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.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 Fibrogenesis failure of type V collagen observed in pulmonary and cutaneous fibroblast culture reinforce the pathogenic participation of this collagen in the pathway of systemic sclerosis(2012) TEODORO, W. R.; MORAIS, J.; MARTIN, P.; VELOSA, A. P. P.; CARRASCO, S.; SOUZA, R. B. C.; KATAYAMA, M. L.; GOLDEINSTEIN-SCHAINBERG, C.; PARRA, E. R.; CAPELOZZI, V. L.; YOSHINARI, N. H.Introduction: Unusual type V collagen (COLV) accumulation was demonstrated in systemic sclerosis (SSc) by our group. In this regard, this study analyzed tridimensional reconstruction (3D), biochemical and molecular profile of COLVα1 and COLVα2 chains in pulmonary and cutaneous fibroblasts culture from patients with SSc. Materials and Methods: Pulmonary and cutaneous fibroblasts for culture were obtained from 7 patients with SSc and from six controls respectively. COLV 3D reconstruction was performed by confocal microscopy. COLVα1 and COLVα2 gene expression was performed by RT-PCR and COLV protein expression by immunoblotting. Results: COL V 3D reconstruction showed distorted and strongly thickened fibers with irregular bundles resulting in a dense network in lung and skin fibroblast cultures from SSc patients compared to the thin fibers from fibroblast controls. Collagen quantification showed significant increased COLV fiber expression in SSc cutaneous and pulmonary fibroblasts (P<0.01) compared with the respective controls. In the same way, molecular evaluation demonstrated an increased significance (P=0.05) of COLVα1 and COLVα2 mRNA expression in cutaneous and pulmonary fibroblasts from SSc patients to that of control groups. The immunoblotting analysis demonstrated the increased weight of the molecular COLV chains. Conclusion: COLV overexpression and an unusual organization of these fibers including molecular and biochemical changes, suggest an interference process of the COLV fibrillogenesis in patients with SSc, reinforcing the participation of this collagen in SSc pathogenesis and open new therapeutic perspectives for these patients.conferenceObject Viral detections reinforce the possible viral participation in the pulmonary fibrosis disease(2012) SANTOS, G. C. dos; PARRA, E. R.; STEGUN, F. W.; CIRQUEIRA, C. S.; DUARTE, M. I. S.; CAPELOZZI, V. L.Introduction: Viruses in general represent a factor of aggression to lung tissue in fibrosing interstitial pneumonias. In this regard, the aim of this study was to investigate the presence or absence of virus infections in 38 patients with interstitial lung diseases. Materials and Methods: Immunohistochemical staining was used for detection of measles virus (MV), cytomegalovirus (CMV), hepatitis-C virus (HCV), adenovirus (ADV), respiratory syncytial virus (RSV), Epstein-Barr virus (EBV) and herpes I and II viruses (HVI and HVII) in open lung biopsies of 13 patients with idiopathic pulmonary fibrosis (IPF); 8 patients with non specific interstitial pneumonia (NSIP); 13 patients with acute interstitial pneumonia (AIP) and 4 patients with idiopathic centrilobular fibrosis (ICF). Gender, age and immunosuppression therapy were also correlated. Results: Epithelial MV and CMV infection was detected in 30.8% and 15.4% of patients with AIP respectively. Endothelial CMV infection was observed in 25% patients with ICF. According to age patients were divided into two groups: patients £43 years and ‡72 years of age. The patients £43 years showed higher MV and CMV infection than the group ‡72 years. HCV infection was not observed. Conclusion: Viral infections observed in these diseases reinforce possible viral participation in pulmonary fibrosis. These findings are particularly relevant given the increased interest in epithelial injury and repair as it relates to the pathogenesis of many diffuse lung diseases.article 39 Citação(ões) na Scopus Experimental diabetes modulates collagen remodelling of joints in rats(2012) ATAYDE, Sandra A.; YOSHINARI, Natalino H.; NASCIMENTO, Dafne P.; CATANOZI, Sergio; ANDRADE, Priscila C.; VELOSA, Ana Paula P.; PARRA, Edwin R.; PASSARELLI, Marisa; NAKANDAKARE, Edna R.; CAPELOZZI, Vera L.; TEODORO, Walcy R.The aim of this study was to evaluate extracellular matrix components in articular cartilage, ligaments and synovia in an experimental model of diabetes. Young Wistar rats were divided into a streptozotocin-induced (STZ; 35 mg/kg) diabetic group (DG; n=15) and a control group (CG; n=15). Weight, blood glucose and plasma anti-carboxymethyllysine were measured 70 days after STZ infusions. Knee joints, patellar ligaments, and lateral and medial collateral ligaments were isolated and stained with hematoxylineosin and Picrosirius. The total collagen content was determined by morphometry. Immunofluorescence was employed to evaluate types I, III, and V collagen in ligaments and synovial tissues and types II and XI collagen in cartilage. Results: Higher blood glucose levels and plasma anti-carboxymethyllysine were observed in DG rats when compared to those in CG rats. The final weight was significantly lower in the DG rats than in the CG rats. Histomorphometric evaluation depicted a small quantity of collagen fibers in ligaments and articular cartilage in DG rats, as well as increased collagen in synovial tissue. There was a decrease in cartilage proteoglycans in DG rats when compared with CG rats. Immunofluorescence staining revealed an increase of collagen III and V in ligaments, collagen XI in cartilage, and collagen I in synovial tissue of DG rats compared with CG rats. Conclusion: The ligaments, cartilage and synovia are highly affected following STZ-induced diabetes in rats, due the remodeling of collagen types in these tissues. This process may promote the degradation of the extracellular matrix, thus compromising joint function. Our data may help to better understand the pathogenesis of joint involvement related to diabetes.conferenceObject Increased hyaluroman syntehase-2 expression has impact in the idiopathic pulmonary fibrosis progression(2012) PARRA, E. R.; CAPELOZZI, V. L.Introduction: Idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting extracellular matrix (ECM) deposition in the lung. Myofibroblasts and ECM components such as collagen and hyaluronan (HA) have an important role in fibrosis. The expression of HAS1 (HA synthase 1), HAS2, HAS3 and hyaluronic acid receptor (CD44) by epithelial and myofibroblastic cells in patients with IPF were analyzed and correlated with survival. Materials and Methods: Epithelial and myofibroblastic expression of HAS1, HAS2, HAS3 and CD44 were evaluated in 27 surgical lung biopsies from patients with IPF in minimal and severe fibrosis by the point-counting technique. The impact of these markers was tested by pulmonary functional tests and follow-up until IPF related death. Results: HAS2 and CD44 expression were significantly increased and directly associated with severe fibrosis. Myofibroblastic HAS2 activity was indirectly associated to DLO/VA (r=) 0.584; P = 0.05). Kaplan Maier curves determined a higher risk of death for patient with high HAS2 (>6.83%) expression than in low expression (Log Rank P = 0.05). Conclusion: Increased HAS2 activity in epithelial and myofibroblastic cells have an impact in the remodeling process as well as survival evolution, suggesting that strategies aimed at preventing the effect of this ECM component may have a greater impact in patient’s outcome.conferenceObject Late Stage of Experimental Pulmonary Fibrosis is Modulated by Collagen V(2012) FABRO, A. T.; MINATEL, I. O.; TEODORO, W. R.; CUENTAS, E. R. Parra; RAINHO, C. A.; CAPELOZZI, V. L.; POPPER, H.Background: The late phase of experimental models of pulmonary fibrosis (PF) tend to recover from fibrotic process, but in different degrees depending on the drug/strain/inflammation. The mechanisms which prolong the process in the late phase in certain strains may participate in the PF. Aim: To determine the immune-fibrotic pattern in pulmonary fibrosis models in the late stage (21 days). Methods: The PF was induced in Bleomycin (BLM-BALB) and Paraquat (PQ-BALB) Balb/c and IL17-RA-Knockout (BLM-IL17KO-C57) and wild C57/B6 (BLM-C57). We used the picrosirius-polarization method and immunofluorescence to morphometrically study peribronchiolar (PB) and peripherical (PP) collagen fibers and collagen III and V, respectively. The results of collagens were confirmed by RT-PCR of cultured pulmonary fibroblasts. Results: The late PQ and BLM-mediated peribronchiolar fibrosis is IL-17 independent, as IL17-RA)/) mice developed similar PB after induction when compared to BLM-BALB, PQ-BALB and BLM-C57. The level of gene expression of collagen I and III did not show differences between the groups of the cultures, validating our results. However, the PP was higher in the C57BL/6, independent of the absence of IL-17RA. The protein expression of Col5 was higher in IL-17RA-KO and lower in BLM-Balb/c. Like-wise, the gene expression of Col5 was higher in IL17RA-KO and lower in BLM-Balb/c. Conclusion: The perpetuation of PF in fibrosis-susceptible mice can be modulated by Col5 in a IL-17ReceptorA-independent manner in the late phase. However, the IL-17 pattern appears to influence the expression of collagen V. This suggests that exposure of the collagen V from the basement membrane is an important component responsible for PF.conferenceObject Stem cells of adipose rabbit tissue are stimulate into chondrocyte-like phenotype by collagen V in vitro(2012) CRUZ, I. Brindo da; GOLDENSTEIN-SCHAINBERG, C.; FULLER, R.; VELOSA, A. P. P.; CARRASCO, S.; PARRA, E. R.; CAPELOZZI, V. L.; YOSHINARI, N. H.; TEODORO, W. R.Introduction: Among a variety of biological functions, including an anti-inflammatory effect, collagen V (COLV) regulates the diameter of collagen fibers with an important role in the development of functional tissues. Therefore the aim of this study was to evaluate, in rabbits, the influence of COLV in the induction of differentiation of adipose tissue-derived stem cells to a chondrocyte-like cell phenotype. Materials and Methods: New Zealand Rabbits were used as source of adipose tissues for the isolation of mesenchymal stem cells (MSCs). Preliminary characterization of mesenchymal lineage and differentiation into chondrocyte-like phenotype was confirmed by immunofluorescence analysis using antibodies to collagens I, II (polyclonals), III and CD34 (monoclonals). After 2 and 3 weeks in culture with and without COLV, the cell aggregates were fixed for 2 h in 4% formaldehyde, dehydrated with ethanol, washed with xylene and embedded in paraffin. Different sections were cut and stained with Toluidine blue, Alcian blue and Picrosirius red respectively. Results: Proteoglicans and collagen fibers were observed by assessment of the different stains, confirming the collagen expression. Remarkably, compared to control cultures, in the presence of COLV timulation, MSCs were capable to increase production of collagen I and II, confirming its chondrocyte-like cell phenotype. Conclusion: We conclude that COLV may facilitate the differentiation of rabbit adipose tissue-derived stem cells into a chondrocyte-like phenotype and this result can be considered to be candidate for therapies.- Different morphology, stage and treatment affect immune cell infiltration and long-term outcome in patients with non-small-cell lung carcinoma(2012) SOUZA, Paola da Costa; PARRA, Edwin Roger; ATANAZIO, Marcelo Junqueira; SILVA, Osmar Bianchi da; NOLETO, Gustavo Sousa; AB'SABER, Alexandre Muxfeldt; FERNEZLIAN, Sandra de Morais; TAKAGAKI, Tereza; CAPELOZZI, Vera LuizaAims: Development of effective immune-based therapies for patients with non-small-cell lung carcinoma (NSCLC) depends on an accurate characterization of complex interactions that occur between immune cells and the tumour environment. Methods and results: Innate and adaptive immune responses were evaluated in relation to prognosis in 65 patients with surgically excised NSCLC. Immunohistochemistry and morphometry were used to determine the abundance and distribution of immune cells. We found low numbers of immune cells and levels of cytokines in the tumour environment when compared with surrounding parenchyma. Smoking was associated inversely with the adaptive immune response and directly with innate immunity. We observed a prominent adaptive immune response in squamous cell carcinomas (SCC) but greater innate immune responses in adenocarcinomas and large cell carcinomas. Cox model analysis showed a low risk of death for smoking <41 packs/year, N-0 tambour stage, squamous carcinoma, CD4(+) > 16.81% and macrophages/monocytes >4.5%. Collectively, the data indicate that in NSCLC there is not a substantive local immune cell infiltrate within the tumour. Conclusion: Although immune cell infiltration is limited in NSCLC it appears to have an impact on prognosis and this may be of relevance for new immunotherapeutic approaches.