Uso de neumocitos de tipo II en el tratamiento de enfermedades pulmonares asociadas con fibrosis pulmonar

Se describe el empleo de neumocitos tipo II como agentes inhibidores de la proliferación de fibroblastos, por lo que pueden ser utilizados en la elaboración de un medicamento para el tratamientode enfermedades pulmonares que cursan con fibrosis pulmonar.Peer reviewedConsejo Superior de Investigaciones Científicas (España)T3 Traducción de patente europe

In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats

This study examines the activity of the antioxidant N-acetylcysteine on bleomycin-induced pulmonary fibrosis in rats with emphasis on the early inflammatory phase. Rats receiving N-acetylcysteine (300 mg kg−1 day−1, intraperitoneal) had less augmented lung wet weight, and lower levels of proteins, lactate dehydrogenase, neutrophil and macrophage counts in bronchoalveolar lavage fluid and lung myeloperoxidase activity with a betterment of histological score at 3 days postbleomycin. A diminished lung GSH/GSSG ratio and augmented lipid hydroperoxides were observed 3 days postbleomycin. These changes were attenuated by N-acetylcysteine. Alveolar macrophages from bleomycin-exposed rats released augmented amounts of superoxide anion and nitric oxide. N-Acetylcysteine did not modify superoxide anion generation but reduced the increased production of nitric oxide. N-Acetylcysteine suppressed the bleomycin-induced increased activation of lung NF-κB (shift assay and immunohistochemistry), and decreased the augmented levels of the early inflammatory cytokines, tumour necrosis factor-α, interleukin-β, interleukin-6 and macrophage inflammatory protein-2 observed in bronchoalveolar lavage fluid at 1 and 3 days postbleomycin exposure. At 15 days postbleomycin, N-acetylcysteine decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content: 6351±669 and 4626±288 μg per lung in drug vehicle- and N-acetylcysteine-treated rats, respectively; P<0.05). Semiquantitative histological assessment at this stage showed less collagen deposition in N-acetylcysteine-treated rats compared to those receiving bleomycin alone. These results indicate that N-acetylcysteine reduces the primary inflammatory events, thus preventing cellular damage and the subsequent development of pulmonary fibrosis in the bleomycin rat model.This work was supported by Grant 1FD97-1143 from the European Union (Regional Development Funds, FEDER), CICYT (Spanish Government), Regional Government (Generalitat Valenciana) and Grant FIS98/1367 (Spanish Ministry of Health).Peer reviewe

Improved Alveolar Dynamics and Structure After Alveolar Epithelial Type II Cell Transplantation in Bleomycin Induced Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressively and ultimately fatal lung disease. Previously it has been shown that intratracheal administration of alveolar epithelial type II cells (AE2C) in the animal model of bleomycin-induced pulmonary fibrosis is able to reverse fibrosis and restore surfactant protein levels. However, to date, it has not been evaluated whether these changes involve any improvement in alveolar dynamics. Consequently, the aim of the present work was to study lung physiology after AE2C transplantation at different time points during the development of injury and fibrosis. Lung fibrosis was induced by intratracheal instillation of bleomycin (4U/kg) in rat lungs. The animals were transplanted with AE2C (2.5 x 10(6) cells/animal) 3 or 7 days after bleomycin instillation. Assessments were done at day 7 and 14 after the induction of fibrosis to plot time dependent changes in lung physiology and mechanics. To assess the pressures and rates at which closed alveoli reopens invasive pulmonary tests using a small-animal mechanical ventilator (Flexivent (R), Scireq, Canada) including de-recruitability tests and forced oscillation technique as well as quasi-static pressure volume loops were performed. Afterwards lungs were fixed by vascular perfusion and subjected to design-based stereological evaluation at light and electron microscopy level. AE2C delivered during the lung injury phase (3 days) of the disease are only able to slightly recover the volume of AE2C and volume fraction of LB in AE2C. However, it did not show either positive effects regarding ventilated alveolar surface nor any increase of lung compliance. On the other hand, when AE2C are delivered at the beginning of the fibrotic phase (7 days after bleomycin instillation), an increased ventilated alveolar surface to control levels and reduced septal wall thickness can be observed. Moreover, transplanted animals showed better lung performance, with increased inspiratory capacity and compliance. In addition, a detailed analysis of surfactant active forms [mainly tubular myelin, lamellar body (LB)-like structures and multilamellar vesicles (MLV)], showed an effective recovery during the pro-fibrotic phase due to the healthy AE2C transplantation. In conclusion, AE2C transplantation during fibrogenic phases of the disease improves lung performance, structure and surfactant ultrastructure in bleomycin-induced lung fibrosis

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosisdisease progression

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case–control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37¡0.7 mmHg (0.049¡0.093 kPa) per month) compared to GA genotype (0.12¡1 mmHg (0.016¡0.133 kPa) per month) and GG genotype (0.2¡0.6 mmHg (0.027¡0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.Supported by grants from FIS-PI; FISPI060064, FIS-IDIBAPS CM05/00118, Sociedad Española de Neumologia y Cirugia Torácica (SEPAR)-Fundación Respira and Faculdade Capivari, Spain.Peer reviewe

Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model

Rationale Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals

Effect of isotopic mass on the photoluminescence spectra of beta zinc sulfide

Zinc sulfide is a wide bandgap semiconductor which crystallizes in either the wurtzite modification (a-ZnS), the zincblende modification (b-ZnS) or as one of several similar tetrahedrally coordinated polytypes. In this work, we report a photoluminescence study of different samples of isotopically pure b-ZnS crystals, and crystals with the natural isotopic abundances, at 15 and 77 K. The derivatives of the free and bound exciton energies on isotopic mass have been obtained. They allow us to estimate the contribution of the zinc and sulfur vibrations to the bandgap renormalization energy by electron-phonon interaction. A two-oscillator model based on the zinc and sulfur renormalization energies has been used to account for the temperature dependence of the bandgap energy in ZnS. The results are compared with those found for other tetrahedrally coordinated semiconductors.Comment: 19 pages, 4 Postscript figures, sent to Solid State Communication

Novel experimental model of maintained acute lung injury

Trabajo presentado en el 23rd Annual Congress European Respiratory Society (ERS) celebrado del 7 al 11 de septiembre de 2013 en Barcelona (España)Abstract publicado en "European Respiratory Journal" 42 (Suppl 57): 50s-51s (2013)Rationale: Several animal models have been developed to study acute lung injury (ALI); however the majority of these studies are focused on different mechanisms within the acute phase. These models do not allow studying the mechanisms in the later phases or testing any possible long-term treatment. The aim of this study was to develop an experimental ALI model simulating bronchial aspiration of gastric contents with bacterial superinfection with alveolar epithelial damage persisting over time. Methods: Sprague-Dawley rats (200-250g) were anesthetized with isofl uorane. ALI was induced by intratracheal instillation of HCl (1 μl/g, 0.1 mol/L pH=1.4) followed by instillation of LPS from Escherichia coli O55:B5 (0, 10, 20, 30 or 40μg/g b.w.) two hours later. Control rats were treated with intratracheal instillations of saline. After 72h, the animals were sacrifi ced and bronchoalveolar lavage fl uid (BALF) was sampled for further analysis of total protein concentration by bicinchoninic acid method. Results: At 72 h, rats suffered a signifi cant loss of weight proportional to the administered dose of LPS (5.6% with 10μg/g b.w, 12.6% with 20μg/g b.w, 14.2% with 30μg/g b.w and 17.7% with 40μg/g b.w). Control rats gained in weight at 72h. LPS at 10, 20, 30 and 40μg/g b.w induced a 1.7, 2.5, 2.9 and 3.4 fold increase in total protein concentration in BAL fl uid, respectively, refl ecting a substantial increase proportional to the LPS dose. Conclusion: The degree of weight loss and the increase of total protein concentration in BAL fl uid in the current model may refl ect disease severity and progression. This model would be useful in future for new therapeutical optionsGrant acknowledgements: FIS-PI12/02548 and Fundació Parc TaulíPeer Reviewe

Profibrotic role of inducible heat shock protein 90α isoform in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-β, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.This work was supported by Spanish Ministerio de Economía, Industria y Competitividad, Gobierno de España Grant RTI2018-095214-B-I00, as well as by the Instituto de Formación e Investigación Marqués de Valdecilla IDIVAL (InnVal 17/22; InnVal 20/34), 2020UCI22-PUB-0003 Gobierno de Cantabria (to A.V.V.), SAF2016-75195-R (to J.M.), SAF2017-82905-R (to R.M.), and (NextVal 18/14) to A.P

Antiviral drug candidates for entry inhibition of SARS-CoV-2

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EC50 and CC50 of 39 antiviral drug candidates

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