). CONCLUSION: SQCC Formula can alleviate lung fibrosis in rats possibly by activating the ASS1/src/STAT3 signaling pathway in the lung tissues.


Assuntos
Medicamentos de Ervas Chinesas , Fibrose Pulmonar , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Masculino , Ratos , Bleomicina , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/efeitos dos fármacos , Quinases da Família src/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Carbono-Carbono Ligases/efeitos dos fármacos , Carbono-Carbono Ligases/metabolismo
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