The current therapeutic approaches for this condition are unsatisfactory. After animals are sacrificed, lung weight, collagen content and fibrosis scores are determined. Two therapies, nintedanib and pirfenidone, are fda approved and are recommended by clinical practice guidelines for the treatment of ipf. Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and hodgkins lymphoma. Radiationinduced pulmonary fibrosis refers to a condition of inflammation and subsequent scarring of lung tissues caused by radiation. Rightmiddlelobes wereresected at this timein five bleomycintreated andtwocontrol animals. The prevalence and incidence of ipf appears to be increasing over the. Pulmonary fibrosis induced by h5n1 viral infection in mice. Bleomycin in the setting of lung fibrosis induction. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a. If you are a society or association member and require assistance with obtaining online access instructions please contact our journal customer services team. Quantification of pulmonary fibrosis in a bleomycin mouse. Prevention of bleomycininduced pulmonary fibrosis by a. 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.
Bleomycin induced pulmonary fibrosis in mice that are genetically deficient in fibrinogen. Diagnosis of idiopathic pulmonary fibrosis american thoracic. Abstract pulmonary fibrosis was induced in eightbaboons with bleomycin. The mechanism of bleomycininduced pneumonitis bip involves oxidative damage, relative deficiency of the deactivating. Oxidative damage deficiency of bleomycin hydrolase genetic susceptibility inflammatory cytokines fibrosis incidence. Pulmonary fibrosis is induced by a strong inflammatory response to lung injury. Characterizing idiopathic pulmonary fibrosis patients using us. Bleomycininduced lung fibrosis to study novel compounds against idiopathic pulmonary fibrosis ipf, we optimized the bleomycininduced lung fibrosis model in mice. Antiflammin1 attenuates bleomycininduced pulmonary fibrosis. Here we compared mouse lung fibrosis induced by pulmonary. Melatonin inhibits endoplasmic reticulum stress and. Dec 01, 2000 mice deleted for the plasminogen activator inhibitor1 pai1 gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy.
Jci bleomycininduced pulmonary fibrosis in fibrinogennull. The bleomycin induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions despite the wellrecognized dissimilarities. Our findings suggest that af1 has potential as a new therapeutic tool for pulmonary fibrosis. Drug induced pulmonary disease is lung disease brought on by a bad reaction to a medicine. In the bleomycininduced pulmonary fibrosis model, tlr2 expression was detected in 29. Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. Rightmiddlelobes wereresected at this timein five bleomycin treated andtwocontrol animals. Longitudinal assessment of bleomycininduced lung fibrosis. The bleomycininduced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions despite the wellrecognized dissimilarities. Approaches to inducing experimental pulmonary fibrosis fig. However, in this model, mmp7 levels were measured and found to not be induced by bleomycin instillation. 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. Ongoing challenges in pulmonary fibrosis and insights from the. While recent ipf treatment guidelines listed this threedrug combination.
Although some types of pulmonary fibrosis maintain a signif. Sequence of events in bleomycininduced pulmonary fibrosis after administration of bleomycin, there is the onset of an acute inflammatory response lasting up to 8 days, followed by fibrogenic changes resulting in deposition of matrix and distortion of lung structure out to 28 or 35 days. Feitai attenuates bleomycininduced pulmonary fibrosis in rats. Many types of lung injury can result from medicines. Understanding the mechanisms of blm induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. The bleomycininduced pulmonary fibrosis model is the standard model of human lung fibrosis. Idiopathic pulmonary fibrosis ipf is a chronic progressive interstitial lung disease that causes chronic respiratory distress and cough, which. This improved model is induced by oropharyngeal administration of bleomycin into the lungs of c57bl6 mice. Idiopathic pulmonary fibrosis ipf is a chronic, progressive. Idiopathic pulmonary fibrosis american thoracic society.
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. N induces emt during radiation induced and bleomycin induced pulmonary fibrosis. This study was undertaken to test the hypothesis that the histologic pattern of bleomycininduced lung damage in the chronic stages in the rat does not really mimic the particular histologic pattern of usual interstitial pneumonia uip, the pattern that defines idiopathic pulmonary fibrosis ipf in human beings. Idiopathic pulmonary fibrosis ipf is the most common and predominantly lethal form. Bleomycininduced pulmonary fibrosis in fibrinogennull mice. Apr 10, 2017 development of pulmonary fibrosis induced by intratracheal administration of bleomycin in mice is often unpredictable. Hirsutella sinensis mycelium attenuates bleomycininduced. Metformin reduces bleomycininduced pulmonary fibrosis in mice. The pathogenesis of bleomycininduced 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.
Diffuse pulmonary fibrosis is associated with bleomycin administration to humans. In the 2011 ats ersjrsalat guidelines for ipf diagnosis and. Pulmonary toxicity of bleomycin a case series from a. Idiopathic pulmonary fibrosis ipf is a chronic and progressive disease characterized by the aberrant deposition of extracellular matrix leading to extensive lung remodeling. Idiopathic pulmonary fibrosis ipf is a progressive and irreversible lung disease of unclear etiology that predominantly occurs in middleaged and elderly adults 1,2.
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. Antiflammin1 af1, a derivative of uteroglobin ug, is a synthetic nonapeptide with diverse biological functions. Metformin reduces bleomycininduced pulmonary fibrosis in. This study was undertaken to test the hypothesis that the histologic pattern of bleomycin induced lung damage in the chronic stages in the rat does not really mimic the particular histologic pattern of usual interstitial pneumonia uip, the pattern that defines idiopathic pulmonary fibrosis ipf in human beings. Abstract idiopathic pulmonary fibrosis ipf is a destructive inflammatory disease with limited therapeutic options. Recent work by usuki and fukuda 48 clearly documented this. Phan, jamesvarani, anddavid smith department ofpathology, university ofmichigan medicalschool, annarbor, michigan 48109 abstract endotracheal bleomycin administration in rats andotheranimal species causes rapid development ofpulmonary fibrosis, characterized by increased lung collagen synthesis and.
One hundred and twenty male spraguedawley rats were randomly divided into four groups, referred to as the salinewater, salinefeitai, blmwater, and blmfeitai groups. Idiopathic pulmonary fibrosis ipf is a severe and progressive respiratory disease with poor prognosis. This study aimed to determine the antiinflammatory effects of pn against bleomycininduced pulmonary fibrosis in mice. Although the relative importance of inflammation in the progression of pulmonary fibrosis has been debated, many forms of the disease are believed to be induced, at least initially, by a strong inflammatory response crystal et al. Jnk inhibition reduces lung remodeling and pulmonary. The mechanism of bleomycin induced pneumonitis bip involves oxidative damage, relative deficiency of the.
Bleomycininduced interstitial pulmonary fibrosis in baboons. Ipf also belongs to a group of interstitial lung diseases that are characterized by various patterns of inflammation and fibrosis. Two recovered following treatment and one patient died due to irreversible pulmonary damage. Dysregulated cell signaling in pulmonary fibrosis fig. This direct cellular damage can lead to bleomycininduced pulmonary fibrosis also called.
Bleomycin has been widely used in rodents to model pulmonary fibrosis for the study of mechanisms involved in fibrogenesis and for evaluation of. Blm 100 mgkg body weight was administered to c57bl6 mice. The jnk inhibitor cc930 had previously been tested in the mouse bleomycininduced pulmonary fibrosis model, having shown a dosedependent reduction in lung fibrosis scores. Changes in pulmonary endothelial cell properties during bleomycin. It is usually impossible to predict who will develop lung disease from a medicine. Lung with endstage pulmonary fibrosis and honeycombing fig.
The bleomycin induced pulmonary fibrosis model is the standard model of human lung fibrosis. Molecular and cellular mechanisms of pulmonary fibrosis. Research open access antiflammin1 attenuates bleomycin. Antiflammin1 af1, a derivative of uteroglobin ug, is a synthetic nonapeptide with diverse. Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment. There is a high degree of variability among individual animals in the extent of fibrosis and the fibrosis often tends to resolve spontaneously if inhaled bleomycin is administered as single shot. In the bleomycin induced pulmonary fibrosis model, tlr2 expression was detected in 29. Because ug plays an important role in inhibiting pulmonary fibrosis, we sought to determine whether af1 could also protect against pulmonary fibrosis.
Research open access antiflammin1 attenuates bleomycininduced pulmonary fibrosis in mice wei liu1, jing wan1, jianzhong han1, chen li1,3, dandan feng1, shaojie yue2, yanhong huang1, yi chen1, qingmei cheng1, yang li1 and ziqiang luo1 abstract background. Although this is age and dose related, the toxicity is unpredictable. The fibrosis was atypical in its distribution and not readily compatible with typical forms of pulmonary fibrosis, and was finally attributed to the longterm use of nitrofurantoin. Histopathology is the gold standard for assessing lung fibrosis in rodents, however it precludes repeated and longitudinal. Dailymed bleomycin bleomycin sulfate injection, powder.
The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycininduced pulmonary fibrosis in rats. Dec 31, 2019 pulmonary toxicities occur in 10% of treated patients. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Overview of idiopathic pulmonary fibrosis, evidencebased. Resolution of bleomycininduced murine pulmonary fibrosis.
Relaxin was previously shown to induce a matrixdegrading phenotype in human lung fibroblasts in vitro and to inhibit. The present study investigated the effects of melatonin on endoplasmic reticulum er stress and epithelialmesenchymal transition emt during blminduced lung fibrosis. Hydrolysis of cyclic nucleotides by phosphodiesterases fig. Pirfenidone attenuates bleomycininduced pulmonary fibrosis. This condition is relatively common and follows radiation therapy administered to the chest region for certain cancers such as breast, lung, and neck cancers. All three developed bleomycin induced pulmonary toxicity in the form of pulmonary fibrosis during treatment of the disease. Jci bleomycininduced pulmonary fibrosis in fibrinogen. Panax notoginseng attenuates bleomycininduced pulmonary. Complications may include pulmonary hypertension, respiratory failure, pneumothorax, and lung cancer.
The sequential reactions of lung cells to this drug have now been investigated in mice following injection of 20 mgkg bleomycin twice per week for 4 to 8 weeks. Pulmonary fibrosis is the formation of scar tissue in the small air sacs alveoli of the lungs. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Nlrp3 participates in the regulation of emt in bleomycin. Dec 16, 2018 radiation induced pulmonary fibrosis refers to a condition of inflammation and subsequent scarring of lung tissues caused by radiation. Feitai, a composite formula consisting of several herbs, is used in china as a folk remedy for treating patients with pulmonary tuberculosis. Bleomycininduced chronic lung damage does not resemble.
Frequent roentgenograms are recommended see adverse reactions, pulmonary. As a matter of fact, a medline search of the last five years 19972001 showed that among 100 articles on pulmonary fibrosis induced by bleomycin having the method of administration explicited in the abstract, 83% used the single intratracheal dose of bleomycin and 17% used either repeated intratracheal doses or other routes of bleomycin. Panax notoginseng pn is a traditional chinese herb experimentally proven to have antiinflammatory effects, and it is used clinically for the treatment of atherosclerosis, cerebral infarction, and cerebral ischemia. Idiopathic pulmonary fibrosis ipf is a rare lifethreating interstitial. In the present study, we investigated whether af1 has a protective effect against bleomycin induced pulmonary fibrosis. Bleomycininduced pulmonary fibrosis in mice that are genetically deficient in fibrinogen. Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. Microrna profiling implicates the insulinlike growth. Druginduced pulmonary disease is lung disease brought on by a bad reaction to a medicine. 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. Microrna profiling implicates the insulinlike growth factor. Structural and functional correlations in a large animal. Mode of treatment, severity of the condition and the treatment outcome varied among the three. We hypothesized that pai1 deficiency reduces fibrosis by promoting plasminogen activation and accelerating the clearance of fibrin matrices that accumulate within the damaged lung.
After 4565 ukg of bleomycin, lung volumes and diffusing capacity were reduced, and static lungpressurevolumecurves wereshifted to the right. Apr 24, 2018 idiopathic pulmonary fibrosis ipf is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Pulmonary toxicities occur in 10% of treated patients. Get a printable copy pdf file of the complete article 5. Microanatomy of bleomycin induced lung fibrosis intratracheal administration of bleomycin to rodents is considered to thoroughly reproduce the histologic alterations that are found in human pulmonary fibrosis. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for il17a. Dasatinib attenuated bleomycininduced pulmonary fibrosis. Other, less common forms of lung injury include organizing pneumonia and hypersensitivity pneumonitis 3. Idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. Development and timecourse of bleomycininduced pulmonary. Home prereg pharmacist drug induced lung disease the table below lists some drugs known to cause drug induced lung disease drug pulmonary syndromes amiodarone interstitial pneumonitis or pulmonary fibrosis, pleural effusions, pulmonary infiltrate with anticoagulants, bleomycin, bromocriptine, busulfan, granulocytemacrophage colonystimulating factor, il2. Preclinical animal models are currently largely limited to small animals which have a number of shortcomings.
This condition can be suspected if the patient has been exposed to a likely causative drug, develops new signs and symptoms, and has a remittence of these symptoms once the drug is withheld. We found that af1 attenuated bleomycininduced pulmonary fibrosis. Mouse models of bleomycininduced pulmonary fibrosis. Despite the fact that effective treatments are absent and the. Original article metformin ameliorates bleomycininduced. Guidelines for the diagnosis and treatment of idiopathic pulmonary. Pulmonary fibrosis may also result in an increased risk for pulmonary emboli, which can be prevented by anticoagulants. The pulmonary fibrosis model induced by intratracheal injection of blm is one of the most widely used methods worldwide, as it is similar to human pulmonary fibrosis 28. Emt participates in the process of blminduced pulmonary fibrosis we first confirmed the median lethal dose of blm in a549 and rle6tn cells using the cck8 assay. As mouse models of bleomycin induced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease. The bleomycin model of pulmonary fibrosis request pdf.
Common and distinct mechanisms of induced pulmonary fibrosis by. 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. Vagotomy attenuates bleomycininduced pulmonary fibrosis. In these two mouse models, pulmonary fibrosis is caused by radiation induced or bleomycin. The result indicated that the appropriate concentrations of blm in treated cells at 24 h were 120. Understanding the mechanisms of blminduced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating. Apr 18, 2017 oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis ipf. Case presentation a 51yearold woman was admitted with progressive shortness of breath. Types of lung problems or diseases that may be caused by medicines include. It leads to high mortality, and the average survival time after diagnosis is about 25 years. This induces aberrant myofibroblast differentiation.
The above results showed that pai1 deficiency enhances fibrinolytic activity and limits both fibrin accumulation and collagen deposition after bleomycin administration. Resolution of blminduced murine pulmonary fibrosis by the adoptive transfer of splenocytes. Bleomycininduced chronic lung damage does not resemble human. Pulmonary fibrosis is a chronic, progressive, and irreversible condition that occurs in many clinical situations. Bleomycininduced pulmonary fibrosis is a widely used experimental model for human lung fibrosis. Because whole splenocytes can ameliorate lpsinduced lung injury in mice, as an initial assessment, we examined the potency of the adoptive transfer of splenocytes in ameliorating blminduced murine pulmonary fibrosis.
The intratracheal instillation of bleomycin in mice induces early damage to alveolar epithelial cells and development of inflammation followed by fibrotic tissue changes and represents the most widely used model of pulmonary fibrosis to investigate human ipf. The pathogenesis of bleomycininduced pulmonary fibrosis in mice. 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. Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix ecm and remodeling of the lung architecture. We have previously shown that fibrosis is induced in isolated sheep lung. Interstitial lung diseases ilds and pulmonary fibrosis are. Vagotomy attenuates bleomycininduced pulmonary fibrosis in. This study aimed to determine the antiinflammatory effects of pn against bleomycin induced pulmonary fibrosis in mice.
Resolution of bleomycininduced murine pulmonary fibrosis via. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Although surgical lung biopsy was recommended by the 2011 international guidelines. Bleomycin lung toxicity radiology reference article. Druginduced pulmonary toxicity is a diagnosis of exclusion. Several reports indicate that melatonin alleviates bleomycin blminduced pulmonary fibrosis in rodent animals.
Inken wierstra, in advances in cancer research, 20. As mouse models of bleomycininduced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease. 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 may worsen over time and can sometimes lead to early heart failure. Idiopathic pulmonary fibrosis ipf is a devastating disease, which is characterized. Mice deleted for the plasminogen activator inhibitor1 pai1 gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. Longitudinal assessment of bleomycininduced lung fibrosis by. In this study, we extensively investigate the effects and mechanisms of feitai on bleomycin blminduced pulmonary fibrosis in rats. Microanatomy of bleomycininduced lung fibrosis intratracheal administration of bleomycin to rodents is considered to thoroughly reproduce the histologic alterations that are found in human pulmonary fibrosis. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. Fibrosisin duced destruction of the lung parenchyma can be fatal 1,2. Dasatinib attenuated bleomycin induced pulmonary fibrosis in mice article pdf available in growth factors 335 november 2015 with 410 reads how we measure reads. Pulmonary fibrosis is a condition in which the lungs become scarred over time. This scarring makes the lungs stiffer and affects the exchange of oxygen and carbon dioxide in the alveoli.
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