Host-microbe interaction & Vascular Dysfunction
Using human samples and novel genetically modified mice, we have shown how the absence and mutation of the endoprotective proteins Caveolin-1 and BMPR2 modulate the inflammatory response and change the normal function of lung endothelial cells (EC) during PAH. In particular, our work uncovered how Cav-1 deficiency leads to eNOS dysfunction – a major EC enzyme – contributing to lung vascular disease (Oliveira et al., 2017). Our work has been critical in showing the relationship between Cav-1/eNOS and how it impacts BMPR2/TGF-β signaling, especially in female animals (Erewele, Castellon, Loya, et al., 2022). Moreover, we have been uncovering how pathogen-induced EC injury plays a key role in the onset of PAH (Oliveira, 2022).
Representative confocal micrography showing a remodeled pulmonary artery during pulmonary arterial hypertension (PAH). Immunohistochemistry was used to investigate the expression of Caveolin-1 (red) in CD31+ endothelial cells (green). Nuclei were stained using DAPI (blue).
Adult Schistosoma mansoni attached to a primary culture of mesenteric endothelial cells.
Sepsis, Anesthesia & Innate Immunity
Sepsis is a severe illness leading to more than 200,000 deaths yearly. One key characteristic of sepsis is the systemic hypotension caused by the presence of bacteria and their toxins in the blood vessels. In this sense, we observed that the volatile anesthetic sevoflurane potentiates macrophage bactericidal and anti-inflammatory response in endotoxemia, which lays the foundation of new knowledge to possibly improve the survival of septic patients (Gerber et al., 2019). We also showed how the key purinergic enzyme CD39 modulates the function of the P2X7R in macrophages and, thus, attenuates sepsis-induced liver injury (Savio et al., 2017). Moreover, we contributed to testing the effect of pharmaceutical compounds (Esparza et al., 2023 – in prep.) and a novel probe (Colucci-Guyon et al., 2019; Batista, Oliveira, et al., 2022) on sepsis and as a novel research tool for leishmaniosis and neutrophil-related research, respectively.
Illustrative photo of anesthetics (left side). P2X7 receptor expression in lipopolysaccharide (LPS)-activated peritoneal macrophages (right side).
Endothelial-immune cell crosstalk
Our recent work found that depletion of lung EC-Cav-1 is traceable in the plasma from human PAH patients as a component of extracellular vesicles (EVs). The specific EV cell-derived cargo has been implicated in several inflammatory diseases, including cardiopulmonary diseases. In line with these observations, our exciting data shows that EC-derived Cav-1+ EVs and Cav-1 loss reduce endo-protective BMPR2 expression and contribute to pro-fibrotic macrophage activation and TGF-β-mediated vascular remodeling (Oliveira et al., 2019). Thus, identifying how EC-EC and EC-immune cell communication via EVs leads to endothelial dysfunction and pulmonary vascular remodeling is an important step for research on reducing mortality and morbidity during PAH.
Representative confocal micrography showing endothelial cells (green) using a novel genetically modified animal model to investigate endothelial phenotypes and extracellular vesicle shedding. Nuclei were stained using DAPI (blue). Other lung cell types are observed in red (mTomato).
Plasma extracellular Vesicles loaded into a Nanoparticle Analyzer (NanoSight).
Purinergic Signaling & Inflammation
During my graduate research, I identified the expression and function of the damage-associated molecular pattern receptors called P2X7 (massive ATP-activated receptors) on mesentery ECs and how losing their expression critically impairs the purinergic signaling and NO production by ECs (Oliveira et al., 2013, 2016). I also observed that in the chronic stage of schistosomiasis, pro-fibrotic TGF-β induced a defect in the function of P2X7R on macrophages (Oliveira et al., 2014). Recently, together with our cols., we also helped to identify that Cav-1 contributes to defective P2X7R function in macrophages (Savio et al., 2020), which may be a key step for schistosomiasis-induced inflammation. Although some anti-parasitic treatments are available against schistosomiasis, they are ineffective in fully recovering the inflammatory damage associated with the disease. Moreover, no targeted therapy exists for S. mansoni-associated lung disease.
Fluorescent micrograph showing the murine mesentery (left side). Intracellular Calcium measurement in peritoneal macrophages (right side).
“At the University we teach because we research”
By Carlos Chagas Filho, a Brazilian physician, biologist, and scientist.