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Background Identification of biomarkers associated with the diagnosis and prognosis of silicosis would be highly advantageous in the clinical setting. The aim of this study is to evaluate inflammatory and oxidative stress biomarkers in subjects exposed to silica. Methods A cross-sectional study of crystal craftsmen currently (n = 34) or formerly (n = 35) exposed and a group of nonexposed subjects (n = 12) was performed. Personal respirable dust samples were collected. Plasma inflammatory mediators (bone morphogenetic protein- BMP2 and chemokines CXCL16, and CCL5), oxidative stress enzymes (thiobarbituric acid reactive substances [TBARs] and superoxide dismutase [SOD]), and nitrite (NO2 - ) were analyzed in parallel with nitric oxide in exhaled breath (FeNO). Results Being currently or formerly exposed to silica was related to increased levels of CXCL16 and TBARs. Currently, exposed subjects showed decreased levels of SOD. Thirty-seven craftsmen with silicosis (26 formerly and 11 currently exposed) showed higher levels of CXCL16, which was positively associated with the radiological severity of silicosis. Compared with the nonexposed, subjects with silicosis had higher levels of TBARs and those with complicated silicosis had lower levels of SOD. In multivariate analysis, higher levels of CXCL16 were associated with exposure status and radiological severity of silicosis. Smoking was not a confounder. FeNO did not distinguish between the exposure status and the presence of silicosis. Conclusion CXCL16 emerged as a potential biomarker that could distinguish both silica exposure and silicosis. TBARs were elevated in exposed individuals. However, their clinical applications demand further investigation in follow-up studies of representative samples.

Objective Chagas heart disease is developed as a result of the infection with Trypanosoma cruzi. Protein malnutrition contributes to secondary immunodeficiency. The aim of this study was to investigate the role of a low protein diet on the production of endothelin-1 and CX3CL1 in blood and cardiac tissue samples in an experimental model with T. cruzi infection. Methods Fisher rats were submitted to low protein (6%) and normal protein (15%) diets and then infected with the Y strain of T. cruzi. At days 15 and 120, parasites and immune cells were evaluated. Results The low protein diet reduced body weight and circulating serum proteins, but promoted elevation of CX3CL1 and endothelin-1 levels in infected animals, which were unable to control blood parasitemia replication. In heart tissue, the low protein diet reduced cardiac CX3CL1, endothelin-1 and leucocyte infiltration in the acute phase, in particular CD68 and CD163 macrophage phenotypes. Conclusion Together, these results highlight the participation of endothelin-1 and CX3CL1 in the inflammatory process of Chagas diesease, both being mediators partially controlled by the host nutritional status. Objectif La maladie cardiaque de Chagas se developpe a la suite d'une infection par Trypanosoma cruzi. La malnutrition proteique contribue a une immunodeficience secondaire. Le but de cette etude etait d’etudier le role d'un regime pauvre en proteines sur la production d'endotheline-1 et de CX3CL1 dans des echantillons de sang et de tissus cardiaques dans un modele experimental d'infection par T. cruzi. Methodes Des rats Fisher ont ete soumis a des regimes de teneur faible (6%) et normal (15%) en proteines et ont ensuite ete infectes avec la souche Y de T. cruzi. Aux jours 15 et 120, les parasites et les cellules immunitaires ont ete evalues. Resultats Le regime alimentaire faible en proteines a reduit le poids corporel et les proteines seriques, mais a promu l’elevation de CX3CL1 et de l'endotheline-1 chez les animaux infectes, qui etaient incapables de controler la replication parasitemique. Dans le tissu cardiaque, le regime alimentaire faible en proteines a reduit le CX3CL1 cardiaque, l'endotheline-1 et l'infiltration leucocytaire dans la phase aigue, en particulier les phenotypes macrophages CD68 et CD163. Conclusion L'ensemble de ces resultats met en evidence la participation de l'endotheline-1 et du CX3CL1 dans le processus inflammatoire de la maladie de Chagas, les deux etant des mediateurs partiellement controles par l’etat nutritionnel de l'hote. Objetivo La enfermedad cardiaca por Chagas se desarrolla como resultado de una infeccion por Trypanosoma cruzi. La desnutricion proteica contribuye a un estado de inmunodeficiencia secundaria. El objetivo de este estudio era investigar el papel de una dieta baja en proteinas sobre la produccion de la Endotelina-1 y la CX3CL1 en sangre y muestras de tejido cardiaco, en un modelo experimental con infeccion por T. cruzi. Metodos Se sometieron ratas de Fisher a una de dos dietas: baja en proteinas (6%) y con contenido proteico normal (15%), y despues se les infecto con la cepa Y de T. cruzi. En los dias 15 y 120 se evaluaron parasitos y celulas del sistema inmune. Resultados La dieta pobre en proteinas redujo el peso corporal y las proteinas circulantes en suero, pero promovio la elevacion de los niveles de CX3CL1 y endotelina-1 en animales infectados, que no fueron capaces de controlar la replicacion de la parasitemia en sangre. En tejido cardiaco, la dieta pobre en proteinas redujo la CX3CL1 cardiaca, la endotelina-1 y la infiltracion de leucocitos en la fase aguda, en particular los fenotipos de macrofagos CD68 y CD163. Conclusion Juntos, estos resultados evidencian la participacion de la endotelina-1 y la CX3CL1 en el proceso inflamatorio de la enfermedad de Chagas, siendo ambos mediadores parcialmente controlados por el estatus nutricional del hospedero.

Objectives The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. Methods Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. Results All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen/74931 μm2 in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen/74931 μm2 in infected by AAS and 6294.40 ± 896.04 collagen/74931 μm2 in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen/74931 μm2) and Bz-resistant AAS strains (4024 ± 1272.44 collagen/74931 μm2), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen/74931 μm2) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. Conclusions These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated. Objectifs La forme cardiaque de la maladie de Chagas se manifeste par une inflammation cardiaque progressive qui conduit a des myocardites, a la fibrose et a des anomalies de conductions electrocardiographiques (ECG). Compte tenu de ces caracteristiques, le but de cette etude etait d’evaluer prospectivement les premiers changements ECG chez des chiens qui ont ete inocules experimentalement avec des souches de T. cruzi sensibles au Benznidazole (Bz) (Berenice-78) et resistantes au Bz (VL-10 et AAS) et, plus tard, d’evaluer l'efficacite du traitement au Bz pour prevenir ces alterations de l’ECG. Methodes les changements dans l’ECG des d'animaux traites et non traites ont ete evalues de facon prospective sur un maximum de 270 jours apres l'infection, date a laquelle la quantification du collagene (oreillette droite) a ete realisee. Resultats Tous les chiens infectes avaient une forte intensite de fibrose cardiaque (4616,00 ± 1715,82 collagene/74931 μm2 chez les chiens infectes par la souche Berenice-78, 5839,2±1423,49 collagene/74931 μm2 chez ceux infectees par la souche AAS et 6294,40±896,04 collagene/74931 μm2 chez ceux infectes avec la souche VL-10), alors que 78,57% de tous les chiens infectes ont montre des alterations ECG. La therapie au Bz reduit ou empeche la fibrose dans les infections avec les souches Berenice-78 sensibles au Bz (2813,00±607,13 collagene/74931 μm2) et avec les souches AAS resistantes au Bz (4024±1272,44 collagene/74931 μm2), coincidant avec seulement 10% d'alterations de l’ECG a 270 jours. Cependant, chez les animaux infectes par une souche VL-10 resistante au Bz, un traitement specifique ne modifie pas le depot de collagene (6749,5±1596,35 collagene/74931 μm2) et il y avait un premier bloc auriculo-ventriculaire et une surcharge de la chambre a 120 et 270 jours apres l'infection, avec 75% d'examens ECG anormaux. Conclusions Ces resultats indiquent qu'un traitement efficace contre les parasites au stade precoce de la maladie de Chagas peut conduire a une reduction significative de la frequence et de la gravite de la maladie cardiaque induite par le parasite, meme si les parasites ne sont pas totalement elimines. Objetivos La afeccion cardiaca de la enfermedad de Chagas se presenta como una inflamacion cardiaca progresiva que conlleva a una miocarditis, fibrosis y anomalias en el electrocardiograma (ECG). Teniendo en cuenta estas caracteristicas, el objetivo de este estudio era evaluar de forma prospectiva los cambios tempranos en el ECG de perros a los que se les habia inoculado, de manera experimental, con cepas de T. cruzi susceptibles al Benznidazol (Bz) (Berenice-78) y resistentes al Bz (VL-10 y AAS), y posteriormente evaluar la eficacia del tratamiento con Bz para prevenir las alteraciones en el ECG. Metodos Se evaluaron, de forma prospectiva, los cambios en el ECG de los animales tratados y sin tratar, hasta 270 dias despues de la infeccion, punto en el cual se hizo una cuantificacion del colageno (en el atrio derecho). Resultados Todos los perros infectados tenian una alta densidad de fibrosis en el corazon (4616.00±1715.82 colageno/74931 μm2 en perros infectados con la cepa Berenice-78, 5839.2±1423.49 colageno /74931 μm2 en perros infectados con AAS y 6294.40±896.04 colageno /74931 μm2 en animales infectados con la cepa VL-10), mientras que un 78.57% de todos los perros infectados mostraban alteraciones en el ECG. La terapia con Bz redujo o previno la fibrosis en cepas susceptibles a Bz, Berenice-78, (2813.00±607.13 colageno/74931 μm2) y en cepas AAS, resistentes a Bz (4024±1272.44 colageno /74931 μm2), coincidiendo con solo un 10% de las alteraciones en el ECG a dia 270. Sin embargo, en aquellos animales infectados con una cepa VL-10 Bz-resistente, el tratamiento especifico no altero la deposicion de colageno (6749.5±1596.35 colageno/74931 μm2) y primero hubo un bloqueo atrioventricular y sobrecarga de la camara en los dias 120 y 270 despues de la infeccion, siendo anormales un 75% de los examenes de ECG. Conclusiones Estos hallazgos indican que un tratamiento antiparasitario efectivo, en una etapa temprana de la enfermedad de Chagas, puede conllevar a una reduccion significativa en la frecuencia y la severidad de la enfermedad cardiaca inducida por el parasito, inclusive sin una eliminacion completa de los parasitos.

Summary The aim of this study was to investigate the effects of Trypanosoma cruzi (T. cruzi)infection on myocardial morphology, single cardiomyocyte contractile function andexercise tolerance in rats. Adult Wistar rats were randomized into control (n = 14)and infected (n = 14) groups. Infected animals were inoculated with T. cruzi Y strain(300,000 trypomastigotes⁄50 g body weight). After 9 weeks, the animals were sub-jected to a treadmill running protocol. Then, the right atrium (RA) and left ventricle(LV) were removed for morphological and cell contractile evaluation. The infectedanimals exhibited a significant reduction in distance travelled, total time to fatigueand workload. In addition, these animals had hypertrophy, increased myocardial cel-lularity, and an increase in the proportion of collagen and blood vessels. RA and LVmyocytes from infected animals showed marked contractile dysfunction under basalconditions and a reduced contractile response to b-adrenergic stimulation. The work-load of infected animals was correlated closely with the amplitude of cell shorteningof RA and LV myocytes. T. cruzi infection influenced the myocardial morphologyand the mechanical properties of RA and LV single myocytes negatively and reducedexercise tolerance. Single cardiomyocyte contractile dysfunction could constitute anadditional mechanism of cardiac impairment and reduced exercise tolerance in thisinfection.Keywordscellular contractility, Chagas’ cardiomyopathy, myocytes, physical capacity

SUMMARY Chagas heart disease (CHD), caused by Trypanosoma cruzi infection, is a significant cause of morbidity and mortality in South and Central America. Enalapril, an angiotensin converting enzyme (ACE) inhibitor, is an important drug used to ameliorate heart functional capacity and its remodelling in individuals presenting CHD. In this study, we evaluated the effects of enalapril on systemic and cardiac immune response during experimental acute CHD. C57BL ⁄ 6 mice infected with 50 trypomastigote forms of T. cruzi (Colombian strain) were treated daily with enalapril (25 mg ⁄ kg) and, after 30 days, a reduction in seric levels of IFNgamma, TNF-alpha, CCL5 ⁄ RANTES and nitric oxide, but not in that of IL-10, was detected. This imbalance of cytokines reflects in a reduction of heart mononuclear infiltration and in an increasing of cardiac mast cells. Enalapril also presents a new and interesting in vitro and in vivo antiT. cruzi activity probably acting on parasite oxidative pathway via cytochrome-P450. Our data show that enalapril exerts an important anti-T. cruzi and anti-inflammatory activity during acute CHD reducing inflammatory cells and, possibly, preventing fibrotic process in the chronic phase. Nevertheless, further studies are still necessary to clarify the mechanisms by which this drug is acting on the parasites and on the immune pathways.

Aims Cardiomyocyte apoptosis is reported to be involved in the pathogenesis of human chronic Chagas cardiomyopathy (CCC). Members of the tumour necrosis factor (TNF) superfamily (TNF-α, FasLigand/CD95L, and TNF-related apoptosis-inducing ligand) are known to activate the death receptor pathway. We therefore investigated whether levels of TNF-α, FasLigand/CD95L, and TRAIL correlated with changes in heart function of patients with Chagas disease (n = 31). Methods and results Concentrations of TNF-α and TRAIL were clearly augmented in individuals with severe form CCC (n = 16). Levels of FasLigand/CD95L were greater in chagasic patients than in non-infected individuals (n = 15) but did not differentiate between clinical forms of Chagas disease. There was a good correlation between TNF-α (r = 0.85 and r = 0.68, P < 0.0001) or TRAIL (r = 0.68 and r = 0.60, P < 0.001) and left ventricular ejection fraction (LVEF) and left ventricular diastolic diameter (LVDD), respectively. In addition, TNF-α (r = 0.57, P = 0.0001), TRAIL (r = 0.56, P = 0.001), and FasLigand/CD95L (r = 0.51, P = 0.001) showed a good correlation with brain natriuretic peptide, a well-known parameter of ventricular dysfunction in CCC. There was a weak correlation between levels of FasLigand/CD95L (r = 0.50, P < 0.004) and both LVEF and LVDD. There was no correlation between levels of TNF superfamily ligands and chronotropic incompetence, maximal heart rate, or number of ventricular premature beats in 24 h. Conclusion Plasma levels of TNF superfamily ligands are elevated in patients with functional but not arrhythmogenic disturbances, and these death receptor ligands may be potential markers of ventricular dysfunction in CCC.