ABSTRACT
SUMMARY: The potential anti-inflammatory and antifibrotic activity of polyphenolic extracts of blueberry and grape was evaluated in a mouse model of lung damage induced by subcutaneous administration of bleomycin. The results of testing the polyphenolic extracts on two different systemic administration variants of bleomycin (intraperitoneal and subcutaneous) were compared. It was found that regardless of the method of bleomycin administration, indirect cross-acute and subacute damage to the pulmonary system was observed. Both patterns exhibited the same prevalence and severity. The administration of polyphenolic extracts of blueberry and grape to mice resulted in a significant decrease in theseverity of acute and subacute patterns of lung damage, suggesting their protective properties for the microcirculatory bed and a pronounced anti-inflammatory effect.
La potencial actividad antiinflamatoria y antifibrótica de los extractos polifenólicos de arándano y uva se evaluó en un modelo de daño pulmonar en ratón inducido por la administración subcutánea de bleomicina. Se compararon los resultados de las pruebas de los extractos polifenólicos en dos variantes diferentes de administración sistémica de bleomicina (intraperitoneal y subcutánea). Se encontró que, independientemente del método de administración de bleomicina, se observaba daño indirecto cruzado, agudo y subagudo al sistema pulmonar. Ambos patrones exhibieron la misma prevalencia y gravedad. La administración de extractos polifenólicos de arándano y uva a ratones dio como resultado una disminución significativa en la gravedad de los patrones agudos y subagudos de daño pulmonar, lo que sugiere sus propiedades protectoras del lecho micro- circulatorio y un efecto antiinflamatorio pronunciado.
Subject(s)
Animals , Mice , Bleomycin/toxicity , Plant Extracts/administration & dosage , Lung Injury/chemically induced , Lung Injury/drug therapy , Polyphenols/administration & dosage , Blueberry Plants/chemistry , Vitis/chemistry , Disease Models, Animal , Lung Injury/pathology , Lung/drug effects , Anti-Inflammatory Agents/administration & dosageABSTRACT
La toxicidad pulmonar por antineoplásicos es muy variable dependiente del grupo far-macológico; la bleomicina es uno de los medicamentos en los que se ha reportado este evento. Este citostático puede lesionar el endotelio pulmonar y el epitelio alveolar para llevar a un proceso inflamatorio y fibrótico del intersticio con repercusiones potencial-mente fatales.A continuación, se presenta un caso de enfermedad intersticial tipo neumonía organi-zada asociada a bleomicina en un paciente de 68 años con diagnóstico linfoma Hodg-kin clásico de tipo esclerosis nodular, con estudio imagenológico normal previo al tratamiento
Antineoplastic pulmonary toxicity is highly variable depending on the pharmacological group; bleomycin is one of the drugs in which this event has been reported. This cyto-static can injure the pulmonary endothelium and the alveolar epithelium to lead to an in-flammatory and fibrotic process of the interstitium with potentially fatal repercussions. The following is a case of interstitial disease type organizing pneumonia associated with bleomycin in a 68-year-old patient diagnosed with classical Hodgkin lymphoma of nodular sclerosis type, with imaging study prior to normal treatment
Subject(s)
Humans , Male , Aged , Pulmonary Fibrosis , Bleomycin/toxicity , Hodgkin Disease/drug therapy , Tomography, X-Ray Computed , Antineoplastic Agents/therapeutic useABSTRACT
SUMMARY: An experimental morphological and morphometric study of the antifibrotic function of blueberry and grape extracts was carried out on a model of lung injury in mice induced by intraperitoneal administration of bleomycin. During intraperitoneal administration of bleomycin to mice, acute and subacute damage to the pulmonary system was noted. Both patterns had the same prevalence and severity. The administration of polyphenolic extracts of blueberry and grape to mice showed a significant reduction in the severity of the acute and subacute pattern of lung injury. Blueberry and grape extracts reduce the acute phase of damage to the microvasculature, enhance phagocytic function, have an anti-inflammatory effect, reducing the degree of lymphohistiocytic infiltration and locoregional foci of residual inflammatory effects.
Se realizó un estudio experimental morfológico y morfométrico de la función antifibrótica de extractos de arándano y uva en un modelo de lesión pulmonar en ratones inducida por la administración intraperitoneal de bleomicina. Durante la administración intraperitoneal de bleomicina a ratones, se observaron daños agudos y subagudos en el sistema pulmonar. Ambos patrones tuvieron la misma prevalencia y severidad. La administración de extractos polifenólicos de arándano y uva a ratones mostró una reducción significativa en la severidad del patrón agudo y subagudo de lesión pulmonar. Los extractos de arándano y uva reducen la fase aguda del daño a la microvasculatura, mejoran la función fagocítica, tienen un efecto antiinflamatorio, reducen el grado de infiltración linfohistiocítica y los focos locorregionales de efectos inflamatorios residuales.
Subject(s)
Animals , Mice , Pulmonary Fibrosis/drug therapy , Bleomycin/toxicity , Plant Extracts/administration & dosage , Blueberry Plants/chemistry , Polyphenols/administration & dosage , Antifibrotic Agents/administration & dosage , Pulmonary Fibrosis/chemically induced , Disease Models, Animal , Antibiotics, Antineoplastic/toxicityABSTRACT
Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-β1 (TGF-β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin-1β (IL-1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-κB (NF-κB) and hypoxia‑inducible factor‑1α (HIF-1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1α and NF-κB.
Subject(s)
Animals , Rats , Anti-Inflammatory Agents , Bleomycin/toxicity , Fibronectins/metabolism , Fibrosis , Inflammasomes/metabolism , Ivermectin/adverse effects , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pulmonary Fibrosis/drug therapyABSTRACT
BACKGROUND@#Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis, partially by activating lung fibroblasts. However, how macrophages communicate with lung fibroblasts is largely unexplored. Exosomes can mediate intercellular communication, whereas its role in lung fibrogenesis is unclear. Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis.@*METHODS@#In vivo, bleomycin (BLM)-induced lung fibrosis model was established and macrophages infiltration was examined. The effects of GW4869, an exosomes inhibitor, on lung fibrosis were assessed. Moreover, macrophage exosomes were injected into mice to observe its pro-fibrotic effects. In vitro, exosomes derived from angiotensin II (Ang II)-stimulated macrophages were collected. Then, lung fibroblasts were treated with the exosomes. Twenty-four hours later, protein levels of α-collagen I, angiotensin II type 1 receptor (AT1R), transforming growth factor-β (TGF-β), and phospho-Smad2/3 (p-Smad2/3) in lung fibroblasts were examined. The Student's t test or analysis of variance were used for statistical analysis.@*RESULTS@#In vivo, BLM-treated mice showed enhanced infiltration of macrophages, increased fibrotic alterations, and higher levels of Ang II and AT1R. GW4869 attenuated BLM-induced pulmonary fibrosis. Mice with exosomes injection showed fibrotic features with higher levels of Ang II and AT1R, which was reversed by irbesartan. In vitro, we found that macrophages secreted a great number of exosomes. The exosomes were taken by fibroblasts and resulted in higher levels of AT1R (0.22 ± 0.02 vs. 0.07 ± 0.02, t = 8.66, P = 0.001), TGF-β (0.54 ± 0.05 vs. 0.09 ± 0.06, t = 10.00, P < 0.001), p-Smad2/3 (0.58 ± 0.06 vs. 0.07 ± 0.03, t = 12.86, P < 0.001) and α-collagen I (0.27 ± 0.02 vs. 0.16 ± 0.01, t = 7.01, P = 0.002), and increased Ang II secretion (62.27 ± 7.32 vs. 9.56 ± 1.68, t = 12.16, P < 0.001). Interestingly, Ang II increased the number of macrophage exosomes, and the protein levels of Alix (1.45 ± 0.15 vs. 1.00 ± 0.10, t = 4.32, P = 0.012), AT1R (4.05 ± 0.64 vs. 1.00 ± 0.09, t = 8.17, P = 0.001), and glyceraldehyde-3-phosphate dehydrogenase (2.13 ± 0.36 vs. 1.00 ± 0.10, t = 5.28, P = 0.006) were increased in exosomes secreted by the same number of macrophages, indicating a positive loop between Ang II and exosomes production.@*CONCLUSIONS@#Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.
Subject(s)
Animals , Mice , Angiotensin II , Bleomycin/toxicity , Exosomes , Fibroblasts , Lung , Macrophages , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Receptor, Angiotensin, Type 1ABSTRACT
OBJECTIVE@#To study the changes in mRNA and long non-coding RNA (lncRNA) expression profiles in a mouse model of bleomycin-induced lung fibrosis and identify lung fibrosis-related mRNA for coding-noncoding coexpression (CNC) bioinformatics analysis of the differential lncRNAs.@*METHODS@#Lung fibrosis was induced by intratracheal injection of bleomycin in 10 C57BL/6 mice and another 10 mice with intratracheal injection of saline served as the control group. Lung tissues were harvested from the mice at 14 days after the injections and lung fibrosis was assessed using Masson and HE staining. LncRNA chip technology was used to screen the differentially expressed mRNAs and lncRNAs in mice with lung fibrosis, and GO and KEGG pathway analyses of the differential mRNAs were performed using NCBI database and UCSC database to identify possible fibrosis-related mRNAs, which were validated by qRT-PCR to construct a coding and non-coding co- expression network with the differential lncRNAs.@*RESULTS@#Compared with the control mice, the mice with intratracheal injection of bleomycin showed obvious lung fibrosis. The results of gene chip analysis showed that 127 mRNAs were upregulated and 184 mRNAs were down-regulated in the model group as compared with the control group. GO and pathway analysis suggested that the differentially expressed genes participated mainly in immune response, cell differentiation, and cytoskeletons; the involved signal pathways were associated mainly with cytokine and cytokine receptor interaction and chemokine signal transduction. Bioinformatics analysis identified a significant coexpression network between the fibrosisrelated mRNA and the differentially expressed lncRNA.@*CONCLUSIONS@#In mice with lung fibrosis, the differential expressions of fibrosis-related mRNAs in the lung tissues are closely correlated with the co- expressions of a large number of differential lncRNAs, which points to a new direction for investigation of the pathogenesis of pulmonary fibrosis.
Subject(s)
Animals , Mice , Bleomycin/toxicity , Gene Expression Profiling , Gene Regulatory Networks , Mice, Inbred C57BL , Pulmonary Fibrosis/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/geneticsABSTRACT
PURPOSE: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis. To understand the role of MMP-2 and MMP-9 in pulmonary fibrosis, we evaluated the sequential dynamic change and different cellular sources of the 2 MMPs along the time course and their differential expression in the bronchoalveolar lavage (BAL) fluid and in the lung parenchyma of the bleomycin-induced pulmonary fibrosis models in rats. MATERIALS AND METHODS: The level of MMPs in BAL fluid of 54 bleomycin-treated rats was assessed by zymography from 1 to 28 days after intratracheal bleomycin instillation. The level of MMPs in lung parenchyma was evaluated by immunohistochemistry. RESULTS: MMP-2 and MMP-9 were markedly increased in both the BAL fluid and in the lung parenchyma of the bleomycin-treated rats, especially in the early phase with the peak on the 4th day. The levels of both MMPs in the BAL fluid correlated generally well to those in lung parenchyma, although the level of MMP-9 in BAL fluid was higher than MMP-2. In the lung parenchyma, the 2 MMPs, in early stage, were predominantly expressed in the inflammatory cells. In late stage, type II pneumocytes and alveolar epithelial cells at the periphery of the fibrotic foci retained MMP expression, which was more prominent in the cells showing features of cellular injury and/or repair. CONCLUSION: In bleomycin-induced pulmonary fibrosis, MMP-2 and MMP-9 may play important roles, especially in the early phase. In the late stage, the MMP-2 and MMP-9 may play a role in the process of repair.
Subject(s)
Animals , Male , Rats , Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Bronchioles/enzymology , Bronchoalveolar Lavage Fluid/cytology , Disease Models, Animal , Enzyme Activation , Gelatin , Immunohistochemistry , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neutrophils/pathology , Pulmonary Fibrosis/chemically induced , Rats, Sprague-DawleyABSTRACT
The current study aimed to investigate the effect of oral supplementation with the nitric oxide [NO] precursor; namely, L- arginine [ARG] and the NO synthesis inhibitor; namely, NG-nitro-L- arginine methyl ester [L-NAME] on bleomycin [BLM]-induced pulmonary toxicity. BLM was administered i.p. at a dose of 15 mg/kg, three times a week, for a total period of four weeks to male Wistar rats. Treatment with either ARG [500 mg/kg/day] or L-NAME [100 mg/kg/day] was commenced with BLM and continued up to the end of the experiment. Appropriate controls were performed. The results of the study indicated that the lung toxicity exerted by chronic administration of BLM is alleviated by ARG, while exacerbated by L-NAME supplementation and could address a possible protective role of NO
Subject(s)
Animals, Laboratory , Bleomycin/toxicity , Arginine , Antibiotics, Antineoplastic , Nitric Oxide , Rats, Wistar , Oxidants , CollagenABSTRACT
Fibrosis of organs and tissues are major causes of morbidity and mortality in human. The currently available pharmacologically based treatments are unsatisfactory. As an experimental animal model antitumor antibiotic drug bleomycin (BLM) is widely used to produce lung fibrosis. The present study has been undertaken to investigate the possible role of a potent immunomodulator Staphylococcus protein-A (SpA) in the modulation of lung lesions caused by treatment of BLM. In mice BLM, 0.5 mg in 200 microliters of normal saline and SpA, 6 micrograms in 200 microliters of normal saline was administered singly or in combination twice a week for 4 weeks. The fibrotic lesions in the lungs were observed after 4 weeks of BLM treatment. After 4 weeks treatment of SpA, the hyperreactive changes in bronchi and bronchioles were observed. In the co-treatment group of BLM and SpA, the effects observed were in the form of enhanced lesions in the lung parenchyma. Moreover, the pleural lesions were also observed in co-treatment group (BLM + SpA). Opposite to the assumption, SpA being a potent immunomodulator was not able to reduce the lung lesions produced by BLM.
Subject(s)
Animals , Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Drug Synergism , Male , Mice , Pulmonary Fibrosis/chemically induced , Staphylococcal Protein A/toxicityABSTRACT
Se presentan 19 pacientes con Ca. testicular en etapas B1, B2, B3, y C sometidos a quimioterapia con PVB entre 1981-1987 en nuestro Servicio. Se analizan los signos de toxicidad con este esquema quimioterápico. Hubo R.C. (respuesta completa) en 14 pacientes y R.P. (respuesta parcial) en 3 enfermos en etapa B3 (que se convirtieron en R.C. con cirugía y más quimioterapia) y en 2 pacientes en etapa C (1 paciente muerto de su enfermedad y 1 paciente vivo con enfermedad). De 19 pacientes tratados con el esquema PVB solo o en combinación con cirugía tenemos 17 enfermos vivos y sin evidencia de enfermedad