Potential antifibrotic effect of blueberry and grape polyphenol extracts in acute and subacute bleomycin-induced lung tissue injury models in mice / Potencial efecto antifibrótico de los extractos de polifenoles de arándano y uva en modelos de lesión tisular pulmonar aguda y subaguda inducida por bleomicina en ratones

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.

Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

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.

Preparation of purified proteins from fresh Pheretima and their inhibitory effect against pulmonary fibrosis in mice / 南方医科大学学报

OBJECTIVE@#To develop a convenient method for rapid purification of fresh Pheretima proteins and assess the inhibitory effect of these proteins against pulmonary fibrosis.@*METHODS@#The crude extract of fresh Pheretima was obtained by freeze-drying method and then purified by size exclusion chromatography. The composition of the purified proteins was analyzed by mass spectrometry. MRC-5 cells were treated with 5 ng/mL TGF-β1 alone (model group) or in combination with SB431542 (2 μmol/L) or the purified proteins (13.125 μg/mL), and the cytotoxicity of purified proteins and their inhibitory effects on cell proliferation were detected with CCK8 assay. Flow cytometry was used to detect the changes in cell apoptosis, and the cellular expressions of α-SMA, Vimentin, E-cadherin, collagen I, Smad2/3 and P-Smad2/3 were detected using RT-PCR and Western blotting. In the animal experiment, adult male C57BL/6 mice were subjected to intratracheal instillation of bleomycin followed by treatment with the purified proteins (5 mg/mL) for 21 days, after which HE and Masson staining was used to observe the pathological changes in the lung tissue of the mice.@*RESULTS@#We successfully obtained purified proteins from fresh Pheretima protein by size exclusion chromatography. Treatment with the purified proteins significantly inhibited TGF-β1-induced proliferation of MRC-5 cells (P < 0.01), reduced the cellular expressions of α-SMA, Vimentin and collagen I (P < 0.001 or P < 0.01), increased the expression of E-cadherin (P < 0.01), and inhibited the expressions of Smad2/3 and P-Smad2/3 (P < 0.001 or P < 0.01). In male C57BL/6 mice models of bleomycin-induced pulmonary fibrosis, treatment with the purified proteins obviously reduced the number of inflammatory cells and fibrotic area in the lungs.@*CONCLUSION@#The purified proteins from fresh Pheretima obtained by size exclusion chromatography can inhibit pulmonary fibrosis in mice by regulating the TGF-β/ Smad pathway.

The study of Yangyinyiqi mixture anti bleomycin-induced pulmonary fibrosis on rats by intervening matrix metalloproteinase-9 and tissue inhibitors of matrix metallopreoteinases-1 / El estudio de la mezcla Yangyinyiqi en fibrosis pulmonar inducida por anti-bleomicina en ratas por intervención en la matriz metaloproteinasa-9 e inhibidores de tejido de matriz metaloproteinasa-1

To investigate effectsof Yangyinyiqi Mixture on pulmonary fibrosis caused by bleomycin. SD ratswere divided randomly into: model group(distilled water,1 mL·0.1 kg-1), dexamethasone acetate group (dexamethasone acetate, the dosage was reduced gradually), low-dose group (Yangyinyiqi Mixture, 11 g·kg-1), moderate-dose group (Yangyinyiqi Mixture, 22 g·kg-1), high-dose group (Yangyinyiqi Mixture, 44 g·kg-1) and control group (distilled water, 1 mL·0.1 kg-1). Yangyinyiqi Mixture and dexamethasone acetate were intragastrically administrated. Lung tissue was collected for histopathological examination. Compared with control group, collagen markedly increased and HYP content significantly increased on 7th day in model group (p<0.01). On 28th day, collagen was diffusely deposited, alveolar was destroyed, and HYP content significantly increased (p<0.01). Compared with model group, bleomycin-induced suffering injury caused MMP-9 expression levels to rapidly increase (7and 14 days, p<0.01). TIMP-1 markedly increased (7and 14 days, p<0.01) and stayed at a high level to28th day. Yangyinyiqi Mixture exerted an effect against pulmonary fibrosis, which could involved prevention of collagen deposition through inhibitingMMP-9 and TIMP-1 expression.

El trabajo investiga los efectos de la mezcla Yangyinyiqi sobre la fibrosis pulmonary causada por bleomicina. Ratas SD se dividieron aleatoriamente en: grupo modelo (agua destilada, 1 mL·0.1 kg-1), grupo acetate de dexametasona (acetate de dexametasona, la dosis se redujo gradualmente), grupo de dosis baja (mezcla Yangyinyiqi, 11 g·kg-1), grupo de dosis moderada (mezcla Yangyinyiqi, 22 g·kg-1), grupo de dosis alta (mezcla Yangyinyiqi, 44 g·kg-1) y grupo control (agua destilada, 1 Ml·0.1 kg-1). La mezcla de Yangyinyiqi y el acetate de dexametasona se administraron por vía intragástrica. Se recolectó tejido pulmonary para examen histopatológico. En comparación con el grupo control, el colágeno aumentó notablemente y el contenido de HYP aumentó significativamente el séptimo día en el grupo modelo (p<0.01). El día 28, el colágeno se depositó difusamente, se produjo destrucción alveolar y el contenido de HYP aumento significativamente (p<0.01). En comparación con el grupo modelo, la lesión inducida por bleomicina causó que los niveles de expression de MMP-9 aumentaron rápidamente (7 y 14 días, p<0.01). TIMP-1 aumentó notablemente (7 y 14 días, p<0.01) y se mantuvo en un nivel alto hasta el día 28. La mezcla Yangyinyiqi ejerció un efecto contra la fibrosis pulmonary, lo que podría implicar la prevención del deposito de colágenio mediante la inhibición de la expression de MMP-9 y TIMP-1.

H. sinensis mycelium inhibits epithelial-mesenchymal transition by inactivating the midkine pathway in pulmonary fibrosis / 医学前沿

The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties. Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung. The epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis. The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis. HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT. In addition, the expression levels of midkine are increased in the lungs of the BLM-induced group. Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT. HSM markedly abrogates the transforming growth factor β-induced EMT-like phenotype and behavior in vitro. The activation of midkine related signaling pathway is ameliorated following HSM treatment, whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro. Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo. Overall, findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.

Efecto de la n-acetilcisteina inhalada en el desarrollo de fibrosis pulmonar de ratas intoxicadas con paraquat / Effect of n-acetylcisteine inhaled in the development of pulmonary fibrosis of intoxicated rats with paraquat

El Paraquat (PQ) es un herbicida de contacto bipiridilico ampliamente utilizado en agricultura. La intoxicación en humanos por este agente ocasiona fibrosis pulmonar. Evaluamos los cambios histológicos pulmonares de ratas intoxicadas con PQ y tratadas con N-aceticisteina (NAC) administrada vía inhalatoria. Realizamos un estudio experimental descriptivo con 25 ratas adultas, machos cepa Wistar, divididas en cinco grupos. Al grupo I no se les administro ni PQ ni NAC. Grupo II, recibió NAC inhalada a 15mg/kg diaria c/12 horas. Grupo III, PQ vía oral (VO) 15mg/kg. Grupo IV, PQ a 15mg/kg, por VO y a la hora NAC 150mg/kg. Grupo V, PQ a 15mg/kg, por VO y a las seis horas NAC dosis de 150mg/kg. Los pulmones fueron extraídos y se evaluaron mediante cortes histológicos. Resultados: Los grupos I y II (supervivencia del 100%, n=10) no desarrollaron sintomatología de intoxicación. Grupos III, IV y V predominaron síntomas respiratorios, diversos grados de edema pulmonar, enfisema, congestión vascular y hemorragia intra-alveolar focal. La eficacia de la NAC sobre la intoxicación por PQ en términos de sobrevivencia al primer día, fue del 100% y al segundo día, fue del 80% (p= 0,005; prueba Chi-cuadrado). El PQ indujo un proceso inflamatorio (agudo-crónico) por infiltrado de segmentados neutrófilos y linfocitos, lo cual fue revertido parcialmente por la administración inhalada de NAC. Conclusión: Los cambios histopatológicos observados a nivel pulmonar fueron aminorados por el tratamiento con NAC, lo que sugiere un posible efecto protector de este fármaco sobre el daño oxidativo inducido por el herbicida

Paraquat (PQ) is a bipyridyl contact herbicide widely used in agriculture. Intoxication in humans by this agent causes pulmonary fibrosis. We evaluated pulmonary histological changes of rats intoxicated with PQ and treated with N-acetycysteine (NAC) administered via inhalation. We conducted a descriptive experimental study with 25 adult rats, male Wistar strain, divided into five groups. Group I was not administered PQ or NAC. Group II, received NAC inhaled at 15mg/kg daily c/12 hours. Group III, PQ orally (VO) 15mg/ kg. Group IV, PQ at 15mg/kg, by VO and at hour NAC 150mg/ kg. Group V, PQ at 15mg/kg, by VO and at six hours NAC dose of 150mg/kg. The lungs were extracted and evaluated by histological sections. Results: Groups I and II (100% survival, n=10) did not develop intoxication symptoms. Groups III, IV and V predominantly respiratory symptoms, various degrees of pulmonary edema, emphysema, vascular congestion and focal intra-alveolar hemorrhage. The efficacy of NAC on PQ poisoning in terms of survival on the first day was 100% and on the second day it was 80% (p = 0.005, Chi-square test). The PQ induced an inflammatory process (acute-chronic) by infiltration of segmented neutrophils and lymphocytes, which was partially reversed by the inhaled administration of NAC. Conclusion: The histopathological changes observed at the pulmonary level were reduced by the treatment with NAC, which suggests a possible protective effect of this drug on the oxidative damage induced by the herbicide.

Fibrosis pulmonar aguda asociada a intoxicación por Paraquat: caso clínico / Acute pulmonary fibrosis associated with Paraquat poisoning: report of one case

Paraquat, a non-selective bipyridyl pesticide, is one of the leading causes of death from intoxication in many parts of Asia and America. It is the second most sold herbicide worldwide, being widely used in Chile. Its ingestion generates toxicity due to the release of superoxide radicals, mainly affecting kidneys, lungs and liver. There is no antidote available. We report a 31 years old male who ingested Paraquat for suicidal purposes. He developed an acute renal and hepatic failure and a rapidly progressive severe respiratory failure with images compatible with acute pulmonary fibrosis. No response to immunosuppressive treatment was observed. He died eight days after admission. The use of cyclophosphamide associated with glucocorticoids could lower risk of death the in these patients, although the pathophysiology of respiratory failure is still under study.

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Percutaneous Vertebroplasty of the Entire Thoracic and Lumbar Vertebrae for Vertebral Compression Fractures Related to Chronic Glucocorticosteriod Use: Case Report and Review of Literature

Glucocorticosteroid-induced osteoporosis is the most frequent of all secondary types of osteoporosis, and can increase the risk of vertebral compression fractures (VCFs). There are promising additions to current medical treatment for appropriately selected osteoporotic patients. Few studies have reported on the efficiency of percutaneous vertebroplasty (PVP) or kyphoplasty for whole thoracic and lumbar glucocorticosteroid-induced osteoporotic vertebral compression fractures. We report a case of a 67-year-old man with intractable pain caused by successional VCFs treated by PVP.

Modifiers of TGF-beta1 effector function as novel therapeutic targets of pulmonary fibrosis

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.

Tratamento das doenças pulmonares fibrosantes / Treatment of fibrotic lung diseases

As doenças fibrosantes pulmonares representam um importante desafio considerando seu curso progressivo para insuficiência respiratória e o grave comprometimento da qualidade de vida dos pacientes acometidos. A fibrose pulmonar idiopática (FPI), doença fibrosante mais prevalente, apesar de inúmeras pesquisas na busca de alvos moleculares e novas drogas, permanece sem um tratamento eficaz e seguro.A análise da patogenia da FPI e a avaliação da severidade da doença estão relacionadas às propostas de tratamento medicamentoso. Abordamos o uso das terapias anti-inflamatórias, drogas antifibróticas e antioxidantes, com ênfase no papel atual dos corticosteroides e imunossupressores, na análise do risco do uso das drogas, além de uma revisão de medicamentos de uso recente. Os tratamentos não medicamentosos, outro aspecto importante na condução dos pacientes portadores de fibrose pulmonar, são revistos em seu papel no alívio dos sintomas e na prevenção de complicações, além da elaboração de um paralelo entre a FPI e outras doenças fibrosantes pulmonares. Concluímos que, apesar de não haver uma droga específica plenamente eficaz para o tratamento da FPI, muito pode ser feito para o alívio do paciente, e que o plano terapêutico deve incluir a análise da gravidade da doença e os desejos e necessidades individuais dos pacientes.

Rapamycin Inhibits Transforming Growth Factor beta1-Induced Fibrogenesis in Primary Human Lung Fibroblasts

PURPOSE: The present study was designed to determine whether rapamycin could inhibit transforming growth factor beta1 (TGF-beta1)-induced fibrogenesis in primary lung fibroblasts, and whether the effect of inhibition would occur through the mammalian target of rapamycin (mTOR) and its downstream p70S6K pathway. MATERIALS AND METHODS: Primary normal human lung fibroblasts were obtained from histological normal lung tissue of 3 patients with primary spontaneous pneumothorax. Growth arrested, synchronized fibroblasts were treated with TGF-beta1 (10 ng/mL) and different concentrations of rapamycin (0.01, 0.1, 1, 10 ng/mL) for 24 h. We assessed m-TOR, p-mTOR, S6K1, p-S6K1 by Western blot analysis, detected type III collagen and fibronectin secreting by ELISA assay, and determined type III collagen and fibronectin mRNA levels by real-time PCR assay. RESULTS: Rapamycin significantly reduced TGF-beta1-induced type III collagen and fibronectin levels, as well as type III collagen and fibronectin mRNA levels. Furthermore, we also found that TGF-beta1-induced mTOR and p70S6K phosphorylation were significantly down-regulated by rapamycin. The mTOR/p70S6K pathway was activated through the TGF-beta1-mediated fibrogenic response in primary human lung fibroblasts. CONCLUSION: These results indicate that rapamycin effectively suppresses TGF-beta1-induced type III collagen and fibronectin levels in primary human lung fibroblasts partly through the mTOR/p70S6K pathway. Rapamycin has a potential value in the treatment of pulmonary fibrosis.

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-inflammatory properties of statins. The purpose of this study was to evaluate the anti-inflammatory effect of simvastatin on bleomycin (BLM)-induced pulmonary fibrosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buffered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The effect of simvastatin on pulmonary fibrosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-p1 levels in bronchoalveolar lavage (BAL) fluid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused significant change in BAL fluid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no effect on cytokine levels, HD significantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no effect on a BLM-induced pulmonary fibrosis model, while the high dose caused partial improvement in profibrotic cytokine levels.

Influência do biofármaco DNA-hsp65 na lesão pulmonar induzida por bleomicina / Influence of a DNA-hsp65 vaccine on bleomycin-induced lung injury

OBJETIVO: Avaliar a influência do biofármaco DNA-hsp65 em um modelo de distúrbio fibrosante pulmonar experimental. MÉTODOS: Foram estudados 120 camundongos machos C57BL/6, divididos em quatro grupos: grupo SS, animais tratados com salina (placebo) e injetados com salina intratraqueal (IT); grupo SB, tratados com salina (placebo) e injetados com bleomicina IT; grupo PB, tratados com plasmídeo, sem gene bacteriano, e injetados com bleomicina IT; e grupo BB, tratados com DNA-hsp65 e injetados com bleomicina IT. A bleomicina foi injetada 15 dias após a última imunização, e os animais sacrificados seis semanas após o uso da droga IT. O pulmão esquerdo retirado foi utilizado para análise morfológica, e o pulmão direito para dosagens de hidroxiprolina. RESULTADOS: A proporção de camundongos que apresentaram morte não-programada depois de 48 h da injeção IT foi maior no grupo SB em comparação ao grupo SS (57,7% vs. 11,1%). A área percentual média de interstício septal foi maior nos grupos SB e PB (53,1 ± 8,6% e 53,6 ± 9,3%, respectivamente) em comparação aos grupos SS e BB (32,9 ± 2,7% e 34,3 ± 6,1%, respectivamente). Os grupos SB, PB e BB mostraram aumentos nos valores médios da área de interstício septal corada por picrosirius em comparação ao grupo SS (SS: 2,0 ± 1,4%; SB: 8,2 ± 4,9%; PB: 7,2 ± 4,2%; e BB:6,6±4,1%).O conteúdo pulmonar de hidroxiprolina no grupo SS foi inferior ao dos demais grupos (SS: 104,9 ± 20,9 pg/pulmão; SB: 160,4 ±47,8 pg/pulmão; PB:170,0 ± 72,0 pg/pulmão; e BB: 162,5 ± 39,7 pg/pulmão). CONCLUSÕES: A imunização com o biofármaco DNA-hsp65 interferiu na deposição de matriz não-colágena em um modelo de lesão pulmonar induzida por bleomicina.

OBJECTIVE: To evaluate the effects of immunization with a DNA-hsp65 vaccine in an experimental model of pulmonary fibrosis. METHODS: A total of 120 male C57BL/6 mice were distributed into four groups: SS, injected with saline (placebo) and then receiving intratracheal (IT) instillation of saline; SB, injected with saline (placebo) and then receiving IT instillation of bleomycin; PB, treated with plasmid only, without bacterial genome, and then receiving IT instillation of bleomycin; and BB, treated with the vaccine and then receiving IT instillation of bleomycin. Bleomycin was instilled 15 days after the last immunization, and the animals were killed six weeks thereafter. The left and right lungs were removed, the former for morphological analysis and the latter for hydroxyproline measurements. RESULTS: The proportion of deaths within the first 48 h after the IT instillation (deaths attributed to the surgical procedure) was higher in the SB group than in the SS group (57.7% vs. 11.1%). The mean area of pulmonary interstitial septa was greater in the SB and PB groups (53.1 ± 8.6% and 53.6±9.3%, respectively) than in the SS and BB groups (32.9 ± 2.7% and 34.3 ± 6.1%, respectively). The mean area of interstitial septa stained by picrosirius was greater in the SB, PB and BB groups than in the SS group (8.2 ± 4.9%, 7.2 ± 4.2% and 6.6 ± 4.1%, respectively, vs. 2.0±1.4%). The total hydroxyproline content in the lung was significantly lower in the SS group (104.9 ± 20.9 pg/lung) than in the other groups (SB: 160.4 ± 47.8 pg/lung; PB: 170.0 ± 72.0 pg/lung; and BB: 162.5 ± 39.7 pg/lung). CONCLUSIONS: Immunization with the DNA-hsp65 vaccine reduced the deposition of noncollagen matrix in a model of bleomycin-induced lung lesion.

protective effect of cetirizine against bleomycine induced pulmonary fibrosis in rats

To evaluate the protective effect of cetrizine against bleomycin induced pulmonary fibrosis in rats. Male Sprague-Dawley rats [n=30], received an intratracheal injection of bleomycin [7.5 IU/kg] in saline solution for induction of pulmonary fibrosis. Two treatment groups received daily cetirizine five and 20mg/kg/day, seven days before and four weeks after administering a single-dose bleomycin [7.5IU/kg]. The cytokines [IL-8, TNF-alpha, TGF-alpha1] through ELISA kits, the amount of collagen in the lungs [hydroxyproline content], and pharmacological activity of the lung strip tissues were determined. The cytokine levels have been decreased in the treated groups by cetirizine 5 [p< 0.05] and 20 [p<0.01] mg/kg/day, in comparison to positive control group. Cetirizine may have a protective effect against bleomycine induced pulmonary fibrosis as evident by the reduction of the severity of lung tissue changes, collagen amounts and cytokines levels caused by bleomycine in rats lungs tissues

Idiopathic pulmonary fibrosis: a decade of progress

Embora diagnósticos de fibrose pulmonar idiopática continuem sendo devastadores, avanços recentes têm melhorado nossa compreensão a respeito de muitas das facetas desta doença. Estas descobertas, juntamente com o aumento da disponibilidade geral de ensaios terapêuticos, encerram a promessa de um futuro mais promissor para pacientes com fibrose pulmonar idiopática. Por exemplo, nós temos agora uma compreensão mais abrangente a respeito dos critérios diagnósticos e da história natural da doença. Vários estudos têm mostrado que a mensuração simples da fisiologia pulmonar ou troca gasosa pode ser usada para prever a sobrevida do paciente. Através da identificação de várias vias moleculares que têm papéis importantes na patogênese da fibrose pulmonar idiopática, os pesquisadores têm produzido uma lista crescente de possíveis novos alvos terapêuticos para a doença. Vários ensaios terapêuticos prospectivos e controlados têm sido realizados. Outros estão em andamento ou ainda estão em fase de planejamento. Estes esforços têm avançado nosso conhecimento atual sobre fibrose pulmonar idiopática e levantado novas questões importantes, assim como têm gerado o interesse e o impulso necessários para avançar terreno na luta contra esta doença desafiadora. Este artigo oferece ao leitor um panorama dos avanços recentes nas pesquisas sobre fibrose pulmonar idiopática, tendo como foco a história natural, patogênese e tratamento.

Although idiopathic pulmonary fibrosis remains a devastating diagnosis, recent advances have improved our understanding of many facets of this disease. These breakthroughs, combined with the increased general availability of therapeutic trials, hold the promise of a brighter future for idiopathic pulmonary fibrosis patients. For example, we now have a more comprehensive understanding of the diagnostic criteria and natural history of the disease. Several studies have shown that simple measurement of pulmonary physiology or gas exchange can be used to predict patient survival. By identifying several molecular pathways that play significant roles in the pathogenesis of idiopathic pulmonary fibrosis, investigators have produced a growing list of novel potential therapeutic targets for the disease. Several prospective, controlled therapeutic trials have been conducted. Others are ongoing or are still in the planning stages. These efforts have advanced our current knowledge of idiopathic pulmonary fibrosis and have raised new important questions, as well as having generated the interest and momentum needed to gain additional ground in the fight against this challenging disease. This article offers the reader a view of the recent advances in idiopathic pulmonary fibrosis research, with a focus on natural history, pathogenesis and treatment.

Possible association of low dose methotrexate therapy for rheumatoid arthritis with chronic pulmonary fibrosis

Low dose methotrexate [MTX] treatment is used extensively as a second-line therapy in RA. Two forms of interstitial lung diseases are related to low dose MTX therapy, the first is acute methotrexate pneumonitis which is a life-threatening complication that occurs in less than 10% of RA patients treated with MTX. The other interstitial lung affection is chronic pulmonary fibrosis [PF]. To evaluate whether chronic PF can be a significant complication in RA patient treated with low dose methotrexate [MTX]. The study was performed on 40 RA patients who fulfilled the American College of Rheumatology classification criteria for RA, The patients were classified into two separate groups. The first group consisted of 20 RA patients who were being treated with low dose MTX at the time of initial assessment, while the other group comprised another 20 RA patients who were not being treated with MTX, but treated with second-line therapy other than MTX. Pulmonary function tests were performed for all patients at the time of initial assessment using the standard protocol. All patients underwent HRCT chest scanning. Supine views were taken in serial slices 10 mm apart and 1 mm in width. According to the study design, the patients were followed over 18 months from the time of the initial assessment. Clinically, the patients were assessed regularly at time intervals of 3 months particularly for development of any chest illness together with the patient compliance of drug therapy and its effect on disease. Follow up chest radiographs and HRCT were performed at the end point. The age of the patients and disease duration in the MTX group were 52.1+ 2.9 years and 8.9 +/- .2 years respectively while in the other group they were 50.8 +/- 2.1 years and 9.2 +/- 5.1 years respectively. Pulmonary function results at baseline assessment expressed no significant differences between the two groups with p value > 0.05. On initial HRCT chest scanning, 3 patients were found to have PF interstitial lung disease pattern, two of them were being treated with MTX. There was no significant difference in the dose and duration of MTX treatment between the two RA patients treated with MTX and has PF on initial evaluation and those who were being treated with the drug and had no evidence of PF on HRCT on chest scanning at the initial evaluation. Change in pulmonary function tests from the time of initial assessment to the end of the study was not clinically or statistically significant in both groups [p value > 0.05]. Furthermore, there was no clinical or pulmonary function evidence that MTX had any deteriorating effect on PF detected in two patients on initial assessment even when compared with the patients who were not being treated with it. This study showed no clinical, physiological or radiological evidence that low dose MTX treatment used successfully in treatment of RA is associated with chronic fibrotic lung disease

Tratamiento de la fibrosis pulmonar idiopática con colchicina / Treatment of idiopathic pulmonary fibrosis with colchicine

Background: Experimental and clinical evidences suggest that colchicine can be effective in the treatment of patients with idiopathic pulmonary fibrosis. Aim: To assess the effect of colchicine in the treatment of idiopathic pulmonary fibrosis. Patients and methods: Patients with clinically diagnosed idiopathic pulmonary fibrosis were treated with colchicine in doses of 0.5 to 1 mg/day, according to tolerance and followed for periods ranging from 7 to 40 months. The clinical and radiological score reported by Watters et al was used for the longitudinal assessment of patients. Maintenance or improvement in forced vital capacity and maintenance or decrease in alveolar arterial O2 gradient during follow up, were considered as positive therapeutic responses. Results: Seventeen patients (10 male, aged 61 to 81 years old) were studied. Their basal score for dyspnea was 5.8 (over 20), for the chest X ray examination was 2.4 (over 3) and for CT scan was 2.8 (over 3). Basal FVC was 77 percent of predicted value (range 51-108 percent), basal FEV, was 82 percent (range 59-117 percent) and FEV1/FVC was 0.82 (range 0.68-0.95). PaO2 at rest was 78 mm Hg (ranges 63-97). Alveolar-arterial PO2 gradient was 16 mm Hg (range 5-31.6) at rest and 31 mm Hg (range 5.7-51.4) after exercise. Six patients (35 percent) had a positive response to therapy. Conclusions: The response rates of these patients to colchicine are at least similar to those obtained with steroids, but with less side effects