Disfunção ventricular esquerda em hamsters com doença de Chagas tratados com etanercept / Left ventricular dysfunction in hamsters with Chagas disease and treated with etanercept

Objetivo: a doença afeta mais de 10 milhões de pessoas na América Latina. Leva a cardiomiopatia dilatada inflamatória em 30% dos pacientes como conseqüência tardia da infecção pelo protozoário Trypanosoma cruzi, com pior prognóstico que as outras cardiomiopatias dilatadas. estudos prévios mostram aumento dos níveis circulantes do fator de necrose tumoral-alfa (TNF-x) em pacientes com cardiomiopatia chagásica crônica. Assim, o objetivo do presente trabalho foi avaliar efeito do bloqueio do TNF-x com Etanercept na função ventricular esquerda em hamsters sírios cronicamente infectados pelo T. cruzi...

Nitric oxide paradox in asthma

Asthma results from allergen-driven intrapulmonary Th2 response, and is characterized by intermittent airway obstruction, airway hyperreactivity (AHR), and airway inflammation. Accumulating evidence indicates that inflammatory diseases of the respiratory tract are commonly associated with elevated production of nitric oxide (NO). It has been shown that exhaled NO may be derived from constitutive NO synthase (NOS) such as endothelial (NOS 3) and neural (NOS 1) in normal airways, while increased levels of NO in asthma appear to be derived from inducible NOS2 expressed in the inflamed airways. Nevertheless, the functional role of NO and NOS isoforms in the regulation of AHR and airway inflammation in human or experimental models of asthma is still highly controversial. In the present commentary we will discuss the role of lipopolysaccharides contamination of allergens as key element in the controversy related to the regulation of NOS2 activity in experimental asthma.

Lipid mediators, tumor necrosis factor and nitric oxide and their interactions in immune-complex-induced lung injury

We investigated the contribution of eicosanoids, platelet-activating factor, tumor necrosis factor and nitric oxide to the neutrophil influx and development of pulmonary haemorrhagic lesions following immune-complex-induced pneumonitis in rats and possible interactions between these mediators. Increased levels of leukotriene B4 and tumor necrosis factor, measured by enzyme immunoassay and L-929 cytotoxicity assay, were found in the bronchoalveolar lavage 1 and 4 h after induction of the reaction, respectively, and their release was dependent on the previous generation of platelet activating factor. Antagonism of leukotriene B4 receptors by RO-0254094 (2-[(5-carboxypentyl])oxy]-6-[6-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl] benzenepropanoic acid), inhibition of nitric oxide synthesis by l-NAME (NW-nitro-l-arginine methyl ester) and antagonism of PAF-receptors by WEB-2170 (5-(2-chlorphenyl)-3-4-dihydro-10-methyl-3-((4-morpholinyl)carbonyl)-2H,7H-cyclopenta (4,5)thieno(3,2-f)(1,2,4)-triazolo-4,3,a)91,4)diazepine), significantly inhibited the intensity of haemorrhage, evaluated by the increased levels of extravascular hemoglobin in homogenates of lung tissues. Little evidence support the role of tumor necrosis factor in these lesions. The infiltration of neutrophils, evaluated by measuring myeloperoxidase in homogenates of lungs, was reduced by compounds L-663,536 (3-[1-(4 chlorobenzyl)-3-t-butyl thio-5-isopropylindol-2-yl]-2-2-dimethylpropanoic acid), WEB-2170 and l-NAME. These results indicate that neutrophil infiltration and haemorrhagic lesions in immune-complex-induced lung inflammation are mediated by platelet activating factor, leukotriene B4 and nitric oxide and point out to interesting interactions between these mediators.

A new murine model of persistent lung eosinophilic inflammation

We summarize here the main characteristics of a novel model of pulmonary hypersensitivity. Mice were immunized with a subcutaneous implant of a fragment of heat solidified chicken egg white and 14 days later challenged with ovalbumin given either by aerosol or by intratracheal instillation. This procedure induces a persistent eosinophilic lung inflammation, a marked bone marrow eosinophilia, and Th2-type isotypic profile with histopathological findings that resemble human asthma. Further, this model is simple to perform, reproducible in different strains of mice, does not require adjuvants nor multiple boosters. Based on these characteristics we propose it as a suitable murine model of allergic eosinophilic lung inflammation.

The influence of T cell subsets on Trypanosoma cruzi multiplication in different organs

Several studies in mice have strengthened the active role played either by CD4+, CD8+ or both T cell subsets in conferring resistance of Trypanosoma cruzi infection. To date, no studies reported the role played by T cell subsets on parasite multiplication in different organs. In the present work, mice were infected with CL strain of T. cruzi and T cell subset activities were blocked by i.p. injection of monoclonal antibody (mAb) directed against CD4, or IAk, or CD8 molecules. The effect of these treatments was determined by counting the number of parasite nests in heart and liver sections 16 days after infection. Our results showed that mice treated with anti-CD4 or anti-IAk mAbs presented a significant increase in the parasite load in the hearts and in the livers. Conversely, the number of parasites in hearts of anti-CD8 treated mice did not increase significantly. This treatment, however, resulted in a 20-fold increase in the number of parasites found in the liver. Simultaneous depletion of both T cell subsets by treatment of mice with anti-CD4/CD8 mAbs had, in the heart, the same effect as the CD4 depletion. Interestingly, this treatment caused a dramatic increase (200-fold) in the T. cruzi parasitism of the liver. These results indicate that the activity of T cell subsets against T. cruzi varies according to the infected organ.

Resistance mechanisms to experimental paracoccidioides brasilienses infection

Natural resistance and acquired immune responses to Paracoccidioides brasiliensis infection were investigated employing resistant and susceptible inbred mice infected with Pb18, a virulent isolate. Intraperitoneally infected susceptible mice present an innefficient macrophage activation, depressed DTH reactions, high levels of specific antibodies mainly of the IgG2b and IgA isotypes, evident polyclonal activation of IgG1, IgG2b and IgG2a producing B cells and a progressive disease. Resistant mice on the contrary, present an efficient macrophage activation, adequate DTH responses, low levels of specific antibodies mainly of the IgG2a isotype and absence of polyclonal activation of B cell resulting in the resolution of the infectious process. Similar results were obtained when the intratracheal or intravenous routes of infection were used. The previous subcutaneous infection with Pb18 establishes a stable cell-mediated immunity that makes the innately susceptible B10. A mice resistant to P. brasiliensis ip infection. This murine model, which mimics the benign and severe chronic forms of the human disease, is proposed as a framework of our current knowledge of the host-parasite interactions in paracoccidioidomycosis and as a basis ofor future challenge in continuing analyses.