Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. Structural and functional correlations in a large animal. Lysyl oxidase promotes bleomycininduced lung fibrosis. Although many different agents may damage the lung, the patterns of cellular injury and repair are relatively constant. Bleomycininduced diffuse interstitial pulmonary fibrosis in. The distal airway stemprogenitor cells dascs have been shown to have potent regenerative capacity after lung injury. Pdf antifibrotic mechanism of cinobufagin in bleomycin. Produces single and double stranded breaks in dna uses.
Mice deleted for the plasminogen activator inhibitor1 pai1 gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. Pulmonary delivery of docosahexaenoic acid mitigates. Idiopathic pulmonary fibrosis ipf is a chronic, progressive, fibrosing interstitial lung disease characterized by alveolar epithelial cell injury, aberrant proliferation of fibroblasts and excessive extracellular matrix ecm deposition leading to progressive fibrosis and loss of lung function, which accounts for about 20% of all cases of interstitial lung disease. We investigated the effects of ahr signals on the process of lung fibrosis and changes in immunological features using a bleomycin blminduced lung fibrosis mouse model. Two hours after pbsblm instillation, the animals received intratracheally either pbs alone or 2 x 105 peps or 4 x 105 bone marrowderived macrophages or 6 x 105 bone marrowderived dendritic cells all resuspended in 50 l of pbs to reach. The bleomycininduced pulmonary fibrosis model is the standard model of human lung fibrosis. Although amifostine has been found to protect lungs from the toxic effects of radiation and blm, its application is limited due to associated.
Lox expression is significantly upregulated in bleomycin blm induced lung fibrosis, and knockdown of lox expression or inhibition of lox activity alleviates the lung fibrosis. The mechanisms of cell toxicity are well described based on in vitro experiments on dna. Pirfenidone attenuates bleomycininduced pulmonary fibrosis. Idiopathic pulmonary fibrosis is characterized by loss of lung epithelial cells and inexorable progression of fibrosis with no effective and approved treatments. It leads to high mortality, and the average survival time after diagnosis is about 25 years. Antifibrotic mechanism of cinobufagin in bleomycininduced pulmonary fibrosis in mice article pdf available in frontiers in pharmacology 10. Get a printable copy pdf file of the complete article 5.
Idiopathic pulmonary fibrosis ipf is a chronic fibrotic lung disease that is prevalent in individuals 50 years of age, with a median survival of 35 years and limited therapeutic options. We found that gossypol dosedependently inhibits bleomycininduced collagen accumulation and tgf. Other, less common forms of lung injury include organizing pneumonia and hypersensitivity pneumonitis 3. We have previously shown that fibrosis is induced in isolated sheep lung. Idiopathic pulmonary fibrosis ipf is a severe and progressive respiratory disease with poor prognosis. Lung injury and fibrosis was induced in female c57bl6 mice by intratracheal instillation of 1. Oct 21, 2019 elucidating the cellular and molecular mechanism could help in the development of effective anti.
The aim of the study was, therefore, to investigate the effect of pde4 inhibition in experimental model of pf. The most serious complication of bleomycin, occurring upon increaing dosage, is pulmonary fibrosis and impaired lung function. Scfskp2 e3 ligase is a target for cancer therapy, but there have been no reports about skp2 as a target for ipf. These results suggest that further investigations regarding the role of n3 polyunsaturated fatty acids in fibrotic lung injury and repair are needed. In this work, we aimed to define the role of mouse dascs mdascs in response to bleomycin induced lung fibrosis. We examined whether disrupting skp2 suppressed pulmonary fibrosis in a bleomycin blminduced mouse. A predicted lossoffunction allele of capn9 is common in southeast asia, with the frequency of homozygosity matching the prediction of hardyweinberg equilibrium. Curdione attenuated bleomycininduced pulmonary fibrosis in mice. The angiogenic activity in the lung was significantly decreased, however, and cxcl11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. To the editor we have read with much interest the recent article by borzone and colleagues that found that bleomycin blminduced chronic lung damage does not resemble human idiopathic pulmonary fibrosis ipf. All animal care and experimental procedures complied with guidelines approved by. Cigarette smoking aggravates bleomycininduced experimental. Aryl hydrocarbon receptor signals attenuate lung fibrosis in.
Reversal of bleomycininduced rat pulmonary fibrosis by a xenograft. Bleomycin has been widely used in rodents to model pulmonary fibrosis for the study of mechanisms involved in fibrogenesis and for evaluation. Preclinical animal models are currently largely limited to small animals which have a number of shortcomings. The initial site of injury was the intima of pulmonary arteries and veins where endothelial cells became edematous and were separated from the underlying basement membrane by large blebs. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect.
In this work, we aimed to define the role of mouse dascs mdascs in response to bleomycininduced. Thus, we examined how the uptake of srt1720 affected fibrosis in bleomycintreated mice by histochemistry. The authors have undertaken a study evaluating the effect of pm on bleomycin induced pulmonary fibrosis in a murine model. Dasatinib attenuated bleomycininduced pulmonary fibrosis in mice article pdf available in growth factors 335 november 2015 with 407 reads how we measure reads.
Department of pediatrics of xijing hospital, fourth military medical university. Idiopathic pulmonary fibrosis ipf is a disease characterized by diffused alveolar inflammation and extensive interstitial fibrosis, which is related with various cells, inflammatory factors, fibrosis related cytokines, and transforming growth factor. After stimulating pulmonary fibrosis in spraguedawley rats by endotracheal injection of bleomycin. Tanshinone iia attenuates bleomycininduced pulmonary. Dasatinib attenuated bleomycininduced pulmonary fibrosis. Furthermore, in a model of bleomycin induced skin fibrosis, investigators showed mice lacking the pge 2 mpges1 null mice were resistant to bleomycin induced skin fibrosis. Idiopathic pulmonary fibrosis ipf is a progressive disease with poor prognosis and no curative therapies. Cxcl11 treatment significantly reduced bleomycinincluced pulmonary fibrosis without altering specific lung. In the present study, we investigated whether af1 has a protective effect against bleomycin induced pulmonary fibrosis.
Relaxin was previously shown to induce a matrixdegrading phenotype in human lung fibroblasts in vitro and to inhibit. This is comparable to the 90% increase in nrftreated in vitro compared with untreated nrf. The major limitation of bleomycin therapy is the potential for lifethreatening interstitial pulmonary fibrosis also called fibrosing alveolitis in up to 10 percent of patients receiving the drug. Pulmonary fibrosis pf is characterized by excessive accumulation of collagen in the lungs. In this study, we examined the application of diterpene phenol extract of rosmarinus officinalis dero as an antiinflammatory agent for treating bleomycin blm induced pulmonary fibrosis in rat model. Bleomycininduced chronic lung damage does not resemble. Surviving mice in the two groups appeared to overcome bleomycins toxicity. Pdf dasatinib attenuated bleomycininduced pulmonary. In this report, we use a miniosmotic pump model of bleomycin induced pulmonary fibrosis to investi. Little is known about salvage treatment for refractory cases. Phosphodiesterase pde 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. Particulate matter increases the severity of bleomycin.
The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. Fibrosis copyright 2019 calpain 9 as a therapeutic. This is the first report to show that no is an important factor in the progression of pulmonary fibrosis, and that no has protective effects against blm induced pulmonary fibrosis. Pulmonary fibrosis is a component of many interstitial lung diseases, including idiopathic pulmonary fibrosis, a chronic, progressive disease for which there is currently no effective therapy.
A 63yearold man who had been diagnosed with stage i seminoma and undergone a high orchiectomy 1 year previously. Aryl hydrocarbon receptor signals attenuate lung fibrosis. In the rat model, this drug attenuates bleomycininduced pulmonary fibrosis. These results would favor the conclusion that bleomycin induces pulmonary fibrosis, by causing directly andor indirectly lung. Tanshinone iia attenuates bleomycininduced pulmonary fibrosis via modulating angiotensinconverting enzyme 2 angiotensin17 axis in rats. We studied the coparticipation of elastase induced mild emphysema in bleomycin induced pf in mice by analyzing oxidative stress, inflammation and lung histology. Curdione attenuated bleomycin induced pulmonary fibrosis in mice. To evaluate the antioxidant effects of pomegranate seed extract pse on bleomycin treated rats.
Pf was induced in c57bl6n mice by instillation of bleomycin. Rightmiddlelobes wereresected at this timein five bleomycintreated andtwocontrol animals. Bleomycin blm is an effective curative option in the management of several malignancies including pleural effusions. Srt1720, a sirt1 activator, aggravates bleomycininduced. Huajie wu 1,3, yan li 4, yanxia wang 2,3, dunquan xu 2, congcong li 5, manling liu 2, xin sun 1, zhichao li 2,3. Oxidative stress plays an important role in the pathogenesis of bleomycininduced lung fibrosis and many antioxidant agents have been used for the treatment of this disease in animals. Tumour necrosis factor tnf, secreted by activated am, has been strongly implicated in the pathogenesis of pulmonary fibrosis zhang et al. A 63yearold man who had been diagnosed with stage i seminoma and undergone a high orchiectomy 1 year. Our findings demonstrate that intratracheal administration of dha, a single pufa, protected mice from the development of bleomycininduced pulmonary inflammation and fibrosis. One of the major limits of histological scoring concerns the fact that it is observerdependent and consequently subject to variability, which may preclude comparative studies between different laboratories. Pulmonary fibrosis pf is the final stage of various interstitial lung. Emphysema is characterized by loss of the extracellular matrix ecm and alveolar enlargement. Combination of salvia miltiorrhiza and ligustrazine.
Original article inhibition of bleomycininduced pulmonary. Preventive effects of pomegranate seed extract on bleomycin. Curdione ameliorates bleomycininduced pulmonary fibrosis. After 4565 ukg of bleomycin, lung volumes and diffusing capacity were reduced, and static lungpressurevolumecurves wereshifted to the right. We investigated the effects of ahr signals on the process of lung fibrosis and changes in immunological features using a bleomycin blm induced lung fibrosis mouse model. Bleomycin induced lung injury pulmonary fibrosis ipf bleomycin is a chemotherapeutic agent used to treat cancers such as hodgkins lymphoma. Lung epithelial progenitors protect from bleomycin induced. Bleomycin induces dna strand breaks, resulting in pulmonary inflammation, injury, and subsequent interstitial fibrosis. Here we demonstrate that skp2 is a promising therapeutic target for ipf. Effects of phosphodiesterase 4 inhibition on bleomycin. The mechanism of bleomycininduced pneumonitis bip involves oxidative damage, relative deficiency of the deactivating. Here, we employed a mouse model of bleomycininduced pulmonary fibrosis to test whether gossypol inhibits pulmonary fibrosis in vivo. First, the toxic effects of curdione to the mice and cells were.
Several studies have reported that in the early stages of lung damage induced by bleomycin, the lesions are associated with biochemical and functional changes that resemble those of human pulmonary fibrosis, namely, inflammatory cell infiltration, increased. Prevention and treatment of bleomycininduced pulmonary. Oxidative damage deficiency of bleomycin hydrolase genetic susceptibility inflammatory cytokines fibrosis incidence. Proteaseactivated receptor par1 is a gproteincoupled receptor that mediates critical signalling pathways in pathology and physiology. The pathogenesis of bleomycininduced pulmonary fibrosis in mice. To evaluate the antioxidant effects of pomegranate seed. Idiopathic pulmonary fibrosis ipf is a progressive lung disease with no effective medication. We found bleomycin induced pulmonary fibrosis in mice, and cigarette smoking augmented bleomycin induced fibrosis reflected by both in fibrotic area and percentages of collagen in the lungs. Andrographolide andro, extracted from chinese herbal andrographis paniculata, could attenuate bleomycin blm induced pulmonary fibrosis via inhibition of inflammation and oxidative stress, however, the antifibrotic mechanisms have not been clarified. It has been suggested that bleomycin induces sensitivity to oxygen toxicity and recent studies support the role of the proinflammatory cytokines il18 and il1beta in the mechanism of bleomycininduced lung injury. Nitric oxide exerts protective effects against bleomycin. This scarring makes the lungs stiffer and affects the exchange of oxygen and carbon dioxide in the. Serotonin exhibits accelerated bleomycininduced pulmonary.
Apr 18, 2017 oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis ipf. Idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. Oxidative stress plays an important role in the pathogenesis of bleomycin induced lung fibrosis and many antioxidant agents have been used for the treatment of this disease in animals. The equilibrium of nuclear factorerythroidrelated factor 2 nrf2btb broadcomplex, tramtrack and bricabrac and cnc capncollar protein homology 1, bach1 determines the expression level of antioxidant factors, further regulating the function of oxidation. In a preclinical model, systemic administration of cxcl11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycintreated mice. In the process, the study aimed to identify, isolate and characterize stem cells of the adult lung. Curdione ameliorates bleomycininduced pulmonary fibrosis by. Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and hodgkins lymphoma. Resolution of bleomycininduced murine pulmonary fibrosis via a.
Bleomycins are a family of compounds produced bystreptomyces verticillis. Characterization of lung stem cell niches in a mouse model of. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Amifostine analog, drde30, attenuates bleomycininduced. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. With poor prognosis and aberrant lung remodeling, pulmonary fibrosis exhibits worldwide prevalence accompanied by an increase in burden in terms of hospitalization and death. The results suggest that cxcl11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling. Andrographolide ameliorates bleomycininduced pulmonary.
This unit describes methods for delivering bleomycin, either directly into the lung or systemically, to create models of pulmonary fibrosis in rodents. Therefore, we investigated the effect of exogenous mdascs by transplanting them into the lungs of bleomycininjured mice. Blm was administered intratracheally to c57bl6jjcl mice and either 5,11dihydroindolo3,2bcarbazole6carboxaldehyde ficz, a natural ahr ligand, or vehicle was. Conditional deletion of nedd42 in lung epithelial cells. The preclinical model of bleomycin induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis ipf, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. Posttreatment with protectin dx ameliorates bleomycin. Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. Our findings demonstrate that intratracheal administration of dha, a single pufa, protected mice from the development of bleomycin induced pulmonary inflammation and fibrosis. Bleomycin induces epithelialtomesenchymal transition via. Prevention of bleomycininduced pulmonary fibrosis by a.
It has been suggested that bleomycin induces sensitivity to oxygen toxicity and recent studies support the role of the proinflammatory cytokines il18 and il1beta in the mechanism of bleomycin induced lung injury. Cxcl11 attenuates bleomycininduced pulmonary fibrosis via inhibition of vascular remodeling marie d. The protective effect of naringin against bleomycininduced. Borzone g, moreno r, urrea r et al 2001 bleomycininduced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. We aimed to investigate the effect of two ppar ligands, telmisartan and rosiglitazone, on lung injury and fibrosis induced by intratracheal bleomycin blm. Antiflammin1 attenuates bleomycininduced pulmonary fibrosis. Hence we used the bleomycin induced pulmonary fibrosis model. Get a printable copy pdf file of the complete article 1.
For this purpose, the mice were administered with curdione for every 2 days, followed by blm injection as described. Microrna profiling implicates the insulinlike growth. Prevention and treatment of bleomycininduced pulmonary fibrosis. Reversal of bleomycininduced rat pulmonary fibrosis. We believe that there is a model of blminduced lung fibrosis that more closely resembles the pathological and functional changes observed in human ipf. Apr 24, 2018 bleomycin blm is an effective curative option in the management of several malignancies including pleural effusions. Jci bleomycininduced pulmonary fibrosis in fibrinogen. Methods pulmonary fibrosis was induced by intranasal instillation of bleomycin into wildtype mice with or without a specific par1 antagonist ie, p1pal12, a pepducin that blocks the par1gprotein interaction. The bleomycin model of pulmonary fibrosis springerlink. Cxcl11 attenuates bleomycininduced pulmonary fibrosis via. The aim of this study was to investigate the role of 5ht in bleomycin blm induced pulmonary fibrosis through wildtype c57bl6 wt and tph1 knockout. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Bleomycin induces molecular changes directly relevant to.
The aim of the current study was to investigate the protective effect of naringin on bleomycininduced pulmonary fibrosis in rats. Pulmonary fibrosis was induced in eight baboons with bleomycin. After 4565 ukg of bleomycin, lung volumes and diffusing capacity were reduced, and static lung pressurevolume curves were shifted to the right. Bleomycin is a cytostatic drug commonly employed in the treatment of cancer. Abstract pulmonary fibrosis was induced in eightbaboons with bleomycin. Antifibrotic mechanism of cinobufagin in bleomycininduced. Srt1720, a sirt1 activator, aggravates bleomycininduced lung. In the present study, we investigated the underlying mechanism behind bleomycin. We hypothesized that pai1 deficiency reduces fibrosis by promoting plasminogen activation and accelerating the clearance of fibrin matrices that accumulate within the damaged lung. Fibrosis was assessed by hydroxyproline analysis, immunohistochemistry, quantitative pcr and western blot for fibrotic markers expression. Jan 14, 2020 among the numerous pulmonary fibrosisemt models, the most common and successful model is bleomycininduced pulmonary fibrosisemt, both in vivo and in vitro 17,24,36. Bleomycininduced lung injury usually occurs in 318% of treated patients this figure will vary dependent on detection method used, although there is a marked increased risk if the total cumulative dose is more than 450 units. Tanshinone iia attenuates bleomycin induced pulmonary fibrosis via modulating angiotensinconverting enzyme 2 angiotensin17 axis in rats. One of the side effects is pulmonary toxicity, which can be life threatening in approximately 10% of patients.
In our study, we see similar levels of pge 2 in the first 7 days after bleomycin injury but these levels markedly decrease in the dhatreated mice at late time points. Strict guidelines from the committee were followed regarding the care and handling of mice, anesthesia, and. Differential mechanisms of the effect of peroxisome. Although amifostine has been found to protect lungs from the toxic effects of radiation and blm, its application is limited due to associated toxicity. Posttreatment with protectin dx ameliorates bleomycininduced pulmonary fibrosis and lung dysfunction in mice. Bleomycin lung toxicity radiology reference article. After animals are sacrificed, lung weight, collagen content and fibrosis scores are determined. Elucidating the cellular and molecular mechanism could help in the development of effective anti. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the. In this report, we use a miniosmotic pump model of bleomycininduced pulmonary fibrosis to investi.
Idiopathic pulmonary fibrosis ipf is a chronic lung condition that is. We examined whether disrupting skp2 suppressed pulmonary fibrosis in a bleomycin blm induced mouse. Research open access microrna profiling implicates the. Distal airway stem cells ameliorate bleomycininduced. Right middle lobes were resected at this time in five bleomycin treated and two control animals. We first sought to evaluate the effects of curdione on the development of pulmonary fibrosis. Background idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Pulmonary fibrosis pf is a group of devastating and largely irreversible diseases.
Among the numerous pulmonary fibrosisemt models, the most common and successful model is bleomycininduced pulmonary fibrosisemt, both in vivo and in vitro 17,24,36. Elastase modifies bleomycininduced pulmonary fibrosis in. The mechanism of bleomycin induced lung injury includes oxidative damage via oxidantmediated. Bleomycininduced interstitial pulmonary fibrosis in baboons. Antiflammin1 af1, a derivative of uteroglobin ug, is a synthetic nonapeptide with diverse biological functions. Bleomycin treatment by miniosmotic pump produced a pulmonary fibrosis in c57bl6j mice consisting of regions of subpleural atelectasis, at six weeks post treatment, as shown in figure 1a, which is consistent with previous reports of this model 3, 33, 34. Mechanisms of bleomycininduced lung damage springerlink.
Previous studies verified that blm can induce emt of a549 cells via the tgf. Srt1720 enhances lung fibrosis in bleomycintreated mice. Enzymes involved in collagen biosynthesis, including lysyl oxidase lox, have been proposed as potential therapeutic targets for idiopathic pulmonary fibrosis. Bleomycin was administrated by intraperitoneal injection at a dose of 40 mgkg on days 1, 5, 8, 11 and 15. Pulmonary fibrosis is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis of the pulmonary interstitium alveolar walls and septa, perivascular, perilymphatic and peribronchiolar connective tissues. With regard to the roles of no in the progression of fibrosis, there have been several reports showing the protective roles of no in cardiac 22 and renal 23. It is believed that lung inflammation initiates lung fibrosis, however, the etiological mechanism of this disease has not yet been fully elucidated. May 29, 2012 fibrosis induced by bleomycin was a deliberate injury given to the lung tissue to tease out progenitors residing within the tissue for exigencies. Quantification of pulmonary fibrosis in a bleomycin mouse. Cellular senescence and emt crosstalk in bleomycin.
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