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Bioprinted 3D and 4D tissues and organs are expected to revolutionize the biomedical field, eliminating the need for laboratory animals, but little is known about the future impacts of these technologies on drug development.

Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis, and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of control, chagasic, and BMC transplanted mice. Out of the 9390 unique genes quantified in all samples, 1702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both resotrative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.

Trypanosoma cruzi infection is a major cause of cardiomyopathy. Previous gene profiling studies of infected mouse hearts have revealed prominent changes in gene expression within many functional pathways. This variety of transcriptomic changes in infected mice raises the question of whether gene expression alterations in whole hearts are due to changes in infected cardiac myocytes or other cells or even to systemic effects of the infection on the heart. We employed microarrays to examine infected cardiac myocyte cultures 48 h post-infection. Statistical comparison of gene expression levels of 7624 well annotated unigenes in four independent cultures of infected and uninfected myocytes detected substantial (or=1.5 absolute fold changes) in 420 (5.5%) of the sampled genes. Major categories of affected genes included those involved in immune response, extracellular matrix and cell adhesion. These findings on infected cardiac myocytes in culture reveal that alterations in cardiac gene expression described in Chagas disease are the consequence of both direct infection of the myocytes themselves as well as resulting from the presence of other cell types in the myocardium and systemic effects of infection.

While being an essential part of general anesthesia for surgery and at times even a life-saving intervention in critically ill patients, mechanical ventilation has a strong potential to cause harm. Certain ventilation strategies could prevent, at least to some extent, the injury caused by this intervention. One essential element of so-called ‘lung-protective’ ventilation is the use of lower tidal volumes. It is uncertain whether higher levels of positive end-expiratory pressures have lung-protective properties as well. There are indications that too high oxygen fractions of inspired air, or too high blood oxygen targets, are harmful. Circumstantial evidence further suggests that spontaneous modes of ventilation are to be preferred over controlled ventilation to prevent harm to respiratory muscle. Finally, the use of restrictive sedation strategies in critically ill patients indirectly prevents ventilation-induced injury, as daily spontaneous awakening and breathing trials and bolus instead of continuous sedation are associated with shorter duration of ventilation and shorten the exposure to the injurious effects of ventilation.

Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries. About 30% of Trypanosoma cruzi-infected individuals develop this severe symptomatic form of the disease, characterized by intense inflammatory response accompanied by fibrosis in the heart. We performed an extensive microarray analysis of hearts from a mouse model of this disease and identified significant alterations in expression of approximately 12% of the sampled genes. Extensive up-regulations were associated with immune-inflammatory responses (chemokines, adhesion molecules, cathepsins, and major histocompatibility complex molecules) and fibrosis (extracellular matrix components, lysyl oxidase, and tissue inhibitor of metalloproteinase 1). Our results indicate potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets in chronic Chagas disease.