The prevalence and incidence of ipf appears to be increasing over the. Pulmonary fibrosis is the formation of scar tissue in the small air sacs alveoli of the lungs. Dailymed bleomycin bleomycin sulfate injection, powder. 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. Complications may include pulmonary hypertension, respiratory failure, pneumothorax, and lung cancer.
Rightmiddlelobes wereresected at this timein five bleomycin treated andtwocontrol animals. While recent ipf treatment guidelines listed this threedrug combination. This condition is relatively common and follows radiation therapy administered to the chest region for certain cancers such as breast, lung, and neck cancers. Vagotomy attenuates bleomycininduced pulmonary fibrosis in. Resolution of blminduced murine pulmonary fibrosis by the adoptive transfer of splenocytes. Antiflammin1 af1, a derivative of uteroglobin ug, is a synthetic nonapeptide with diverse. Longitudinal assessment of bleomycininduced lung fibrosis. Idiopathic pulmonary fibrosis ipf is a chronic, progressive.
The mechanism of bleomycininduced pneumonitis bip involves oxidative damage, relative deficiency of the deactivating. 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. Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment. 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. Druginduced pulmonary disease is lung disease brought on by a bad reaction to a medicine. Changes in pulmonary endothelial cell properties during bleomycin. Idiopathic pulmonary fibrosis ipf is a chronic progressive interstitial lung disease that causes chronic respiratory distress and cough, which. We believe that there is a model of blminduced lung fibrosis that more closely resembles the pathological and functional changes observed in human ipf. Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and hodgkins lymphoma.
Drug induced pulmonary disease is lung disease brought on by a bad reaction to a medicine. 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. This direct cellular damage can lead to bleomycininduced pulmonary fibrosis also called. Pulmonary toxicities occur in 10% of treated patients. Idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. In the bleomycin induced pulmonary fibrosis model, tlr2 expression was detected in 29. Metformin reduces bleomycininduced pulmonary fibrosis in mice. Get a printable copy pdf file of the complete article 5. Hirsutella sinensis mycelium attenuates bleomycininduced. 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. Bleomycininduced pulmonary fibrosis is a widely used experimental model for human lung fibrosis. Feitai, a composite formula consisting of several herbs, is used in china as a folk remedy for treating patients with pulmonary tuberculosis. Feitai attenuates bleomycininduced pulmonary fibrosis in rats. In this study, we extensively investigate the effects and mechanisms of feitai on bleomycin blminduced pulmonary fibrosis in rats.
Idiopathic pulmonary fibrosis ipf is the most common and predominantly lethal form. We found that af1 attenuated bleomycininduced pulmonary fibrosis. Dec 16, 2018 radiation induced pulmonary fibrosis refers to a condition of inflammation and subsequent scarring of lung tissues caused by radiation. Longitudinal assessment of bleomycininduced lung fibrosis by. The pathogenesis of 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. Bleomycininduced lung fibrosis to study novel compounds against idiopathic pulmonary fibrosis ipf, we optimized the bleomycininduced lung fibrosis model in mice. 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. Many types of lung injury can result from medicines. N induces emt during radiation induced and bleomycin induced pulmonary fibrosis. Original article metformin ameliorates bleomycininduced. Bleomycininduced pulmonary fibrosis in mice that are genetically deficient in fibrinogen. Metformin reduces bleomycininduced pulmonary fibrosis in. Preclinical animal models are currently largely limited to small animals which have a number of shortcomings.
To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a. 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. 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. 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.
Dysregulated cell signaling in pulmonary fibrosis fig. 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. Diagnosis of idiopathic pulmonary fibrosis american thoracic. Bleomycininduced chronic lung damage does not resemble human. Idiopathic pulmonary fibrosis ipf is a devastating disease, which is characterized. 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. Because ug plays an important role in inhibiting pulmonary fibrosis, we sought to determine whether af1 could also protect against pulmonary fibrosis. Apr 18, 2017 oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis ipf. Here we compared mouse lung fibrosis induced by pulmonary. 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.
Histopathology is the gold standard for assessing lung fibrosis in rodents, however it precludes repeated and longitudinal. Types of lung problems or diseases that may be caused by medicines include. Jnk inhibition reduces lung remodeling and pulmonary. 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. 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.
Approaches to inducing experimental pulmonary fibrosis fig. 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 animals are sacrificed, lung weight, collagen content and fibrosis scores are determined. The severity of fibrosis varies among different strains of mice and investigation on different strains and finding the mechanisms of variation is important in understanding the pathogenesis of. 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. Overview of idiopathic pulmonary fibrosis, evidencebased. This study aimed to determine the antiinflammatory effects of pn against bleomycin induced pulmonary fibrosis in mice. Hydrolysis of cyclic nucleotides by phosphodiesterases fig. Bleomycininduced chronic lung damage does not resemble. Idiopathic pulmonary fibrosis ipf is a severe and progressive respiratory disease with poor prognosis.
Nlrp3 participates in the regulation of emt in bleomycin. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Abstract idiopathic pulmonary fibrosis ipf is a destructive inflammatory disease with limited therapeutic options. After 4565 ukg of bleomycin, lung volumes and diffusing capacity were reduced, and static lungpressurevolumecurves wereshifted to the right.
Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. In the 2011 ats ersjrsalat guidelines for ipf diagnosis and. Frequent roentgenograms are recommended see adverse reactions, pulmonary.
Idiopathic pulmonary fibrosis ipf is a chronic and progressive disease characterized by the aberrant deposition of extracellular matrix leading to extensive lung remodeling. Rightmiddlelobes wereresected at this timein five bleomycintreated andtwocontrol animals. Bleomycininduced pulmonary fibrosis in fibrinogennull mice. Inken wierstra, in advances in cancer research, 20.
Despite the fact that effective treatments are absent and the. Pulmonary fibrosis is induced by a strong inflammatory response to lung injury. Antiflammin1 af1, a derivative of uteroglobin ug, is a synthetic nonapeptide with diverse biological functions. The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycininduced pulmonary fibrosis in rats. Recent work by usuki and fukuda 48 clearly documented this.
Pulmonary fibrosis may also result in an increased risk for pulmonary emboli, which can be prevented by anticoagulants. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Oxidative damage deficiency of bleomycin hydrolase genetic susceptibility inflammatory cytokines fibrosis incidence. The bleomycin induced pulmonary fibrosis model is the standard model of human lung fibrosis. The mechanism of bleomycin induced pneumonitis bip involves oxidative damage, relative deficiency of the. If you are a society or association member and require assistance with obtaining online access instructions please contact our journal customer services team. Bleomycin lung toxicity radiology reference article. The jnk inhibitor cc930 had previously been tested in the mouse bleomycininduced pulmonary fibrosis model, having shown a dosedependent reduction in lung fibrosis scores. In these two mouse models, pulmonary fibrosis is caused by radiation induced or bleomycin. Antiflammin1 attenuates bleomycininduced pulmonary fibrosis. In the present study, we investigated whether af1 has a protective effect against bleomycin induced pulmonary fibrosis. Case presentation a 51yearold woman was admitted with progressive shortness of breath. Pulmonary fibrosis may worsen over time and can sometimes lead to early heart failure.
Development and timecourse of bleomycininduced pulmonary. Apr 10, 2017 development of pulmonary fibrosis induced by intratracheal administration of bleomycin in mice is often unpredictable. Ipf also belongs to a group of interstitial lung diseases that are characterized by various patterns of inflammation and fibrosis. Although some types of pulmonary fibrosis maintain a signif. 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. 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. 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. This study aimed to determine the antiinflammatory effects of pn against bleomycininduced pulmonary fibrosis in mice. 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. This improved model is induced by oropharyngeal administration of bleomycin into the lungs of c57bl6 mice. Druginduced pulmonary toxicity is a diagnosis of exclusion. Other, less common forms of lung injury include organizing pneumonia and hypersensitivity pneumonitis 3.
Abstract pulmonary fibrosis was induced in eightbaboons with bleomycin. Lung with endstage pulmonary fibrosis and honeycombing fig. Bleomycin in the setting of lung fibrosis induction. Bleomycin induced pulmonary fibrosis in mice that are genetically deficient in fibrinogen. All three developed bleomycin induced pulmonary toxicity in the form of pulmonary fibrosis during treatment of the disease. The bleomycininduced pulmonary fibrosis model is the standard model of human lung fibrosis. Dec 01, 2000 mice deleted for the plasminogen activator inhibitor1 pai1 gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Our findings suggest that af1 has potential as a new therapeutic tool for pulmonary fibrosis. The result indicated that the appropriate concentrations of blm in treated cells at 24 h were 120. Resolution of bleomycininduced murine pulmonary fibrosis. Pulmonary fibrosis induced by h5n1 viral infection in mice. Bleomycininduced interstitial pulmonary fibrosis in baboons.
No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Understanding the mechanisms of blminduced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating. 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. 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. Guidelines for the diagnosis and treatment of idiopathic pulmonary. Characterizing idiopathic pulmonary fibrosis patients using us. The bleomycin model of pulmonary fibrosis request pdf. Mouse models of bleomycininduced 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. Blm 100 mgkg body weight was administered to c57bl6 mice. It is usually impossible to predict who will develop lung disease from a medicine. Microrna profiling implicates the insulinlike growth. The current therapeutic approaches for this condition are unsatisfactory.
Pulmonary toxicity of bleomycin a case series from a. 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. The pathogenesis of bleomycininduced pulmonary fibrosis. Diffuse pulmonary fibrosis is associated with bleomycin administration to humans. Several reports indicate that melatonin alleviates bleomycin blminduced pulmonary fibrosis in rodent animals. Melatonin inhibits endoplasmic reticulum stress and. Microrna profiling implicates the insulinlike growth factor. Although surgical lung biopsy was recommended by the 2011 international guidelines. Two recovered following treatment and one patient died due to irreversible pulmonary damage. We have previously shown that fibrosis is induced in isolated sheep lung.
Research open access antiflammin1 attenuates bleomycin. 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. Radiationinduced pulmonary fibrosis refers to a condition of inflammation and subsequent scarring of lung tissues caused by radiation. Bleomycin has been widely used in rodents to model pulmonary fibrosis for the study of mechanisms involved in fibrogenesis and for evaluation of. Mice deleted for the plasminogen activator inhibitor1 pai1 gene are relatively protected from developing pulmonary fibrosis induced by bleomycin. Two therapies, nintedanib and pirfenidone, are fda approved and are recommended by clinical practice guidelines for the treatment of ipf. Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix ecm and remodeling of the lung architecture. Jci bleomycininduced pulmonary fibrosis in fibrinogennull.
It leads to high mortality, and the average survival time after diagnosis is about 25 years. This scarring makes the lungs stiffer and affects the exchange of oxygen and carbon dioxide in the alveoli. Molecular and cellular mechanisms of pulmonary fibrosis. Relaxin was previously shown to induce a matrixdegrading phenotype in human lung fibroblasts in vitro and to inhibit. Dasatinib attenuated bleomycin induced pulmonary fibrosis in mice article pdf available in growth factors 335 november 2015 with 410 reads how we measure reads. However, in this model, mmp7 levels were measured and found to not be induced by bleomycin instillation. Pulmonary fibrosis is a chronic, progressive, and irreversible condition that occurs in many clinical situations. Prevention of bleomycininduced pulmonary fibrosis by a. Vagotomy attenuates bleomycininduced pulmonary fibrosis. Although this is age and dose related, the toxicity is unpredictable. Idiopathic pulmonary fibrosis ipf is a progressive and irreversible lung disease of unclear etiology that predominantly occurs in middleaged and elderly adults 1,2. This induces aberrant myofibroblast differentiation. 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.
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. 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. Dec 31, 2019 pulmonary toxicities occur in 10% of treated patients. Common and distinct mechanisms of induced pulmonary fibrosis by. Panax notoginseng attenuates bleomycininduced pulmonary.
Ongoing challenges in pulmonary fibrosis and insights from the. Fibrosisin duced destruction of the lung parenchyma can be fatal 1,2. In the bleomycininduced pulmonary fibrosis model, tlr2 expression was detected in 29. 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. Structural and functional correlations in a large animal. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. Idiopathic pulmonary fibrosis ipf is a rare lifethreating interstitial.
Pulmonary fibrosis is a condition in which the lungs become scarred over time. 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. Quantification of pulmonary fibrosis in a bleomycin mouse. Interstitial lung diseases ilds and pulmonary fibrosis are. Pirfenidone attenuates bleomycininduced pulmonary fibrosis. 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. Idiopathic pulmonary fibrosis american thoracic society. 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. Jci bleomycininduced pulmonary fibrosis in fibrinogen. Understanding the mechanisms of blm induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating. The above results showed that pai1 deficiency enhances fibrinolytic activity and limits both fibrin accumulation and collagen deposition after bleomycin administration. Mode of treatment, severity of the condition and the treatment outcome varied among the three.
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