Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic targe...Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.展开更多
The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within...The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.展开更多
BACKGROUND Pulmonary fibrosis(PF)is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation,causing structural damage and lung failure.Stem cell therapy and mes...BACKGROUND Pulmonary fibrosis(PF)is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation,causing structural damage and lung failure.Stem cell therapy and mesenchymal stem cells-extracellular vesicles(MSC-EVs)offer new hope for PF treatment.AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis,oxidative stress,and immune inflammation in A549 cells and bleomycin(BLM)-induced mouse model.METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers[collagen I andα-smooth muscle actin(α-SMA),oxidative stress regulators[nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1),and inflammatory regu-lators[nuclear factor-kappaB(NF-κB)p65,interleukin(IL)-1β,and IL-2].Similarly,they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection.MSC-EVs ion PF mice were detected by pathological staining and western blot.Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.RESULTS Transforming growth factor(TGF)-β1 enhanced fibrosis in A549 cells,significantly increasing collagen I andα-SMA levels.Notably,treatment with MSC-EVs demonstrated a remarkable alleviation of these effects.Similarly,the expression of oxidative stress regulators,such as Nrf2 and HO-1,along with inflammatory regulators,including NF-κB p65 and IL-1β,were mitigated by MSC-EV treatment.Furthermore,in a parallel manner,MSC-EVs exhibited a downregulatory impact on collagen deposition,oxidative stress injuries,and inflammatory-related cytokines in the lungs of mice with PF.Additionally,the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response.The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes,oxidative stress,and inflammatory responses associated with PF.CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition,oxidative stress,and immune-inflammatory responses.展开更多
BACKGROUND Idiopathic pulmonary fibrosis(IPF)is classified under fibrotic interstitial pneumonia,characterized by a chronic and progressive course.The predominant clinical features of IPF include dyspnea and pulmonary...BACKGROUND Idiopathic pulmonary fibrosis(IPF)is classified under fibrotic interstitial pneumonia,characterized by a chronic and progressive course.The predominant clinical features of IPF include dyspnea and pulmonary dysfunction.AIM To assess the effects of pirfenidone in the early treatment of IPF on lung function in patients.METHODS A retrospective analysis was performed on 113 patients with IPF who were treated in our hospital from November 2017 to January 2023.These patients were divided into two groups:control group(n=53)and observation group(n=60).In the control group,patients received routine therapy in combination with methylprednisolone tablets,while those in the observation group received routine therapy together with pirfenidone.After applying these distinct treatment approaches to the two groups,we assessed several parameters,including the overall effectiveness of clinical therapy,the occurrence of adverse reactions(e.g.,nausea,vomiting,and anorexia),symptom severity scores,pulmonary function index levels,inflammatory marker levels,and the 6-min walk distance before and after treatment in both groups.RESULTS The observation group exhibited significantly higher rates than the control group after therapy,with a clear distinction(P<0.05).After treatment,the observation group experienced significantly fewer adverse reactions than the control group,with a noticeable difference(P<0.05).When analyzing the symptom severity scores between the two groups of patients after treatment,the observation group had significantly lower scores than the control group,with a distinct difference(P<0.05).When comparing the pulmonary function index levels between the two groups of patients after therapy,the observation group displayed significantly higher levels than the control group,with a noticeable difference(P<0.05).Evaluating the inflammatory marker data(C-reactive protein,interleukin-2[IL-2],and IL-8)between the two groups of patients after therapy,the observation group exhibited significantly lower levels than the control group,with significant disparities(P<0.05).Comparison of the 6-min walking distance data between the two groups of patients after treatment showed that the observation group achieved significantly greater distances than the control group,with a marked difference(P<0.05).CONCLUSION Prompt initiation of pirfenidone treatment in individuals diagnosed with IPF can enhance pulmonary function,elevate inflammatory factor levels,and increase the distance covered in the 6-min walk test.This intervention is conducive to effectively decreasing the occurrence of adverse reactions in patients.展开更多
Background:To explore the effects and mechanisms of Bu-Yang-Huan-Wu Decoction on pulmonary fibrosis in mice.Methods:Forty-five C57BL/6J mice were randomly divided into three groups:Control,Model,and Bu-Yang-Huan-Wu De...Background:To explore the effects and mechanisms of Bu-Yang-Huan-Wu Decoction on pulmonary fibrosis in mice.Methods:Forty-five C57BL/6J mice were randomly divided into three groups:Control,Model,and Bu-Yang-Huan-Wu Decoction.Pulmonary fibrosis was elicited in mice through a solitary intratracheal administration of 2.5 mg/kg bleomycin.For the control group,mice were given a solitary intratracheal administration of a comparable volume of PBS.Treatment began on the first day after the successful model establishment and lasted for 21 days.The survival rate and body weight of the mice were recorded daily,and on the 22nd day,bronchoalveolar lavage fluid was collected to determine total cells and total protein.The wet/dry weight ratio of lung tissue and hydroxyproline were measured.Lung tissue pathology was observed using hematoxylin and eosin staining and Masson staining.The mRNA expression of epithelial-mesenchymal transition-related proteins(E-cadherin and vimentin)was detected by RT-qPCR,and their protein expression was analyzed by western blot.Results:Compared to the model group,the Bu-Yang-Huan-Wu Decoction treatment notably enhanced both the survival rate and body weight in pulmonary fibrosis mice,significantly reduced lung tissue wet/dry weight ratio,total cells,and protein in bronchoalveolar lavage fluid,and hydroxyproline content.The pathological morphology of lung tissue was significantly improved,with increased expression of the epithelial cell marker E-cadherin mRNA and protein,and decreased expression of the mesenchymal cell marker vimentin mRNA and protein.Conclusion:Bu-Yang-Huan-Wu Decoction can improve the degree of bleomycin-induced pulmonary fibrosis in mice by inhibiting epithelial-mesenchymal transition.展开更多
Idiopathic pulmonary fibrosis(IPF),characterized by aggravated alveolar destruc-tion and fibrotic matrix deposition,tendentiously experiences the stage called acute exacerbation IPF(AE-IPF)and progresses to multiple o...Idiopathic pulmonary fibrosis(IPF),characterized by aggravated alveolar destruc-tion and fibrotic matrix deposition,tendentiously experiences the stage called acute exacerbation IPF(AE-IPF)and progresses to multiple organ damage,especially liver injury.Recent studies have found a variety of immune microenvironment disorders associated with elevated IPF risk and secondary organ injury,whereas current animal models induced with bleomycin(BLM)could not completely reflect the pathologi-cal manifestations of AE-IPF patients in clinic,and the exact underlying mechanisms are not yet fully explored.In the current study,we established an AE-IPF model by tracheal administration of a single dose of BLM and then repeated administrations of lipopolysaccharide in mice.This mouse model successfully recapitulated the clinical features of AE-IPF,including excessive intrapulmonary inflammation and fibrosis and extrapulmonary manifestations,as indicated by significant upregulation of Il6,Tnfa,Il1b,Tgfb,fibronectin,and Col1a1 in both lungs and liver and elevated serum aspartate transaminase and alanine transaminase levels.These effects might be attributed to the regulation of Th17 cells.By sharing this novel murine model,we expect to pro-vide an appropriate experimental platform to investigate the pathogenesis of AE-IPF coupled with liver injury and contribute to the discovery and development of targeted interventions.展开更多
Objective:To assess the effect of D-pinitol on pulmonary fibrosis induced by bleomycin.Methods:Sprague-Dawley rats received intratracheal bleomycin(6 IU/kg)to induce pulmonary fibrosis,followed by administration of ei...Objective:To assess the effect of D-pinitol on pulmonary fibrosis induced by bleomycin.Methods:Sprague-Dawley rats received intratracheal bleomycin(6 IU/kg)to induce pulmonary fibrosis,followed by administration of either D-pinitol(5,10,or 20 mg/kg)or vehicle or methylprednisolone(10 mg/kg)over 28 days after bleomycin administration.Lung function,biochemical parameters,serum biochemistry,mRNA expressions,and histological features were observed.Results:D-pinitol at 10 and 20 mg/kg significantly(P<0.05)attenuated bleomycin-induced bronchoalveolar lavage fluid,decreased myeloperoxidase,nitric oxide,malondialdehyde levels,and increased glutathione and superoxide dismutase level.D-pinitol also improved lung function(enhanced pause,frequency of breathing,expired volume,and tidal volume).Besides,D-pinitol significantly(P<0.05)upregulated Nrf2 and downregulated mRNA expressions of TGF-β,collagen-1,and Smad-3.Furthermore,considerably less inflammation(peribronchial,perivascular,and total),Ashcroft,and interstitial fibrosis scores were observed in the D-pinitol group.Conclusions:D-pinitol exerts its effect against bleomycin-induced pulmonary fibrosis via antioxidative and anti-fibrotic pathways.展开更多
BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is impor...BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.AIM To explore novel hub genes for IPF therapy.METHODS Here,we used public datasets to identify differentially expressed genes between IPF patients and healthy donors.Potential targets were considered based on multiple bioinformatics analyses,especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide,forced vital capacity,and patient survival rate.The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.RESULTS We found that TDO2 was upregulated in IPF patients and predicted poor prognosis.Surprisingly,single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts,indicating that TDO2 may participate in the regulation of proliferation and survival.Therefore,we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β(TGF-β)-induced pulmonary fibrosis.Furthermore,the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation.These findings suggest that TDO2 may be a potential target for IPF treatment.Based on transcription factors-microRNA prediction and scRNA-seq analysis,elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.CONCLUSION We provided new target genes prediction and proposed blocking TGF-βproduction as a potential treatment for IPF.展开更多
Objective:To study the protective effect of cannabidiol(CBD)on rats with pulmonary fibrosis and explore the possible mechanism of the use of CBD in the treatment of pulmonary fibrosis.Methods:Sixty SD rats were random...Objective:To study the protective effect of cannabidiol(CBD)on rats with pulmonary fibrosis and explore the possible mechanism of the use of CBD in the treatment of pulmonary fibrosis.Methods:Sixty SD rats were randomly divided into the normal control group,model group,prednisone group,CBD low,medium and high dose groups(12,36,108 mg/kg,ig),10 rats in each group.Except for the normal control group,the other 5 groups were all induced by tracheal injection of bleomycin to rat models of pulmonary fibrosis.After modeling,the rats were given intragastric administration once a day for 28 consecutive days and samples were taken.The degree of pulmonary edema was detected;the pathological changes of lung tissue were observed by HE and Masson staining;tumor necrosis factorα(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)and lung tissue superoxide dismutase(SOD),malondialdehyde(MDA),hydroxyproline(HYP)contents were measured by ELISA,transforming growth factor-β1(TGF-β1)andα-smooth muscle protein(α-SMA)concentration were detected by immunocytochemical method,real-time fluorescent quantitative PCR(qRT-PCR)method was used to detect the mRNA expression levels of TGF-β1,α-SMA,Nrf2 and nuclear transcription factor-κB p65(NF-κB p65).Results:The lung organ coefficient and W/D value were significantly decreased in the CBD administration group(P<0.05);medium and high doses of CBD could reduce the number of collagen fibers and fibroblasts;the pulmonary fibrosis in the low,medium,and high dose groups of CBD was significantly lower.The levels of TNF-α,IL-1β,and IL-6 in rat serum,as well as MDA and HYP in lung tissue,were significantly lower compared to the model group.Additionally,the level of SOD was significantly increased(P<0.05);The expression ofα-SMA was decreased compared with the model group(P<0.05);the contents of TGF-β1,α-SMA and NF-κB p65 mRNA in lung tissue decreased,and the expression level of Nrf2 mRNA increased(P<0.05).Especially,the high-dose group had the most significant effect.Conclusion:CBD can significantly reduce the degree of pulmonary fibrosis in rats,and its potential mechanism may be related to inhibiting inflammatory response,enhancing antioxidant capacity and inhibiting the protein expression of TGF-β1 andα-SMA.展开更多
BACKGROUND Rationale:No other treatment besides lung transplant is effective for idiopathic pulmonary fibrosis(IPF).Patients with IPF have poor prognosis,which may eventually lead to death.Patient concerns:Two female ...BACKGROUND Rationale:No other treatment besides lung transplant is effective for idiopathic pulmonary fibrosis(IPF).Patients with IPF have poor prognosis,which may eventually lead to death.Patient concerns:Two female patients were diagnosed with IPF.In our recent follow-up,both these patients maintained a good quality of life.CASE SUMMARY Diagnosis:Both patients had dry cough and progressive dyspnea.Interventions:The first patient was treated with prednisone,and the second patient was treated with prednisone and tripterygium glycosides.However,the symptoms did not improve and fibrosis was not controlled.Thus,the Feibi recipe was used.Outcomes:No deterioration was observed after the treatment,and the dry cough and its effect were ameliorated.Furthermore,they are still alive and the quality of their lives has improved.CONCLUSION These two cases suggest that the Feibi recipe and other traditional Chinese medicine therapies could be beneficial for IPF treatment.展开更多
Pulmonary fibrosis(PF)is a chronic,progressive,and irreversible pulmonary interstitial disease with unclear pathogenesis.Currently,there are few treatment options for managing PF.Inhalation therapy,as a routine treatm...Pulmonary fibrosis(PF)is a chronic,progressive,and irreversible pulmonary interstitial disease with unclear pathogenesis.Currently,there are few treatment options for managing PF.Inhalation therapy,as a routine treatment for respiratory diseases,is being used to study the treatment of PF.Some herbal medicines and their active ingredients have been reported to have anti-PF effects.This review aims to provide an overview of the latest developments in inhalation therapy,focusing on the utilization of chemical medicines and herbal medicines for the treatment of PF in both clinical practice and basic research.The inhalation of chemical drugs such as pirfenidone,nintedanib,N-acetylcysteine,and interferon-γhas been shown to demonstrate anti-PF effects.Additionally,the inhalation of various natural products derived from herbal medicines,encompassing polyphenols,alkaloids,flavonoids,saponins,terpenoids,and herbal extracts,contributes to the therapeutic management of PF through diverse mechanisms.The inhalation of both chemical and herbal medicines presents promising advantages in the treatment of PF.Further clinical trials are required to investigate the effectiveness,safety,and mechanism of action of inhalation therapy utilizing natural products derived from herbal medicines.展开更多
OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
Idiopathic pulmonary fibrosis(IPF)is a serious and fatal pulmonary inflammatory disease with an increasing incidenceworldwide.The drugs nintedanib and pirfenidone,are listed as conditionally recommended drugs in the“...Idiopathic pulmonary fibrosis(IPF)is a serious and fatal pulmonary inflammatory disease with an increasing incidenceworldwide.The drugs nintedanib and pirfenidone,are listed as conditionally recommended drugs in the“Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”.However,these two drugs have many adverse reactions in clinical application.Salvianolic acid B(Sal B),a water-soluble component of Salvia miltiorrhiza,could alleviate bleomycin-induced peroxidative stress damage,and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease’s progression.However,Sal B is poorly absorbed orally,and patient compliance is poor when administered intravenously.Therefore,there is an urgent need to find a new non-injection route of drug delivery.In this study,Sal B was used as model drug and l-leucine(LL)as excipient to prepare Sal B dry powder inhaler(Sal B-DPI)by spray drying method.Modern preparation evaluation methods were used to assess the quality of Sal B-DPI.Sal B-DPI is promising for the treatment of IPF,according to studies on pulmonary irritation evaluation,in vivo and in vitro pharmacodynamics,metabolomics,pharmacokinetics,and lung tissue distribution.展开更多
Objective: To study the therapeutic effect of Com pound Biejia Ruangan prescription (CBRP) on rat model with pulmonary fibrosis in duced by bleomycin. Methods: Fifty four male Sprague Dawley rats were rando mly divide...Objective: To study the therapeutic effect of Com pound Biejia Ruangan prescription (CBRP) on rat model with pulmonary fibrosis in duced by bleomycin. Methods: Fifty four male Sprague Dawley rats were rando mly divided into 6 groups (9 rats in each group). From the first day to the 28th day of the experiment, except to those in the sham model control group that were treated with normal saline, the same amount of bleomycin injection as the n ormal saline given to the control group was given through endotracheal instillat ion to all the rats in all the other groups. From the 29th day of the modeling, CBRP solution of different dosages was respectively injected into the rats in th e high, moderate and low CBRP dose group, while equal volume of normal saline w as given to those in the sham model control group and the model control group , and an equal volume of prednisone solution was given to rats in the prednisone group. On the 80th day, the high resolution computerized tomographic (HRCT) images were observed on an equal footing, and HRCT pathology was correlativel y studied. Results: Different HRCT pathological changes were shown in th e rats with pulmonary fibrosis, such as lung consolidation, thickening of interl obular septum and interlobular mesenchyma as well as lobular deformation, nodule shadow, abnormal brochiovascular tract, thickened pleura with irregular junctio n and polished glass like dense shadows. Honeycomb lung was observed in some cases. Pathological sections showed fibrotic proliferation of lung tissues and noticeable pulmonary interstitial fibrosis. CBRP could improve HRCT images of rats with pulmonary fibrosis, and lower fibrotic p roliferation of the lung tissue.Conclusion: CBRP plays its therapeutic role possibly through its effect on the structure of the lung in rats with pulmonary fibrosis.展开更多
Idiopathic pulmonary fibrosis is an untreatable lethal lung disease, which is related to the aberrant proliferation of fibroblasts. M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>...Idiopathic pulmonary fibrosis is an untreatable lethal lung disease, which is related to the aberrant proliferation of fibroblasts. M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>-mAChR) activation exerts proliferative effect on various kinds of cells. However, whether M<sub>3</sub>-mAChR inhibition has a protective effect on pulmonary fibrosis remains unexplored. A rat model of pulmonary fibrosis was established by intratracheal instillation of bleomycin. Darifenacin was used to block M<sub>3</sub>-mAChR. Histological changes were observed using Masson’s Trichrome and hematoxylin and eosin (HE) staining. Hydroxyproline was measured by Hydroxyproline detection kit. Transforming growth factor β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, pulmonary fibroblasts were isolated from lungs of neonatal rat. After treatment, the cell viability, Hydroxyproline level was measured by MTT and Hydroxyproline detection kit respectively. The expression level of extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (N-NF-κB), and microRNA-21 (miR-21) was detected by western blot or quantitative real-time PCR (qRT-PCR). Darifenacin relieved the fibrotic effects provoked by bleomycin. The expression level of hydroxyproline, TGF-β1 and TNF-α level was all downregulated after darifenacin treatment. In lung fibroblasts, darifenacin decreased cell viability and hydroxyproline level induced by bleomycin. Besides, phosphorylation-ERK and nuclear N-NF-κB protein level was downregulated, as well as miR-21 level. M<sub>3</sub>-mAChR antagonist darifenacin attenuates bleomycin-induced pulmonary fibrosis in rats, which may relate to the ERK/NF-κB/miRNA-21 signaling pathway.展开更多
Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β...Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,metabolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an IC_(50) of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.展开更多
Objective:To initially explore traditional Chinese medicine patterns in a bleomycin-induced pulmonary fibrosis mouse model.Methods:Thirty-six C57BL/6 mice were divided by the random number table method(with 12 rats pe...Objective:To initially explore traditional Chinese medicine patterns in a bleomycin-induced pulmonary fibrosis mouse model.Methods:Thirty-six C57BL/6 mice were divided by the random number table method(with 12 rats per group)into three groups:a blank group,a model group,and a number 2 Feibi recipe(FBR-2)group.The pulmonary fibrosis mouse model was established by intratracheal instillation of bleomycin.The FBR-2 group was treated with FBR-2 for 4 weeks.Symptoms in the mice such as mental behavior,food/water intake,body weight,body temperature,respiratory rate,and tongue image were observed.The samples were collected on the 14th day and 28th day after modeling,and lung tissues were visually assessed and microscopically evaluated by staining with hematoxylin-eosin and Masson.The expression levels of hydroxyproline,interleukin(IL)-33,IL-37,tissue plasminogen activator,and plasminogen activator inhibitor-1 were determined by enzyme-linked immunosorbent assay.Results:Mice in the model group were poor in spirit,less active,slow in response,showed reduced food/water intake,body temperature,and body weight,increased respiratory rate,and their tongue color had changed from light red to dark red.However,treatment with FBR-2 significantly improved these symptoms.Extensive inflammatory cell infiltration and collagen fiber deposition were observed in the lung tissues of the model group.Compared with the blank group,the levels of hydroxyproline,IL-33,and plasminogen activator inhibitor-1 in the model group significantly increased(all P<.05),whereas that of tissue plasminogen activator significantly decreased on the 14th day and 28th day(P=.036 and P=.005,respectively).Moreover,FBR-2 improved lung inflammation and fibrinolysis imbalance and reduced collagen fiber deposition.Conclusion:To some extent,our bleomycin-induced pulmonary fibrosis mouse model exhibited traditional Chinese medicine patterns of qi deficiency,blood stasis,and heat retention.展开更多
Backgroud:Danggui Buxue decoction(DBD),a classical prescription in traditional Chinese medicine,has been found to have protective effect on bleomycin-induced pulmonary fibrosis in rats by reducing alveolar inflammatio...Backgroud:Danggui Buxue decoction(DBD),a classical prescription in traditional Chinese medicine,has been found to have protective effect on bleomycin-induced pulmonary fibrosis in rats by reducing alveolar inflammation and fibrosis.However,the biological activity of individual chemical components and mechanism of action of whole formula are not clear.Methods:Potential targets of active ingredients of DBD were collected through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SymMap database.Target genes related to idiopathic pulmonary fibrosis were obtained from the Online Mendelian Inheritance in Man database,Therapeutic Targets Database and Gkb database.Then,the common targets were obtained by overlapping the potential targets of active ingredients in DBD and diseases related targets.The selected targets were subjected to Kyoto Encyclopedia of Genes and Genomes signaling pathway and Gene Ontology analysis,and the network map of active component-target-pathway was established using Cytoscape 3.7.1 software.The active components of DBD with most targets were selected for fibrosis-related marker verification.The mRNA and protein expression of fibrosis markers,α-smooth muscle actin,collagen 1 and fibronectin,were detected in TGF-β1-induced fibroblast cell line after treatment with the active components.Results:The 14 active ingredients,such as quercetin and kaempferol,were screened from DBD.It acts on 26 targets like estrogen receptor 2 and prostaglandin-endoperoxide synthase 2,and mainly involves 38 signaling pathways such as cell inflammation and autophagy.Kaempferol and quercetin are the two compounds with the highest network regulation,which can inhibit the transformation of fibroblasts into myofibroblasts and reduce the expression of fibrosis markersα-smooth muscle actin,collagen 1 and fibronectin.Conclusion:The integration mode of multi-component,multi-target,multi-channel and mechanism of DBD in the treatment of idiopathic pulmonary fibrosis are predicted by means of network pharmacology.Our study could indicate the direction of further anti-fibrotic mechanism research.展开更多
Since stem cell therapy is the most effective treatment in the field of tissue reparation and reconstitution,the present study aimed to explore the different sources of mesenchymal stem cells(MSCs)on the different eff...Since stem cell therapy is the most effective treatment in the field of tissue reparation and reconstitution,the present study aimed to explore the different sources of mesenchymal stem cells(MSCs)on the different effects of pulmonary fibrosis-related cytokines in C57BL/6 mice.For reaching this goal,we isolated MSCs from umbilical cord blood and placenta and used for stem cell therapy in a mouse model of pulmonary fibrosis model.The pulmonary fibrosis model was done by injecting bleomycin into the trachea of C57BL/6 mice.Then we assessed the degree of pulmonary fibrosis in each mouse lung tissue at weeks 1,2,3,and 4.In addition,flow cytometry was used to evaluate the frequency of CD73,CD90,CD106,CD34,CD45,CD14 cells at the mononuclear cell level;and western blotting assays revealed the expression of IκB-α.Our results showed that stem cell therapy by placenta-derived MSC had a lower level of CD34,CD45,CD14 cells at the mononuclear cell level,and that improved pulmonary fibrosis at both molecular and pathological levels.In addition,western blotting assays revealed that the expression of IκB-αwas down-regulated in MSC-treated animals.In addition,placenta-derived MSC was the most effective in improving pulmonary fibrosis in comparison to other sources.This study suggests that MSC might be a novel therapeutic approach in pulmonary fibrosis due to an enhanced anti-inflammatory effect.Also,MSC modification by gene editing could enhance their therapeutic effect in mouse pulmonary fibrosis.展开更多
A number of drugs induce pulmonary injury and subsequently lead to serious lung diseases such as pulmonary fibrosis as the adverse drug reactions.However,an effective preventive approach against drug-induced pulmonary...A number of drugs induce pulmonary injury and subsequently lead to serious lung diseases such as pulmonary fibrosis as the adverse drug reactions.However,an effective preventive approach against drug-induced pulmonary fibrosis has not been established due to poor understanding of common preventive targets in a variety of drugs showing pulmonary toxicity.Epithelial-mesenchymal transition(EMT),a cellular phenotypic change of the epithelial to mesenchymal state,contributes to the development of pulmonary fibrosis through the conversion of damaged alveolar epithelium into myofibroblasts.As several drugs with pulmonary toxicity have been reported to induce EMT,EMT serves as a bridge between the drugs and pulmonary fibrosis.Accumulated evidence supports the potential of EMT as a preventive target against drug-induced pulmonary fibrosis.Additionally,since there are mechanistic differences between the main pharmacological effect and EMT induced by the drug,prevention based on EMT suppression would be possible and would contribute to continuous clinical treatment with the drug to avoid EMT-mediated serious pulmonary fibrosis.Furthermore,targeting EMT seems to be adequate for exerting a preventive effect since EMT in damaged alveolar epithelial cells occurs prior to the development of the pathophysiological state of the whole lung in a bleomycin-induced lung injury rat model.This viewpoint deals with the benefits and perspectives of preventive approaches against druginduced pulmonary fibrosis through the suppression of EMT,which has rarely been addressed.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82174100).
文摘Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.
基金Supported by the Project of Special Funds for Science and Technology Cooperation in Guizhou Provinces and Zunyi City,No.Shengshikehe(2015)53.
文摘The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.
基金Supported by Xi’an Science and Technology Plan Project,No.20200001YX001(1)Xi’an Talent Plan-Elite(Innovative Talents)Project,No.XAYC210062.
文摘BACKGROUND Pulmonary fibrosis(PF)is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation,causing structural damage and lung failure.Stem cell therapy and mesenchymal stem cells-extracellular vesicles(MSC-EVs)offer new hope for PF treatment.AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis,oxidative stress,and immune inflammation in A549 cells and bleomycin(BLM)-induced mouse model.METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers[collagen I andα-smooth muscle actin(α-SMA),oxidative stress regulators[nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1),and inflammatory regu-lators[nuclear factor-kappaB(NF-κB)p65,interleukin(IL)-1β,and IL-2].Similarly,they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection.MSC-EVs ion PF mice were detected by pathological staining and western blot.Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.RESULTS Transforming growth factor(TGF)-β1 enhanced fibrosis in A549 cells,significantly increasing collagen I andα-SMA levels.Notably,treatment with MSC-EVs demonstrated a remarkable alleviation of these effects.Similarly,the expression of oxidative stress regulators,such as Nrf2 and HO-1,along with inflammatory regulators,including NF-κB p65 and IL-1β,were mitigated by MSC-EV treatment.Furthermore,in a parallel manner,MSC-EVs exhibited a downregulatory impact on collagen deposition,oxidative stress injuries,and inflammatory-related cytokines in the lungs of mice with PF.Additionally,the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response.The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes,oxidative stress,and inflammatory responses associated with PF.CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition,oxidative stress,and immune-inflammatory responses.
文摘BACKGROUND Idiopathic pulmonary fibrosis(IPF)is classified under fibrotic interstitial pneumonia,characterized by a chronic and progressive course.The predominant clinical features of IPF include dyspnea and pulmonary dysfunction.AIM To assess the effects of pirfenidone in the early treatment of IPF on lung function in patients.METHODS A retrospective analysis was performed on 113 patients with IPF who were treated in our hospital from November 2017 to January 2023.These patients were divided into two groups:control group(n=53)and observation group(n=60).In the control group,patients received routine therapy in combination with methylprednisolone tablets,while those in the observation group received routine therapy together with pirfenidone.After applying these distinct treatment approaches to the two groups,we assessed several parameters,including the overall effectiveness of clinical therapy,the occurrence of adverse reactions(e.g.,nausea,vomiting,and anorexia),symptom severity scores,pulmonary function index levels,inflammatory marker levels,and the 6-min walk distance before and after treatment in both groups.RESULTS The observation group exhibited significantly higher rates than the control group after therapy,with a clear distinction(P<0.05).After treatment,the observation group experienced significantly fewer adverse reactions than the control group,with a noticeable difference(P<0.05).When analyzing the symptom severity scores between the two groups of patients after treatment,the observation group had significantly lower scores than the control group,with a distinct difference(P<0.05).When comparing the pulmonary function index levels between the two groups of patients after therapy,the observation group displayed significantly higher levels than the control group,with a noticeable difference(P<0.05).Evaluating the inflammatory marker data(C-reactive protein,interleukin-2[IL-2],and IL-8)between the two groups of patients after therapy,the observation group exhibited significantly lower levels than the control group,with significant disparities(P<0.05).Comparison of the 6-min walking distance data between the two groups of patients after treatment showed that the observation group achieved significantly greater distances than the control group,with a marked difference(P<0.05).CONCLUSION Prompt initiation of pirfenidone treatment in individuals diagnosed with IPF can enhance pulmonary function,elevate inflammatory factor levels,and increase the distance covered in the 6-min walk test.This intervention is conducive to effectively decreasing the occurrence of adverse reactions in patients.
文摘Background:To explore the effects and mechanisms of Bu-Yang-Huan-Wu Decoction on pulmonary fibrosis in mice.Methods:Forty-five C57BL/6J mice were randomly divided into three groups:Control,Model,and Bu-Yang-Huan-Wu Decoction.Pulmonary fibrosis was elicited in mice through a solitary intratracheal administration of 2.5 mg/kg bleomycin.For the control group,mice were given a solitary intratracheal administration of a comparable volume of PBS.Treatment began on the first day after the successful model establishment and lasted for 21 days.The survival rate and body weight of the mice were recorded daily,and on the 22nd day,bronchoalveolar lavage fluid was collected to determine total cells and total protein.The wet/dry weight ratio of lung tissue and hydroxyproline were measured.Lung tissue pathology was observed using hematoxylin and eosin staining and Masson staining.The mRNA expression of epithelial-mesenchymal transition-related proteins(E-cadherin and vimentin)was detected by RT-qPCR,and their protein expression was analyzed by western blot.Results:Compared to the model group,the Bu-Yang-Huan-Wu Decoction treatment notably enhanced both the survival rate and body weight in pulmonary fibrosis mice,significantly reduced lung tissue wet/dry weight ratio,total cells,and protein in bronchoalveolar lavage fluid,and hydroxyproline content.The pathological morphology of lung tissue was significantly improved,with increased expression of the epithelial cell marker E-cadherin mRNA and protein,and decreased expression of the mesenchymal cell marker vimentin mRNA and protein.Conclusion:Bu-Yang-Huan-Wu Decoction can improve the degree of bleomycin-induced pulmonary fibrosis in mice by inhibiting epithelial-mesenchymal transition.
基金supported by the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(grant no.:ZYYCXTD-C-202006 to XG and Xiaojiaoyang Li)Beijing Municipal Science and Technology Commission(grant no.:7212174 to Xiaojiaoyang Li)+2 种基金National Natural Science Foundation of China(grant no.:82004045 to Xiaojiaoyang Li)Beijing Nova Program of Science and Technology(grant no.:Z191100001119088 to Xiaojiaoyang Li)the Young Elite Scientists Sponsorship Program by CACM(grant no.:2020-QNRC2-01 to Xiaojiaoyang Li).
文摘Idiopathic pulmonary fibrosis(IPF),characterized by aggravated alveolar destruc-tion and fibrotic matrix deposition,tendentiously experiences the stage called acute exacerbation IPF(AE-IPF)and progresses to multiple organ damage,especially liver injury.Recent studies have found a variety of immune microenvironment disorders associated with elevated IPF risk and secondary organ injury,whereas current animal models induced with bleomycin(BLM)could not completely reflect the pathologi-cal manifestations of AE-IPF patients in clinic,and the exact underlying mechanisms are not yet fully explored.In the current study,we established an AE-IPF model by tracheal administration of a single dose of BLM and then repeated administrations of lipopolysaccharide in mice.This mouse model successfully recapitulated the clinical features of AE-IPF,including excessive intrapulmonary inflammation and fibrosis and extrapulmonary manifestations,as indicated by significant upregulation of Il6,Tnfa,Il1b,Tgfb,fibronectin,and Col1a1 in both lungs and liver and elevated serum aspartate transaminase and alanine transaminase levels.These effects might be attributed to the regulation of Th17 cells.By sharing this novel murine model,we expect to pro-vide an appropriate experimental platform to investigate the pathogenesis of AE-IPF coupled with liver injury and contribute to the discovery and development of targeted interventions.
文摘Objective:To assess the effect of D-pinitol on pulmonary fibrosis induced by bleomycin.Methods:Sprague-Dawley rats received intratracheal bleomycin(6 IU/kg)to induce pulmonary fibrosis,followed by administration of either D-pinitol(5,10,or 20 mg/kg)or vehicle or methylprednisolone(10 mg/kg)over 28 days after bleomycin administration.Lung function,biochemical parameters,serum biochemistry,mRNA expressions,and histological features were observed.Results:D-pinitol at 10 and 20 mg/kg significantly(P<0.05)attenuated bleomycin-induced bronchoalveolar lavage fluid,decreased myeloperoxidase,nitric oxide,malondialdehyde levels,and increased glutathione and superoxide dismutase level.D-pinitol also improved lung function(enhanced pause,frequency of breathing,expired volume,and tidal volume).Besides,D-pinitol significantly(P<0.05)upregulated Nrf2 and downregulated mRNA expressions of TGF-β,collagen-1,and Smad-3.Furthermore,considerably less inflammation(peribronchial,perivascular,and total),Ashcroft,and interstitial fibrosis scores were observed in the D-pinitol group.Conclusions:D-pinitol exerts its effect against bleomycin-induced pulmonary fibrosis via antioxidative and anti-fibrotic pathways.
文摘BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.AIM To explore novel hub genes for IPF therapy.METHODS Here,we used public datasets to identify differentially expressed genes between IPF patients and healthy donors.Potential targets were considered based on multiple bioinformatics analyses,especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide,forced vital capacity,and patient survival rate.The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.RESULTS We found that TDO2 was upregulated in IPF patients and predicted poor prognosis.Surprisingly,single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts,indicating that TDO2 may participate in the regulation of proliferation and survival.Therefore,we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β(TGF-β)-induced pulmonary fibrosis.Furthermore,the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation.These findings suggest that TDO2 may be a potential target for IPF treatment.Based on transcription factors-microRNA prediction and scRNA-seq analysis,elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.CONCLUSION We provided new target genes prediction and proposed blocking TGF-βproduction as a potential treatment for IPF.
基金Post-doctoral Program of Heilongjiang Province (No.LBH-Z22251)Chinese Medicine Research Project of Heilongjiang Province (No.ZHY2022-114)Heilongjiang Chinese Medicine Association Youth Talent Promotion Project (No.2022-QNRC1-27)。
文摘Objective:To study the protective effect of cannabidiol(CBD)on rats with pulmonary fibrosis and explore the possible mechanism of the use of CBD in the treatment of pulmonary fibrosis.Methods:Sixty SD rats were randomly divided into the normal control group,model group,prednisone group,CBD low,medium and high dose groups(12,36,108 mg/kg,ig),10 rats in each group.Except for the normal control group,the other 5 groups were all induced by tracheal injection of bleomycin to rat models of pulmonary fibrosis.After modeling,the rats were given intragastric administration once a day for 28 consecutive days and samples were taken.The degree of pulmonary edema was detected;the pathological changes of lung tissue were observed by HE and Masson staining;tumor necrosis factorα(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)and lung tissue superoxide dismutase(SOD),malondialdehyde(MDA),hydroxyproline(HYP)contents were measured by ELISA,transforming growth factor-β1(TGF-β1)andα-smooth muscle protein(α-SMA)concentration were detected by immunocytochemical method,real-time fluorescent quantitative PCR(qRT-PCR)method was used to detect the mRNA expression levels of TGF-β1,α-SMA,Nrf2 and nuclear transcription factor-κB p65(NF-κB p65).Results:The lung organ coefficient and W/D value were significantly decreased in the CBD administration group(P<0.05);medium and high doses of CBD could reduce the number of collagen fibers and fibroblasts;the pulmonary fibrosis in the low,medium,and high dose groups of CBD was significantly lower.The levels of TNF-α,IL-1β,and IL-6 in rat serum,as well as MDA and HYP in lung tissue,were significantly lower compared to the model group.Additionally,the level of SOD was significantly increased(P<0.05);The expression ofα-SMA was decreased compared with the model group(P<0.05);the contents of TGF-β1,α-SMA and NF-κB p65 mRNA in lung tissue decreased,and the expression level of Nrf2 mRNA increased(P<0.05).Especially,the high-dose group had the most significant effect.Conclusion:CBD can significantly reduce the degree of pulmonary fibrosis in rats,and its potential mechanism may be related to inhibiting inflammatory response,enhancing antioxidant capacity and inhibiting the protein expression of TGF-β1 andα-SMA.
基金Supported by Beijing Natural Science Foundation,No.7202118National Natural Science Foundation of China,No.81573970and Basic Scientific Research Foundation of Beijing University of Chinese Medicine,No.2021-JYB-XJSJJ-033.
文摘BACKGROUND Rationale:No other treatment besides lung transplant is effective for idiopathic pulmonary fibrosis(IPF).Patients with IPF have poor prognosis,which may eventually lead to death.Patient concerns:Two female patients were diagnosed with IPF.In our recent follow-up,both these patients maintained a good quality of life.CASE SUMMARY Diagnosis:Both patients had dry cough and progressive dyspnea.Interventions:The first patient was treated with prednisone,and the second patient was treated with prednisone and tripterygium glycosides.However,the symptoms did not improve and fibrosis was not controlled.Thus,the Feibi recipe was used.Outcomes:No deterioration was observed after the treatment,and the dry cough and its effect were ameliorated.Furthermore,they are still alive and the quality of their lives has improved.CONCLUSION These two cases suggest that the Feibi recipe and other traditional Chinese medicine therapies could be beneficial for IPF treatment.
基金supported by the National Natural Science Foundation of China under Grant[No.82004141]Guangdong Basic and Applied Basic Research Foundation[No.2023A1515011243]+2 种基金Bao'an Traditional Chinese Medicine Development Foundation under Grant[No.2020KJCX-KTYJ-5,2022KJCX-ZJZL-11]Science,Technology,and Innovation Commission of Shenzhen Municipality under Grant[No.JCYJ20190808160407500]Shenzhen Bao’an Traditional Chinese Medicine Hospital Research Program under Grant[No.BAZYY20220701].
文摘Pulmonary fibrosis(PF)is a chronic,progressive,and irreversible pulmonary interstitial disease with unclear pathogenesis.Currently,there are few treatment options for managing PF.Inhalation therapy,as a routine treatment for respiratory diseases,is being used to study the treatment of PF.Some herbal medicines and their active ingredients have been reported to have anti-PF effects.This review aims to provide an overview of the latest developments in inhalation therapy,focusing on the utilization of chemical medicines and herbal medicines for the treatment of PF in both clinical practice and basic research.The inhalation of chemical drugs such as pirfenidone,nintedanib,N-acetylcysteine,and interferon-γhas been shown to demonstrate anti-PF effects.Additionally,the inhalation of various natural products derived from herbal medicines,encompassing polyphenols,alkaloids,flavonoids,saponins,terpenoids,and herbal extracts,contributes to the therapeutic management of PF through diverse mechanisms.The inhalation of both chemical and herbal medicines presents promising advantages in the treatment of PF.Further clinical trials are required to investigate the effectiveness,safety,and mechanism of action of inhalation therapy utilizing natural products derived from herbal medicines.
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
基金supported by Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-D-202002)Scientific Research Project of Tianjin Municipal Education Commission (No.2019KJ083)
文摘Idiopathic pulmonary fibrosis(IPF)is a serious and fatal pulmonary inflammatory disease with an increasing incidenceworldwide.The drugs nintedanib and pirfenidone,are listed as conditionally recommended drugs in the“Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”.However,these two drugs have many adverse reactions in clinical application.Salvianolic acid B(Sal B),a water-soluble component of Salvia miltiorrhiza,could alleviate bleomycin-induced peroxidative stress damage,and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease’s progression.However,Sal B is poorly absorbed orally,and patient compliance is poor when administered intravenously.Therefore,there is an urgent need to find a new non-injection route of drug delivery.In this study,Sal B was used as model drug and l-leucine(LL)as excipient to prepare Sal B dry powder inhaler(Sal B-DPI)by spray drying method.Modern preparation evaluation methods were used to assess the quality of Sal B-DPI.Sal B-DPI is promising for the treatment of IPF,according to studies on pulmonary irritation evaluation,in vivo and in vitro pharmacodynamics,metabolomics,pharmacokinetics,and lung tissue distribution.
基金This study was supported by National Funds of Natur al Science (No.30130220)and Administration of Education against SARS(No.15)
文摘Objective: To study the therapeutic effect of Com pound Biejia Ruangan prescription (CBRP) on rat model with pulmonary fibrosis in duced by bleomycin. Methods: Fifty four male Sprague Dawley rats were rando mly divided into 6 groups (9 rats in each group). From the first day to the 28th day of the experiment, except to those in the sham model control group that were treated with normal saline, the same amount of bleomycin injection as the n ormal saline given to the control group was given through endotracheal instillat ion to all the rats in all the other groups. From the 29th day of the modeling, CBRP solution of different dosages was respectively injected into the rats in th e high, moderate and low CBRP dose group, while equal volume of normal saline w as given to those in the sham model control group and the model control group , and an equal volume of prednisone solution was given to rats in the prednisone group. On the 80th day, the high resolution computerized tomographic (HRCT) images were observed on an equal footing, and HRCT pathology was correlativel y studied. Results: Different HRCT pathological changes were shown in th e rats with pulmonary fibrosis, such as lung consolidation, thickening of interl obular septum and interlobular mesenchyma as well as lobular deformation, nodule shadow, abnormal brochiovascular tract, thickened pleura with irregular junctio n and polished glass like dense shadows. Honeycomb lung was observed in some cases. Pathological sections showed fibrotic proliferation of lung tissues and noticeable pulmonary interstitial fibrosis. CBRP could improve HRCT images of rats with pulmonary fibrosis, and lower fibrotic p roliferation of the lung tissue.Conclusion: CBRP plays its therapeutic role possibly through its effect on the structure of the lung in rats with pulmonary fibrosis.
文摘Idiopathic pulmonary fibrosis is an untreatable lethal lung disease, which is related to the aberrant proliferation of fibroblasts. M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>-mAChR) activation exerts proliferative effect on various kinds of cells. However, whether M<sub>3</sub>-mAChR inhibition has a protective effect on pulmonary fibrosis remains unexplored. A rat model of pulmonary fibrosis was established by intratracheal instillation of bleomycin. Darifenacin was used to block M<sub>3</sub>-mAChR. Histological changes were observed using Masson’s Trichrome and hematoxylin and eosin (HE) staining. Hydroxyproline was measured by Hydroxyproline detection kit. Transforming growth factor β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, pulmonary fibroblasts were isolated from lungs of neonatal rat. After treatment, the cell viability, Hydroxyproline level was measured by MTT and Hydroxyproline detection kit respectively. The expression level of extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (N-NF-κB), and microRNA-21 (miR-21) was detected by western blot or quantitative real-time PCR (qRT-PCR). Darifenacin relieved the fibrotic effects provoked by bleomycin. The expression level of hydroxyproline, TGF-β1 and TNF-α level was all downregulated after darifenacin treatment. In lung fibroblasts, darifenacin decreased cell viability and hydroxyproline level induced by bleomycin. Besides, phosphorylation-ERK and nuclear N-NF-κB protein level was downregulated, as well as miR-21 level. M<sub>3</sub>-mAChR antagonist darifenacin attenuates bleomycin-induced pulmonary fibrosis in rats, which may relate to the ERK/NF-κB/miRNA-21 signaling pathway.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81703463 and 81603277)the National Key R&D Program of China(Grant No.:U1508220)the Liaoning Distinguished Professor Project for Qing Li,and the Doctoral Scientific Research Foundation of Liaoning Province(Grant No.:20170520199).
文摘Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,metabolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an IC_(50) of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.
基金This work was supported by Natural Science Foundation of Beijing Municipality(7202118).
文摘Objective:To initially explore traditional Chinese medicine patterns in a bleomycin-induced pulmonary fibrosis mouse model.Methods:Thirty-six C57BL/6 mice were divided by the random number table method(with 12 rats per group)into three groups:a blank group,a model group,and a number 2 Feibi recipe(FBR-2)group.The pulmonary fibrosis mouse model was established by intratracheal instillation of bleomycin.The FBR-2 group was treated with FBR-2 for 4 weeks.Symptoms in the mice such as mental behavior,food/water intake,body weight,body temperature,respiratory rate,and tongue image were observed.The samples were collected on the 14th day and 28th day after modeling,and lung tissues were visually assessed and microscopically evaluated by staining with hematoxylin-eosin and Masson.The expression levels of hydroxyproline,interleukin(IL)-33,IL-37,tissue plasminogen activator,and plasminogen activator inhibitor-1 were determined by enzyme-linked immunosorbent assay.Results:Mice in the model group were poor in spirit,less active,slow in response,showed reduced food/water intake,body temperature,and body weight,increased respiratory rate,and their tongue color had changed from light red to dark red.However,treatment with FBR-2 significantly improved these symptoms.Extensive inflammatory cell infiltration and collagen fiber deposition were observed in the lung tissues of the model group.Compared with the blank group,the levels of hydroxyproline,IL-33,and plasminogen activator inhibitor-1 in the model group significantly increased(all P<.05),whereas that of tissue plasminogen activator significantly decreased on the 14th day and 28th day(P=.036 and P=.005,respectively).Moreover,FBR-2 improved lung inflammation and fibrinolysis imbalance and reduced collagen fiber deposition.Conclusion:To some extent,our bleomycin-induced pulmonary fibrosis mouse model exhibited traditional Chinese medicine patterns of qi deficiency,blood stasis,and heat retention.
文摘Backgroud:Danggui Buxue decoction(DBD),a classical prescription in traditional Chinese medicine,has been found to have protective effect on bleomycin-induced pulmonary fibrosis in rats by reducing alveolar inflammation and fibrosis.However,the biological activity of individual chemical components and mechanism of action of whole formula are not clear.Methods:Potential targets of active ingredients of DBD were collected through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SymMap database.Target genes related to idiopathic pulmonary fibrosis were obtained from the Online Mendelian Inheritance in Man database,Therapeutic Targets Database and Gkb database.Then,the common targets were obtained by overlapping the potential targets of active ingredients in DBD and diseases related targets.The selected targets were subjected to Kyoto Encyclopedia of Genes and Genomes signaling pathway and Gene Ontology analysis,and the network map of active component-target-pathway was established using Cytoscape 3.7.1 software.The active components of DBD with most targets were selected for fibrosis-related marker verification.The mRNA and protein expression of fibrosis markers,α-smooth muscle actin,collagen 1 and fibronectin,were detected in TGF-β1-induced fibroblast cell line after treatment with the active components.Results:The 14 active ingredients,such as quercetin and kaempferol,were screened from DBD.It acts on 26 targets like estrogen receptor 2 and prostaglandin-endoperoxide synthase 2,and mainly involves 38 signaling pathways such as cell inflammation and autophagy.Kaempferol and quercetin are the two compounds with the highest network regulation,which can inhibit the transformation of fibroblasts into myofibroblasts and reduce the expression of fibrosis markersα-smooth muscle actin,collagen 1 and fibronectin.Conclusion:The integration mode of multi-component,multi-target,multi-channel and mechanism of DBD in the treatment of idiopathic pulmonary fibrosis are predicted by means of network pharmacology.Our study could indicate the direction of further anti-fibrotic mechanism research.
基金This work was financially supported by the National Natural Science Foundation of China(31001638&30870602)This project was supported by the key medical research plan of the Hebei province of China(No.ZD2013063)+1 种基金Tsing-hua University(2009THZ02122)National Heart,Lung,and Blood Institute Research Grant HL 104402 from the National Institutes of Health of the US Public Health Service.
文摘Since stem cell therapy is the most effective treatment in the field of tissue reparation and reconstitution,the present study aimed to explore the different sources of mesenchymal stem cells(MSCs)on the different effects of pulmonary fibrosis-related cytokines in C57BL/6 mice.For reaching this goal,we isolated MSCs from umbilical cord blood and placenta and used for stem cell therapy in a mouse model of pulmonary fibrosis model.The pulmonary fibrosis model was done by injecting bleomycin into the trachea of C57BL/6 mice.Then we assessed the degree of pulmonary fibrosis in each mouse lung tissue at weeks 1,2,3,and 4.In addition,flow cytometry was used to evaluate the frequency of CD73,CD90,CD106,CD34,CD45,CD14 cells at the mononuclear cell level;and western blotting assays revealed the expression of IκB-α.Our results showed that stem cell therapy by placenta-derived MSC had a lower level of CD34,CD45,CD14 cells at the mononuclear cell level,and that improved pulmonary fibrosis at both molecular and pathological levels.In addition,western blotting assays revealed that the expression of IκB-αwas down-regulated in MSC-treated animals.In addition,placenta-derived MSC was the most effective in improving pulmonary fibrosis in comparison to other sources.This study suggests that MSC might be a novel therapeutic approach in pulmonary fibrosis due to an enhanced anti-inflammatory effect.Also,MSC modification by gene editing could enhance their therapeutic effect in mouse pulmonary fibrosis.
基金The works based on the present viewpoint were supported by the funding from the Japan Society for the Promotion of Science(JP16K18945 and JP19K16447).
文摘A number of drugs induce pulmonary injury and subsequently lead to serious lung diseases such as pulmonary fibrosis as the adverse drug reactions.However,an effective preventive approach against drug-induced pulmonary fibrosis has not been established due to poor understanding of common preventive targets in a variety of drugs showing pulmonary toxicity.Epithelial-mesenchymal transition(EMT),a cellular phenotypic change of the epithelial to mesenchymal state,contributes to the development of pulmonary fibrosis through the conversion of damaged alveolar epithelium into myofibroblasts.As several drugs with pulmonary toxicity have been reported to induce EMT,EMT serves as a bridge between the drugs and pulmonary fibrosis.Accumulated evidence supports the potential of EMT as a preventive target against drug-induced pulmonary fibrosis.Additionally,since there are mechanistic differences between the main pharmacological effect and EMT induced by the drug,prevention based on EMT suppression would be possible and would contribute to continuous clinical treatment with the drug to avoid EMT-mediated serious pulmonary fibrosis.Furthermore,targeting EMT seems to be adequate for exerting a preventive effect since EMT in damaged alveolar epithelial cells occurs prior to the development of the pathophysiological state of the whole lung in a bleomycin-induced lung injury rat model.This viewpoint deals with the benefits and perspectives of preventive approaches against druginduced pulmonary fibrosis through the suppression of EMT,which has rarely been addressed.