MARISA DOLHNIKOFF
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Inflammation and Remodeling in Infantile, Juvenile, and Adult Allergic Sensitized Mice(2011) CARNIELI, Denise S.; YOSHIOKA, Eliane; SILVA, Luiz Fernando F.; LANCAS, Tatiana; ARANTES, Fernanda M.; PERINI, Adenir; MARTINS, Milton A.; SALDIVA, Paulo Hilario N.; DOLHNIKOFF, Marisa; MAUAD, ThaisBackground: Airway structural changes occur early in childhood asthma, but it is unknown whether the development of airway alterations in children is similar to that of adults. We compared inflammation and remodeling parameters in allergic sensitized infantile, juvenile, and adult mice. Methods: Infantile mice (18D) were sensitized with three intraperitoneal injections (i.p.) of ovalbumin (OVA) at days 5 and 7 and challenged with OVA at days 14-16. The 18D1 group received an additional challenge at days 9-11. The juvenile mice (40D) received challenges at days 22-24 and 36-38. Adult mice (100D) were sensitized at days 60-62 and received three inhalations at days 77-79 and 96-98. Animals were submitted to whole body plethysmography. Airway eosinophils, CD3+ T-lymphocytes, IL-5+ cells, mucus content, collagen and reticular fibers density, and smooth muscle thickness were quantified. Results: All sensitized animals presented with airway hyperresponsiveness, without differences in eosinophil cell density The density of CD3+ T-cells was higher in the 100D and 1801 groups than in the 18D and 40D groups. Infantile sensitized groups demonstrated increased interleukin-5 expression in the airways. Infantile mice demonstrated more mucus in the bronchiolar epithelium than the 40D and 100D mice. The 18D animals demonstrated less collagen than the 18D1 group. Juvenile and adult mice had increased airway smooth muscle thickness when compared to age-matched controls, but no differences were observed in the infantile groups. Conclusion: We have shown that infantile mice develop inflammatory and structural alterations in the airways that are partially different from those developed in older animals. Pediatr Pulmonol. 2011;46:650-665. (C) 2011 Wiley-Liss, Inc.
- Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue(2011) MORALES, Maina M. B.; PIRES-NETO, Ruy C.; INFORSATO, Nicole; LANCAS, Tatiana; SILVA, Luiz F. F. da; SALDIVA, Paulo H. N.; MAUAD, Thais; CARVALHO, Carlos R. R.; AMATO, Marcelo B. P.; DOLHNIKOFF, MarisaIntroduction: Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients. Methods: We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student's t test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test. Results: Thirty-one ARDS patients (A: PaO(2)/FiO(2) <= 200, 45 +/- 14 years, 16 males) and 11 controls (C:52 +/- 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 +/- 27.2%, C:76.7 +/- 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 +/- 35.2%, C:21.8 +/- 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 +/- 54.3 mu m, C:86.4 +/- 33.3 mu m, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P = 0.03). The extension of normal epithelium showed a positive correlation with PaO(2)/FiO(2) (r(2) = 0.34; P = 0.02) and a negative correlation with plateau pressure (r(2) = 0.27; P = 0.04). The extension of denuded epithelium showed a negative correlation with PaO(2)/FiO(2) (r(2) = 0.27; P = 0.04). Conclusions: Structural changes in small airways of patients with ARDS were characterized by epithelial denudation, inflammation and airway wall thickening with ECM remodeling. These changes are likely to contribute to functional airway changes in patients with ARDS.
- Mechanical evaluation of the resistance and elastance of post-burn scars after topical treatment with tretinoin(2011) DEMATTE, Maria Fernanda; GEMPERLI, Rolf; SALLES, Alessandra Grassi; DOLHNIKOFF, Marisa; LANCAS, Tatiana; SALDIVA, Paulo Hilario Nascimento; FERREIRA, Marcus CastroOBJECTIVE: After burn injuries, scarred skin lacks elasticity, especially in hypertrophic scars. Topical treatment with tretinoin can improve the appearance and quality of the skin (i.e., texture, distensibility, color, and hydration). The objective of this prospective study was to examine the effects of treatment with 0.05% tretinoin for one year on the biomechanical behavior and histological changes undergone by facial skin with post-burn scarring. Setting: Tertiary, Institutional. METHOD: Fifteen female patients who had suffered partial thickness burns with more than two years of evolution were selected. Skin biopsies were obtained initially and after one year of treatment. The resistance and elastance of these skin biopsies were measured using a mechanical oscillation analysis system. The density of collagen fibers, elastic fibers, and versican were determined using immunohistochemical analysis. RESULTS: Tretinoin treatment significantly lowered skin resistance and elastance, which is a result that indicates higher distensibility of the skin. However, tretinoin treatment did not significantly affect the density of collagen fibers, elastic fibers, or versican. CONCLUSION: Topical tretinoin treatment alters the mechanical behavior of post-burn scarred skin by improving its distensibility and thus leads to improved quality of life for patients.
article 6 Citação(ões) na Scopus Effect of Fibrin Glue on Collagen Deposition After Autologous Fascia Grafting in Rabbit Vocal Folds(2011) SCAPINI, Fabricio; SILVA, Luiz Fernando Ferraz da; TSUJI, Domingos Hiroshi; DOLHNIKOFF, Marisa; SENNES, Luiz UbirajaraObjectives: Fibrin glue (FG) is a reaction product of fibrinogen and thrombin that forms a fibrin clot responsible for tissue adhesion. However, FG and its components may interfere with wound healing by interacting with cytokines such as transforming growth factor-beta (TGF-beta). The objective of this study was to investigate the effect of FG on collagen deposition after fascia grafting in the vocal folds of rabbits. Methods: Eighteen rabbits underwent autologous fascia grafting in both vocal folds, and the left side was fixed with FG. Each animal was painlessly sacrificed after 7,30, or 90 clays. The larynx was removed, and the vocal folds were prepared for histomorphometric analysis by picrosirius red staining to evaluate collagen deposition around the graft. Results: There was a significant increase in collagen density around the grafts at 90 days in the vocal folds that were fixed with FG (p = 0.0102) compared with the control vocal folds. Conclusions: Application of FG altered collagen deposition around the fascia grafts, leading to significantly increased collagen density after 90 days. Differences found in the composition of the extracellular matrix in later stages of the healing process are a result of changes that occur in the beginning of this process. Therapeutic interventions, such as the use of FG and/or its components, performed in the early stages of wound healing may interfere with the complex interactions of fibroblasts, inflammatory cells, and cytokines (especially TGF-beta), thereby modulating the healing process.- Effects of different mechanical ventilation strategies on the mucociliary system(2011) PICCIN, Vivien S.; CALCIOLARI, Christiane; YOSHIZAKI, Kelly; GOMES, Susimeire; ALBERTINI-YAGI, Claudia; DOLHNIKOFF, Marisa; MACCHIONE, Mariangela; CALDINI, Elia G.; SALDIVA, Paulo H. N.; NEGRI, Elnara M.To evaluate the effects of different mechanical ventilation (MV) strategies on the mucociliary system. Experimental study. Twenty-seven male New Zealand rabbits. After anesthesia, animals were tracheotomized and ventilated with standard ventilation [tidal volume (Vt) 8 ml/kg, positive end expiratory pressure (PEEP) 5 cmH(2)O, flow 3 L/min, FiO(2) 0.4] for 30 min. Next, animals were randomized into three groups and ventilated for 3 h with low volume (LV): Vt 8 ml/kg, PEEP 5 cmH(2)O, flow 3 L/min (n = 6); high volume (HV): Vt 16 ml/kg, PEEP 5 cmH(2)O, flow 5 L/min (n = 7); or high pressure (HP): Ppeak 30 cmH(2)O, PEEP 12 cmH(2)O (n = 8). Six animals (controls) were ventilated for 10 min with standard ventilation. Vital signals, blood lactate, and respiratory system mechanics were verified. Tracheal tissue was collected before and after MV. Lung and tracheal tissue sections were stained to analyze inflammation and mucosubstances by the point-counting method. Electron microscopy verified tracheal cell ultrastructure. In situ tracheal ciliary beating frequency (CBF), determined using a videoscopic technique, and tracheal mucociliary transport (TMCT), assessed by stereoscopic microscope, were evaluated before and after MV. Respiratory compliance decreased in the HP group. The HV and HP groups showed higher lactate levels after MV. Macroscopy showed areas of atelectasis and congestion on HV and HP lungs. Lung inflammatory infiltrate increased in all ventilated groups. Compared to the control, ventilated animals also showed a reduction of total and acid mucus on tracheal epithelium. Under electron microscopy, injury was observed in the ciliated cells of the HP group. CBF decreased significantly after MV only in the HP group. TMCT did not change significantly in the ventilated groups. Different MV strategies induce not only distal lung alterations but also morphological and physiological tracheal alterations leading to mucociliary system dysfunction.
- Pulmonary arterial involvement leading to alveolar hemorrhage in lymphangioleiomyomatosis(2011) BALDI, Bruno Guedes; PIMENTA, Suzana Pinheiro; KAWASSAKI, Alexandre de Melo; BERNARDI, Fabiola Del Carlo; DOLHNIKOFF, Marisa; CARVALHO, Carlos Roberto Ribeiro
article 0 Citação(ões) na Scopus Necrotizing Bronchiolitis in Influenza A of Swine Origin (H1N1)(2011) MAUAD, Thais; HAJJAR, Ludhmila Abrahao; SILVA, Luiz Fernando Ferraz da; GALAS, Filomena Regina Barbosa Gomes; DOLHNIKOFF, Marisa; SALDIVA, Paulo Hilario Nascimento- Airway epithelium mediates the anti-inflammatory effects of exercise on asthma(2011) VIEIRA, Rodolfo Paula; TOLEDO, Alessandra Choqueta de; FERREIRA, Sergio Cesar; SANTOS, Angela Batista Gomes dos; MEDEIROS, Maria Cristina Rodrigues; HAGE, Marcia; MAUAD, Thais; MARTINS, Milton de Arruda; DOLHNIKOFF, Marisa; CARVALHO, Celso Ricardo Fernandes deAirway epithelium plays an important role in the asthma physiopathology. Aerobic exercise decreases Th2 response in murine models of allergic asthma, but its effects on the structure and activation of airway epithelium in asthma are unknown. BALB/c mice were divided into control, aerobic exercise, ovalbumin-sensitized and ovalbumin-sensitized plus aerobic exercise groups. Ovalbumin sensitization occurred on days 0, 14, 28, 42, and aerosol challenge from day 21 to day 50. Aerobic exercise started on day 22 and ended on day 50. Total cells and eosinophils were reduced in ovalbumin-sensitized group submitted to aerobic exercise. Aerobic exercise also reduced the oxidative and nitrosative stress and the epithelial expression of Th2 cytokines, chemokines, adhesion molecules, growth factors and NF-kB and P2X7 receptor. Additionally, aerobic exercise increased the epithelial expression of IL-10 in non-sensitized and sensitized animals. These findings contribute to the understanding of the beneficial effects of aerobic exercise for chronic allergic airway inflammation, suggesting an immune-regulatory role of exercise on airway epithelium.
- Cholinergic Hyperresponsiveness of Peripheral Lung Parenchyma in Chronic Obstructive Pulmonary Disease(2011) LANCAS, Tatiana; KASAHARA, David Itiro; GROSS, Jefferson Luiz; PIRES-NETO, Ruy Camargo; DEHEINZELIN, Daniel; MAUAD, Thais; NEGRI, Elnara Marcia; DOLHNIKOFF, MarisaBackground: Up to 60% of chronic obstructive pulmonary disease ( COPD) patients can present airway hyperresponsiveness. However, it is not known whether the peripheral lung tissue also shows an exaggerated response to agonists in COPD. Objectives: To investigate the in vitro mechanical behavior and the structural and inflammatory changes of peripheral lung tissue in COPD patients and compare to nonsmoking controls. Methods: We measured resistance and elastance at baseline and after acetylcholine (ACh) challenge of lung strips obtained from 10 COPD patients and 10 control subjects. We also assessed the alveolar tissue density of neutrophils, eosinophils, macrophages, mast cells and CD8+ and CD4+ cells, as well as the content of alpha-smooth muscle actin-positive cells and elastic and collagen fibers. We further investigated whether changes in in vitro parenchymal mechanics correlated to structural and inflammatory parameters and to in vivo pulmonary function. Results: Values of resistance after ACh treatment and the percent increase in tissue resistance (%R) were higher in the COPD group (p <= 0.03). There was a higher density of macrophages and CD8+ cells (p < 0.05) and a lower elastic content (p = 0.003) in the COPD group. We observed a positive correlation between %R and eosinophil and CD8+ cell density (r = 0.608, p = 0.002, and r = 0.581, p = 0.001, respectively) and a negative correlation between %R and the ratio of forced expiratory volume in 1 s to forced vital capacity (r = -0.451, p < 0.05). Conclusions: The cholinergic responsiveness of parenchymal lung strips is increased in COPD patients and seems to be related to alveolar tissue eosinophilic and CD8 lymphocytic inflammation and to the degree of airway obstruction on the pulmonary function test.