EDWIN ROGER PARRA CUENTAS
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conferenceObject Proliferative biomarkers in Idiopathic pulmonary fibrosis: Clinical, radiological and functional significance(2012) PARRA, E. R.; CORNATI, M.; CAPELOZZI, V. L.Introduction: The natural course of idiopathic pulmonary fibrosis (IPF) could be predicted by proliferative markers of the fibrotic process, such as myofibroblasts and interleukins (IL)-13 and IL14. Our primary aim was to determine whether these proliferative markers influence the course of IPF measured by a radiological/functional score. Materials and Methods: Twenty-eight patients with biopsy-proven IPF, who underwent pulmonary evaluation by high-resolution computed tomography (HRCT) fibrosis score and pulmonary function tests, were included in the study. Five normal lung tissues (NLT) were included. Biomarkers in lung tissue were detected by immuno-histochemistry and quantified by histomorphometry for myofibroblasts including alpha-smooth muscle actin (a-SMA), anti-interleukin (IL)-4 and IL-13. Results: Myofibrobalst amount, IL-4 and IL-13 expression were higher in IPF than in NLT (P < 0.01). Myofibroblast expression of a-SMA was positively correlated to IL-14 and IL-13 expression. Lung tissue from patients with high HRCT fibrosis scores expressed significantly greatera-SMA+, IL-4 and IL-13 when compared to patients with low HRCT fibrosis scores (P < 0.05). Negative correlations were found between myofibroblasta-SMA+, vital capacity and diffusing capacity of the lung for carbon monoxide. Conclusions: Proliferative markers, detected by immunohistochemistry, in lung tissue allowed the recognition of a dichotomous distribution of HRCT fibrosis course and influenced pulmonary function tests, suggesting that they may be promising markers of prognosis in these patients.- Morphometric evaluation of nitric oxide synthase isoforms and their cytokine regulators predict pulmonary dysfunction and survival in systemic sclerosis(2013) PARRA, E. R.; AGUIAR, A. C. Junior; SILVA, L. O.; SOUZA, H. S. P.; ESPINOZA, J. D.; CAPELOZZI, V. L.Because histopathological changes in the lungs of patients with systemic sclerosis (SSc) are consistent with alveolar and vessel cell damage, we presume that this interaction can be characterized by analyzing the expression of proteins regulating nitric oxide (NO) and plasminogen activator inhibitor-1 (PAI-1) synthesis. To validate the importance of alveolar-vascular interactions and to explore the quantitative relationship between these factors and other clinical data, we studied these markers in 23 cases of SSc nonspecific interstitial pneumonia (SSc-NSIP). We used immunohistochemistry and morphometry to evaluate the amount of cells in alveolar septa and vessels staining for NO synthase (NOS) and PAI-1, and the outcomes of our study were cellular and fibrotic NSIP, pulmonary function tests, and survival time until death. General linear model analysis demonstrated that staining for septal inducible NOS (iNOS) related significantly to staining of septal cells for interleukin (IL)-4 and to septal IL-13. In univariate analysis, higher levels of septal and vascular cells staining for iNOS were associated with a smaller percentage of septal and vascular cells expressing fibroblast growth factor and myofibroblast proliferation, respectively. Multivariate Cox model analysis demonstrated that, after controlling for SSc- NSIP histological patterns, just three variables were significantly associated with survival time: septal iNOS (P=0.04), septal IL-13 (P=0.03), and septal basic fibroblast growth factor (bFGF; P=0.02). Augmented NOS, IL-13, and bFGF in SSc-NSIP histological patterns suggest a possible functional role for iNOS in SSc. In addition, the extent of iNOS, PAI-1, and IL-4 staining in alveolar septa and vessels provides a possible independent diagnostic measure for the degree of pulmonary dysfunction and fibrosis with an impact on the survival of patients with SSc.
conferenceObject Combining Inhibitor of DNA - Binding Proteins and Angigenic Markers Expression Predict Long Term Survival of Patients with Non-Small Cell Lung Cancer(2013) ANTONANGELO, L.; TUMA, T. S.; VARGAS, F. S.; PARRA, E. R.; TERRA, R. M.; ACENCIO, M.; CAPELOZZI, V. L.Background: Inhibitor of DNA binding (Id) proteins is an emerging promise as biologic marker on oncogenic transformation, cancer progression and tumor angiogenesis, the last, by the regulation of vascular endothelial growth factor (VEGF) expression. Design: We evaluated Ids (1, 2 and 3), VEGF expression and microvessel density (CD34+) in tumor and stromal cells and their impact on survival of 85 patients with surgically excised lung squamous cell carcinoma and adenocarcinoma. Immunohistochemistry and morphometry were used for the quantitation and Kaplan-Meyer survival curves and Cox regression for the statistical analyses. Results: It was found that high Id-1 and VEGF expression and high microvessel density were associated with worse prognosis (Log Rank Test, p<0.001). The Cox model controlled for histological type, age, lymph node stage, Ids, VEGF and microvessel density demonstrated that age, lymph node stage, Id1 and Id3 expression and vascular density were significantly associated with overall survival. A point at the median for Id1, Id3 and vascular density divided patients into 2 groups of different prognosis. Those with higher expression of Id1, Id3 and vascular density had a higher risk of death than those with lower Id-1, Id-3 and microvessel density. Conclusions: Inhibitor of DNA binding (Id) proteins and vascular density are strongly related to prognosis, suggesting that treatment strategies aimed for preventing high Ids synthesis, or local responses to angiogenesis may have impact on NSLC survival.conferenceObject Combining Inhibitor of DNA - Binding Proteins and Angigenic Markers Expression Predict Long Term Survival of Patients with Non-Small Cell Lung Cancer(2013) ANTONANGELO, L.; TUMA, T. S.; VARGAS, F. S.; PARRA, E. R.; TERRA, R. M.; ACENCIO, M.; CAPELOZZI, V. L.Background: Inhibitor of DNA binding (Id) proteins is an emerging promise as biologic marker on oncogenic transformation, cancer progression and tumor angiogenesis, the last, by the regulation of vascular endothelial growth factor (VEGF) expression. Design: We evaluated Ids (1, 2 and 3), VEGF expression and microvessel density (CD34+) in tumor and stromal cells and their impact on survival of 85 patients with surgically excised lung squamous cell carcinoma and adenocarcinoma. Immunohistochemistry and morphometry were used for the quantitation and Kaplan-Meyer survival curves and Cox regression for the statistical analyses. Results: It was found that high Id-1 and VEGF expression and high microvessel density were associated with worse prognosis (Log Rank Test, p<0.001). The Cox model controlled for histological type, age, lymph node stage, Ids, VEGF and microvessel density demonstrated that age, lymph node stage, Id1 and Id3 expression and vascular density were significantly associated with overall survival. A point at the median for Id1, Id3 and vascular density divided patients into 2 groups of different prognosis. Those with higher expression of Id1, Id3 and vascular density had a higher risk of death than those with lower Id-1, Id-3 and microvessel density. Conclusions: Inhibitor of DNA binding (Id) proteins and vascular density are strongly related to prognosis, suggesting that treatment strategies aimed for preventing high Ids synthesis, or local responses to angiogenesis may have impact on NSLC survival.conferenceObject Down Regulation of Angiotensin II Receptor Type 1 (AGTR1) Contrast with Up Regulation of Type 2 (AGTR2) in Idiopathic Pulmonary Fibrosis(2013) PARRA, E. R.; RUPPERT, A. D. P.; RANGEL, M. P.; CAPELOZZI, V. L.Background: Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia. IPF represents a progressive and lethal disorder and is of major concern due to its unresolved pathogenesis and limited responsiveness to currently available therapies. IPF is characterized by alveolar injury, fibroblast proliferation and extracellular matrix (ECM) accumulation with severe loss of respiratory function. Angiotensin II (ANGII) signaling, mediated via angiotensin II receptor type 1 (AGTR1) or type 2 (AGTR2), controls tissue remodeling in fibrosis, but the relevance of AGTR2 and AGTR1 remains elusive. Design: Twenty-seven patients with biopsy-proven IPF disease with pulmonary evaluation by high-resolution computed tomography (HRCT) and pulmonary function tests were studied. Ten normal lung tissues (NLT) were included with controls. AGTR1 and AGTR2 in lung parenchyma were detected by immunohistochemistry and quantified by histomorphometry. Results: Quantitative analysis revealed a significant increase of AGTR2 expression in epithelial, endothelial and fibroblastic cells from patients with IPF when compared to NLT group. In contrast, AGTR1 expression levels are decreased in these cells from patients with IPF when compared with NTL. Pulmonary function tests no showed correlation with expression of AGTR1 or AGTR2. The median follow-up was 42.70 months. Ten patients were still alive, 17 died from causes related to IPF. Kaplan Meier curve, showed that the 5-year survival rate in patients with <0.05% of AGTR1 levels was 58.20% versus 24.66% in the group with ≥ 0.05% of AGTR1 levels (p < 0.05). Conclusions: In summary, we demonstrated increased expression of AGTR2 and decreased expression of AGTR1 in lung tissues from patients with IPF suggesting that they may be promising markers of prognosis in these patients.conferenceObject Collagen V Maintains Experimental Pulmonary Fibrosis In Il17-dependent And -Independent Pathways(2013) FABRO, A. T.; SILVA, P. Q.; ZOCOLARO, W. S.; ALMEIDA, M. S.; MINATEL, I. O.; PRANDO, E. C.; RAINHO, C. A.; VELOSA, A. P.; TEODORO, W. R.; PARRA-CUENTAS, E. R.; POPPER, H. H.; CAPELOZZI, V. L.- Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia(2014) PARRA, E. R.; PINCELLI, M. S.; TEODORO, W. R.; VELOSA, A. P. P.; MARTINS, V.; RANGEL, M. P.; BARBAS-FILHO, J. V.; CAPELOZZI, V. L.Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.
conferenceObject PULMONARY FIBROSIS INDUCED BY BLEOMYCIN IS DRIVEN BY HIGH COLLAGEN V AND TGF-< BETA > SYNTHESIS(2014) MARTINS, V.; LOPES, D. B.; ANTUNES, M.; VELOSA, A. P. P.; TEODORO, W. R.; PARRA, E. R.; CAPELOZZI, V. L.conferenceObject Hyaluronan and its impact in the screening and diagnosis of lung cancer patients(2012) RANGEL, M. P.; SA, V. K. de; MARTINS, J. R. Maciel; PARRA, E. R.; TAKAGAKI, T.; LONGATTO FILHO, A.; REIS, R.; CARRARO, D. M.; CAPELOZZI, V. L.Introduction: Hyaluronic Acid (HA) concentration is elevated in several cancers, but there is no data regarding its concentration related to lung cancer. In this study, we examined the HA concentrations in the tissue and in the sputum of lung cancer patients and its impact on the screening and diagnosis of the disease. Materials and Methods: HA was examined in tissue samples of 45 patients and sputum samples of 90 lung cancer patients. The controls were 25 COPD patients and 15 healthy controls. All the patients and controls underwent a sputum induction. Tissue and sputum samples were incubated with a proteolytic enzyme. The levels of HA were measured by a noncompetitive ELISA-like fluorometric assay. Results: A significant different concentration pattern of HA in the tissue was found between tumoral and non-tumoral samples (P < 0.001). Equally significant was the difference found in the sputum among lung cancer, COPD and healthy individuals (P < 0.001). ROC curve between lung cancer and healthy volunteers furnished an area of 0.821. Assuming a cut-off value of 31.44 ng/mg, the specificity was 100% and the sensitivity was 51%. ROC curve to distinguish COPD patients from lung cancer patients showed an area of 0.698 and the cut-off value of 48.3 ng/mg presented 100% specificity and 33% sensitivity. Conclusion: The results presented suggest a possible role of HA on lung cancer development as well as a promising role as a novel screening and diagnostic marker in the sputum for differentiating normal from lung cancer patients.conferenceObject HIGHER ANGIOTENSIN II RECEPTOR TYPE 1 (AGRT1) EXPRESSION AND LYMPHATIC VASCULATURE RAREFACTION IN PROGRESSIVE PULMONARY PARENCHYMAL REMODELING OF SYSTEMIC SCLEROSIS PATIENTS(2012) PARRA, E. R.; RUPPERT, A. D. P.; CAPELOZZI, V. L.