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1.
Clin Cancer Res ; 22(3): 609-20, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26420858

ABSTRACT

PURPOSE: We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. EXPERIMENTAL DESIGN: Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. RESULTS: Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. CONCLUSIONS: This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints.


Subject(s)
Epithelial-Mesenchymal Transition/genetics , Gene Expression Profiling , Neoplasms/genetics , Neoplasms/immunology , Transcriptome , Biomarkers , Cell Line, Tumor , Cluster Analysis , Computational Biology/methods , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Genomics/methods , Humans , MicroRNAs/genetics , Mutation , Neoplasms/metabolism , Neoplasms/mortality , Neoplasms/pathology , Prognosis , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
2.
Arthritis Rheumatol ; 66(3): 714-25, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24574232

ABSTRACT

OBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor ß (TGFß)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFß- and IFN-regulated genes.


Subject(s)
Lung/metabolism , Macrophage Activation/genetics , Pulmonary Fibrosis/genetics , Scleroderma, Systemic/genetics , 2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , Adult , Antigens/genetics , Antigens/metabolism , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/genetics , Antigens, Differentiation, Myelomonocytic/metabolism , Chemokines, CC/genetics , Chemokines, CC/metabolism , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Disease Progression , Female , Humans , Lung/pathology , Lung/physiopathology , Male , Middle Aged , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/physiopathology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Respiratory Function Tests , Scleroderma, Systemic/complications , Scleroderma, Systemic/pathology , Scleroderma, Systemic/physiopathology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
3.
Ann Thorac Surg ; 96(2): 473-7, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23806228

ABSTRACT

BACKGROUND: Tacrolimus and mycophenolate have now become the most widely used combination for maintenance immunosuppressive regimens after lung transplantation in comparison with cyclosporine and azathioprine. However, limited information is available with respect to their effects on cells, other than those from the immunologic compartment. We hypothesized that different triple therapies could have different effects on airway mucociliary clearance, playing an important role in respiratory infections observed after lung transplantation. METHODS: Ninety rats were assigned to three groups (n = 30 each): control = vehicle, therapy 1 = tacrolimus + mycophenolate + prednisone, and therapy 2 = cyclosporine + azathioprine + prednisone. After 7, 15, or 30 days of treatment by gavage, the animals were killed and the following parameters were studied: mucus transportability, ciliary beating frequency, mucociliary transport velocity, and neutral and acid mucus production. RESULTS: There was a significant decrease in ciliary beating frequency, mucociliary transport velocity, and neutral mucus production in all immunosuppressed animals; indeed, both therapies, mainly therapy 1, caused an increase in acid mucus production for as long as 15 days of treatment. CONCLUSIONS: Both triple therapies impaired airway mucociliary clearance of rats, but therapy 1 had a more deleterious effect. These data suggest that these undesirable effects can contribute to the high incidence of respiratory infections observed in patients undergoing lung transplantation.


Subject(s)
Immunosuppression Therapy/adverse effects , Immunosuppressive Agents/adverse effects , Mucociliary Clearance/drug effects , Animals , Drug Therapy, Combination , Male , Rats , Rats, Wistar
4.
Ann Thorac Surg ; 95(2): 465-70, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23219256

ABSTRACT

BACKGROUND: The pathophysiologic characteristics of primary hyperhidrosis are not well understood and seem to be related to a sympathetic nervous system dysfunction. The resection of thoracic sympathetic chain ganglia is the most effective treatment for hyperhidrosis; however sympathetic ganglia function in normal individuals and in patients with hyperhidrosis is unknown. METHODS: A cross-sectional study, in which 2 groups of 20 subjects were analyzed: the hyperhidrosis group (HYP), comprised of patients with hyperhidrosis who were eligible for thoracic sympathectomy, and the control group (CON) comprised of brain-dead organ donors without a history of hyperhidrosis. For each subject, the following were performed: resection of the third left sympathetic ganglion, measurement of the ganglion's diameter, and immunohistochemical evaluation by quantification of strong and weak expression areas of primary antibodies against acetylcholine and alpha-7 neuronal nicotinic receptor subunit. RESULTS: The presence of a strong alpha-7 subunit expression area was 4.85% in patients with primary hyperhidrosis and 2.34% in controls (p < 0.001), whereas the presence of a weak expression area was 11.48% in the HYP group and 4.59% in the CON group (p < 0.001). Strong acetylcholine expression was found in 4.95% of the total area in the HYP group and in 1.19% in the CON group (p < 0.001), whereas weak expression was found in 18.55% and 6.77% of the HYP and CON groups, respectively (p < 0.001). Furthermore, diameter of the ganglia was 0.71 cm in the HYP group and 0.53 cm in the CON group (p < 0.001). CONCLUSIONS: There is a higher expression of acetylcholine and alpha-7 neuronal nicotinic receptor subunit in the sympathetic ganglia of patients with hyperhidrosis. Furthermore, the diameter of the thoracic sympathetic chain ganglia is larger in such patients.


Subject(s)
Acetylcholine/biosynthesis , Ganglia, Sympathetic/metabolism , Hyperhidrosis/metabolism , Receptors, Cholinergic/biosynthesis , Adult , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Young Adult
5.
Autoimmun Rev ; 11(11): 827-35, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22406224

ABSTRACT

OBJECTIVE: The physiological and mechanical properties of the skin, the primary tissue affected by systemic sclerosis, depend on the assembly of collagen types I, III and V, which form heterotypic fibers. Collagen V (COLV) regulates heterotypic fiber diameter, and the maintenance of its properties is important for maintaining normal tissue architecture and function. Based on a COLV-induced experimental SSc model, in which overexpression of abnormal COLV was a prominent feature, we assumed that this abnormality could be present in SSc patients and could be correlated to disease duration, skin thickening and disease activity. METHODS: Skin biopsies from 18 patients (6 early-stage and 12 late-stage) and 10 healthy controls were studied. Skin thickening assessment was performed with the Modified Rodnan Skin Score (MRSS), and activity was calculated using the Valentini Disease Activity Index. Morphology, morphometry of COLV deposition in dermis, as well as, quantitative RT-PCR and 3D-reconstruction of the dermal fibroblast culture were performed. RESULTS: Structurally abnormal COLV was overexpressed in SSc skin, mainly in the early stages of the disease, when compared to normal controls and late-stage. A positive correlation between COLV expression and MRSS and disease activity was observed. Collagen V alpha-1 and alpha-2 mRNA expression levels were higher in SSc. Tridimensional reconstruction of SSc dermal heterotypic fibers confirmed the presence of atypical COLV. CONCLUSION: Increased synthesis of abnormal COLV and its correlation with disease stage, activity and MRSS suggest that this collagen can be a possible trigger involved in the pathogenesis of SSc.


Subject(s)
Collagen Type V/metabolism , Dermis/metabolism , Dermis/pathology , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/pathology , Adult , Biopsy , Case-Control Studies , Collagen/genetics , Collagen/metabolism , Collagen Type V/genetics , Female , Fibroblasts/metabolism , Gene Expression Regulation , Humans , Male , Middle Aged , Scleroderma, Systemic/genetics , Severity of Illness Index , Skin/metabolism , Skin/pathology , Young Adult
6.
Clinics (Sao Paulo) ; 66(7): 1193-7, 2011.
Article in English | MEDLINE | ID: mdl-21876973

ABSTRACT

INTRODUCTION: Acute respiratory failure has been one of the most important causes of death in intensive care units, and certain aspects of its pulmonary pathology are currently unknown. OBJECTIVES: The objective was to describe the demographic data, etiology, and pulmonary histopathological findings of different diseases in the autopsies of patients with acute respiratory failure. METHOD: Autopsies of 4,710 patients with acute respiratory failure from 1990 to 2008 were reviewed, and the following data were obtained: age, sex, and major associated diseases. The pulmonary histopathology was categorized as diffuse alveolar damage, pulmonary edema, alveolar hemorrhage, and lymphoplasmacytic interstitial pneumonia. The odds ratio of the concordance between the major associated diseases and specific autopsy findings was calculated using logistic regression. RESULTS: Bacterial bronchopneumonia was present in 33.9% of the cases and cancer in 28.1%. The pulmonary histopathology showed diffuse alveolar damage in 40.7% (1,917) of the cases. A multivariate analysis showed a significant and powerful association between diffuse alveolar damage and bronchopneumonia, HIV/AIDS, sepsis, and septic shock, between liver cirrhosis and pulmonary embolism, between pulmonary edema and acute myocardial infarction, between dilated cardiomyopathy and cancer, between alveolar hemorrhage and bronchopneumonia and pulmonary embolism, and between lymphoplasmacytic interstitial pneumonia and HIV/ AIDS and liver cirrhosis. CONCLUSIONS: Bronchopneumonia was the most common diagnosis in these cases. The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions. Further studies are necessary to elucidate the complete pathophysiological mechanisms involved with each disease and the development of acute respiratory failure.


Subject(s)
Lung/pathology , Respiratory Insufficiency/etiology , Respiratory Insufficiency/pathology , Acute Disease , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Autopsy , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Sex Distribution , Socioeconomic Factors , Young Adult
7.
Respir Physiol Neurobiol ; 177(2): 141-8, 2011 Jul 31.
Article in English | MEDLINE | ID: mdl-21453798

ABSTRACT

The impact of obesity on the inflammatory process has been described in asthma, however little is known about the influence of diet-induced obesity on lung remodeling. For this purpose, 56 recently weaned A/J mice were randomly divided into 2 groups. In the C group, mice were fed a standard chow diet, while OB animals received isocaloric high-fat diet to reach 1.5 of the mean body weight of C. After 12 weeks, each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, and the number of eosinophils in bronchoalveolar lavage fluid were higher in OB-OVA than C-OVA. In conclusion, diet-induced obesity enhanced lung remodeling resulting in higher airway responsiveness in the present experimental chronic allergic asthma.


Subject(s)
Airway Remodeling/physiology , Asthma/etiology , Hypersensitivity/etiology , Obesity/complications , Obesity/physiopathology , Actins/analysis , Actins/metabolism , Animals , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Chronic Disease , Collagen/analysis , Collagen/metabolism , Disease Models, Animal , Eosinophils/cytology , Hypersensitivity/pathology , Immunohistochemistry , Lung/physiopathology , Lung/ultrastructure , Male , Mice , Microscopy, Electron, Transmission , Pulmonary Ventilation/physiology
8.
Respir Physiol Neurobiol ; 175(1): 153-63, 2011 Jan 31.
Article in English | MEDLINE | ID: mdl-21050897

ABSTRACT

We hypothesized that bone marrow-derived mononuclear cells (BMDMC) would attenuate the remodeling process in a chronic allergic inflammation model. C57BL/6 mice were assigned to two groups. In OVA, mice were sensitized and repeatedly challenged with ovalbumin. Control mice (C) received saline under the same protocol. C and OVA were further randomized to receive BMDMC (2 × 106) or saline intravenously 24 h before the first challenge. BMDMC therapy reduced eosinophil infiltration, smooth muscle-specific actin expression, subepithelial fibrosis, and myocyte hypertrophy and hyperplasia, thus causing a decrease in airway hyperresponsiveness and lung mechanical parameters. BMDMC from green fluorescent protein (GFP)-transgenic mice transplanted into GFP-negative mice yielded lower engraftment in OVA. BMDMC increased insulin-like growth factor expression, but reduced interleukin-5, transforming growth factor-ß, platelet-derived growth factor, and vascular endothelial growth factor mRNA expression. In conclusion, in the present chronic allergic inflammation model, BMDMC therapy was an effective pre-treatment protocol that potentiated airway epithelial cell repair and prevented inflammatory and remodeling processes.


Subject(s)
Airway Remodeling/physiology , Bone Marrow Cells/physiology , Cell- and Tissue-Based Therapy/methods , Connective Tissue/physiology , Leukocytes, Mononuclear/physiology , Respiratory Hypersensitivity/therapy , Analysis of Variance , Animals , Bronchoalveolar Lavage Fluid , Chronic Disease , Connective Tissue/ultrastructure , Disease Models, Animal , Female , Injections, Intravenous/methods , Intercellular Signaling Peptides and Proteins/metabolism , Interleukin-5/metabolism , Lung/pathology , Lung/ultrastructure , Male , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission/methods , Ovalbumin/immunology , Respiratory Hypersensitivity/etiology , Respiratory Hypersensitivity/pathology
9.
Clinics ; Clinics;66(7): 1193-1197, 2011. tab
Article in English | LILACS | ID: lil-596907

ABSTRACT

INTRODUCTION: Acute respiratory failure has been one of the most important causes of death in intensive care units, and certain aspects of its pulmonary pathology are currently unknown. OBJECTIVES: The objective was to describe the demographic data, etiology, and pulmonary histopathological findings of different diseases in the autopsies of patients with acute respiratory failure. METHOD: Autopsies of 4,710 patients with acute respiratory failure from 1990 to 2008 were reviewed, and the following data were obtained: age, sex, and major associated diseases. The pulmonary histopathology was categorized as diffuse alveolar damage, pulmonary edema, alveolar hemorrhage, and lymphoplasmacytic interstitial pneumonia. The odds ratio of the concordance between the major associated diseases and specific autopsy findings was calculated using logistic regression. RESULTS: Bacterial bronchopneumonia was present in 33.9 percent of the cases and cancer in 28.1 percent. The pulmonary histopathology showed diffuse alveolar damage in 40.7 percent (1,917) of the cases. A multivariate analysis showed a significant and powerful association between diffuse alveolar damage and bronchopneumonia, HIV/AIDS, sepsis, and septic shock, between liver cirrhosis and pulmonary embolism, between pulmonary edema and acute myocardial infarction, between dilated cardiomyopathy and cancer, between alveolar hemorrhage and bronchopneumonia and pulmonary embolism, and between lymphoplasmacytic interstitial pneumonia and HIV/ AIDS and liver cirrhosis. CONCLUSIONS: Bronchopneumonia was the most common diagnosis in these cases. The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions. Further studies are necessary to elucidate the complete pathophysiological mechanisms involved with each disease and the development of acute respiratory failure.


Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Young Adult , Lung/pathology , Respiratory Insufficiency/etiology , Respiratory Insufficiency/pathology , Acute Disease , Age Distribution , Autopsy , Sex Distribution , Socioeconomic Factors
10.
Respir Res ; 11: 1, 2010 Jan 04.
Article in English | MEDLINE | ID: mdl-20047687

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate collagen deposition, mRNA collagen synthesis and TGF-beta expression in the lung tissue in an experimental model of scleroderma after collagen V-induced nasal tolerance. METHODS: Female New Zealand rabbits (N = 12) were immunized with 1 mg/ml of collagen V in Freund's adjuvant (IM). After 150 days, six immunized animals were tolerated by nasal administration of collagen V (25 microg/day) (IM-TOL) daily for 60 days. The collagen content was determined by morphometry, and mRNA expressions of types I, III and V collagen were determined by Real-time PCR. The TGF-beta expression was evaluated by immunostaining and quantified by point counting methods. To statistic analysis ANOVA with Bonferroni test were employed for multiple comparison when appropriate and the level of significance was determined to be p < 0.05. RESULTS: IM-TOL, when compared to IM, showed significant reduction in total collagen content around the vessels (0.371 +/- 0.118 vs. 0.874 +/- 0.282, p < 0.001), bronchioles (0.294 +/- 0.139 vs. 0.646 +/- 0.172, p < 0.001) and in the septal interstitium (0.027 +/- 0.014 vs. 0.067 +/- 0.039, p = 0.026). The lung tissue of IM-TOL, when compared to IM, showed decreased immunostaining of types I, III and V collagen, reduced mRNA expression of types I (0.10 +/- 0.07 vs. 1.0 +/- 0.528, p = 0.002) and V (1.12 +/- 0.42 vs. 4.74 +/- 2.25, p = 0.009) collagen, in addition to decreased TGF-beta expression (p < 0.0001). CONCLUSIONS: Collagen V-induced nasal tolerance in the experimental model of SSc regulated the pulmonary remodeling process, inhibiting collagen deposition and collagen I and V mRNA synthesis. Additionally, it decreased TGF-beta expression, suggesting a promising therapeutic option for scleroderma treatment.


Subject(s)
Collagen Type V , Disease Models, Animal , Lung/metabolism , RNA, Messenger/metabolism , Scleroderma, Systemic/chemically induced , Scleroderma, Systemic/metabolism , Transforming Growth Factor beta/metabolism , Administration, Intranasal , Animals , Down-Regulation/drug effects , Female , Gene Expression/drug effects , Humans , Rabbits
11.
Respir Physiol Neurobiol ; 165(2-3): 202-7, 2009 Feb 28.
Article in English | MEDLINE | ID: mdl-19135181

ABSTRACT

The impact of genetic factors on asthma is well recognized but poorly understood. We tested the hypothesis that different mouse strains present different lung tissue strip mechanics in a model of chronic allergic asthma and that these mechanical differences may be potentially related to changes of extracellular matrix composition and/or contractile elements in lung parenchyma. Oscillatory mechanics were analysed before and after acetylcholine (ACh) in C57BL/10, BALB/c, and A/J mice, subjected or not to ovalbumin sensitization and challenge. In controls, tissue elastance (E) and resistance (R), collagen and elastic fibres' content, and alpha-actin were higher in A/J compared to BALB/c mice, which, in turn, were more elevated than in C57BL/10. A similar response pattern was observed in ovalbumin-challenged animals irrespective of mouse strain. E and R augmented more in ovalbumin-challenged A/J [E: 22%, R: 18%] than C57BL/10 mice [E: 9.4%, R: 11%] after ACh In conclusion, lung parenchyma remodelled differently yielding distinct in vitro mechanics according to mouse strain.


Subject(s)
Asthma/genetics , Asthma/immunology , Extracellular Matrix/immunology , Hypersensitivity/genetics , Hypersensitivity/immunology , Respiratory Mechanics/genetics , Animals , Asthma/chemically induced , Chronic Disease , Disease Models, Animal , In Vitro Techniques , Mice , Mice, Inbred A , Mice, Inbred BALB C , Mice, Inbred C57BL , Ovalbumin/immunology , Ovalbumin/pharmacology , Respiratory Mechanics/immunology , Species Specificity
12.
Respiration ; 77(4): 389-97, 2009.
Article in English | MEDLINE | ID: mdl-18799868

ABSTRACT

BACKGROUND: The impressive association of lung involvement and gastroesophageal reflux in scleroderma raises the possibility of a cause-effect relationship. OBJECTIVES: To determine clinical, radiological and histopathological features of systemic sclerosis (SSc) patients according the presence or absence of centrilobular fibrosis (CLF). METHODS: Twenty-eight SSc patients with lung involvement were submitted to open lung biopsy and the specimens classified for the presence of CLF (bronchocentric distribution of the lesions and intraluminal matter according to the classification of idiopathic interstitial pneumonia). HRCT, pulmonary function tests and esophageal analysis were also performed. Subsequently, cyclophosphamide was introduced for the nonspecific interstitial pneumonia subgroup and antireflux treatment was intensified for isolated CLF patients. RESULTS: Isolated CLF was found in 21% of the biopsies and also found associated to nonspecific interstitial pneumonia in 84% of these patients. The other 3 cases had usual interstitial pneumonia, pulmonary hypertension and respiratory bronchiolitis-associated interstitial lung disease. The histopathological analysis revealed that all 6 patients with isolated CLF had the bronchocentric distribution and intraluminal basophilic content, with foreign bodies detected in one third of them. The central distribution of lung involvement on HRCT was found in 67% of these patients with a consistent patchy distribution (100%). Ground glass (67%) and consolidation (33%) were the predominant patterns found. The constant clinical finding in all isolated CLF cases was dyspnea, esophageal abnormalities and a moderate lung impairment (FVC: 63.83 +/- 16.31%; DLCO: 61.66 +/- 18.84%). Lung function parameters in isolated CLF patients remained stable after 1 year of exclusively intensive antireflux treatment (FVC, p = 0.23; DLCO, p = 0.59). CONCLUSIONS: The novel description of CLF pattern in SSc lung disease with peculiar histological, tomographic and clinical features will certainly contribute to a more appropriate therapeutic approach.


Subject(s)
Lung Diseases, Interstitial/etiology , Scleroderma, Systemic/complications , Adult , Antirheumatic Agents/therapeutic use , Cyclophosphamide/therapeutic use , Esophagus/diagnostic imaging , Esophagus/pathology , Female , Humans , Lung/diagnostic imaging , Lung/pathology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/drug therapy , Middle Aged , Prospective Studies , Proton Pump Inhibitors/therapeutic use , Respiratory Function Tests , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/drug therapy , Tomography, X-Ray Computed
13.
Clinics (Sao Paulo) ; 63(1): 9-14, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18297201

ABSTRACT

INTRODUCTION: Posterior tibial tendon dysfunction is a common cause of adult flat foot deformity, and its etiology is unknown. PURPOSE: In this study, we characterized the morphologic pattern and distribution of types I, III and V collagen in posterior tibial tendon dysfunction. METHOD: Tendon samples from patients with and without posterior tibial tendon dysfunction were stained by immunofluorescence using antibodies against types I, III and V collagen. RESULTS: Control samples showed that type V deposited near the vessels only, while surgically obtained specimens displayed type V collagen surrounding other types of collagen fibers in thicker adventitial layers. Type III collagen levels were also increased in pathological specimens. On the other hand, amounts of collagen type I, which represents 95% of the total collagen amount in normal tendon, were decreased in pathological specimens. CONCLUSION: Fibrillogenesis in posterior tibial tendon dysfunction is altered due to higher expression of types III and V collagen and a decreased amount of collagen type I, which renders the originating fibrils structurally less resistant to mechanical forces.


Subject(s)
Collagen Type III/metabolism , Collagen Type I/metabolism , Collagen Type V/metabolism , Posterior Tibial Tendon Dysfunction/metabolism , Adult , Aged , Case-Control Studies , Female , Fluorescent Antibody Technique , Humans , Middle Aged , Posterior Tibial Tendon Dysfunction/pathology
14.
Am J Forensic Med Pathol ; 29(4): 323-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19259018

ABSTRACT

In immediate fire deaths, pulmonary injury may be the main source of mortality, being important to document the histologic findings for the purpose of excluding other modes of death, such as from asphyxia with no gross findings. In this context, a group of morphologic determinants have been targeted with useful makers of pulmonary injury. To facilitate the determination of whether an individual was deceased before the start of a fire and validate the importance of parenchymal alterations in pulmonary injury in fire deaths, we studied lungs in victims of fire (N = 28) and suffocation (N = 40), creating a mathematical model using cluster analysis. For this purpose, a semiquantitative analysis of the distal parenchyma was performed to evaluate the amount of bronchiolar dilatation, overinsufflation (ductal and alveolar), collapse (ductal and alveolar), passive congestion, alveolar edema, and hemorrhage (interstitial and alveolar). These 7 histologic determinants were useful to discriminate fire (bronchiolar dilatation, ductal overinsuflation, alveolar overinsuflation, alveolar hemorrhage) from suffocation lung injuries (alveolar collapse, congestion, and edema). We conclude that these determinants should be included in the routine of forensic pathology.


Subject(s)
Fires , Forensic Pathology/methods , Lung/pathology , Adolescent , Adult , Aged , Asphyxia/pathology , Autopsy , Child , Child, Preschool , Cluster Analysis , Dilatation, Pathologic/pathology , Female , Hemorrhage/pathology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Pulmonary Alveoli/pathology , Pulmonary Atelectasis/pathology , Pulmonary Edema/pathology , Young Adult
15.
Clinics ; Clinics;63(1): 9-14, 2008. ilus
Article in English | LILACS | ID: lil-474921

ABSTRACT

INTRODUCTION: Posterior tibial tendon dysfunction is a common cause of adult flat foot deformity, and its etiology is unknown. PURPOSE: In this study, we characterized the morphologic pattern and distribution of types I, III and V collagen in posterior tibial tendon dysfunction. METHOD: Tendon samples from patients with and without posterior tibial tendon dysfunction were stained by immunofluorescence using antibodies against types I, III and V collagen. RESULTS: Control samples showed that type V deposited near the vessels only, while surgically obtained specimens displayed type V collagen surrounding other types of collagen fibers in thicker adventitial layers. Type III collagen levels were also increased in pathological specimens. On the other hand, amounts of collagen type I, which represents 95 percent of the total collagen amount in normal tendon, were decreased in pathological specimens. CONCLUSION: Fibrillogenesis in posterior tibial tendon dysfunction is altered due to higher expression of types III and V collagen and a decreased amount of collagen type I, which renders the originating fibrils structurally less resistant to mechanical forces.


Subject(s)
Adult , Aged , Female , Humans , Middle Aged , Collagen Type I/metabolism , Collagen Type III/metabolism , Collagen Type V/metabolism , Posterior Tibial Tendon Dysfunction/metabolism , Case-Control Studies , Fluorescent Antibody Technique , Posterior Tibial Tendon Dysfunction/pathology
16.
Respir Physiol Neurobiol ; 156(2): 171-8, 2007 May 14.
Article in English | MEDLINE | ID: mdl-17056303

ABSTRACT

Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.


Subject(s)
Bronchoconstriction/drug effects , Fluoxetine/pharmacology , Lung Diseases, Interstitial/chemically induced , Respiratory Mechanics/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Airway Resistance/drug effects , Animals , Antidepressive Agents, Second-Generation/pharmacology , Antidepressive Agents, Second-Generation/therapeutic use , Disease Models, Animal , Elasticity/drug effects , Fluoxetine/therapeutic use , Guinea Pigs , Leukemic Infiltration/chemically induced , Leukemic Infiltration/physiopathology , Lung Diseases, Interstitial/physiopathology , Nitric Oxide/metabolism , Selective Serotonin Reuptake Inhibitors/therapeutic use , Statistics, Nonparametric , Stress, Psychological/drug therapy , Swimming/physiology , Swimming/psychology
17.
Ann Thorac Surg ; 77(6): 1883-90, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15172229

ABSTRACT

BACKGROUND: Because biological behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and angiogenesis, p21(waf1/cip1) and microvessel density have been targeted as potentially useful tumor markers. We sought to validate the importance of p21(waf1/cip1) and microvessel density and study their interrelationship, analyzing clinical factors, subclassifications, and tumor and stromal markers. METHODS: We examined p21(waf1/cip1) and other markers in tissue from 61 patients with surgically excised large cell carcinomas. The amount of tumor staining for p21(waf1/cip1) and microvessel density was evaluated by immunohistochemistry and morphometry. The study outcome was survival time until death from recurrent lung cancer. RESULTS: Multivariate Cox model analysis demonstrated that after surgical excision, histologic subtypes were significantly related to survival time (p = 0.02), but quantitative staining of the tumor for p21(waf1/cip1) and microvessel density added prognostic information and these variables were more strongly prognostic than histologic subtype (p = 0.00). Cut points at the median staining of 3.5% and 3.0% for p21(waf1/cip1) and microvessel density, respectively, divided patients into two groups with distinctive survival times. Patients with p21(waf1/cip1) staining of more than 3.5% and microvessel density staining of more than 3.0% had a median survival time of 14 months. CONCLUSIONS: Tumor staining for p21(waf1/cip1) and microvessel density in resected large cell carcinomas and certain other types of lung tumors was strongly related to survival. Patients with more than 3.0% staining in their tumors were at high risk of death from lung cancer and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.


Subject(s)
Carcinoma, Large Cell/pathology , Carcinoma, Neuroendocrine/pathology , Lung Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Large Cell/chemistry , Carcinoma, Large Cell/mortality , Carcinoma, Neuroendocrine/chemistry , Carcinoma, Neuroendocrine/mortality , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/analysis , Cyclooxygenase 2 , Female , Humans , Immunohistochemistry , Isoenzymes/analysis , Lung Neoplasms/chemistry , Lung Neoplasms/mortality , Male , Matrix Metalloproteinase 9/analysis , Membrane Proteins , Middle Aged , Proportional Hazards Models , Prostaglandin-Endoperoxide Synthases/analysis , Retrospective Studies , Survival Rate , Tumor Suppressor Protein p53/analysis
18.
Pathol Res Pract ; 200(10): 681-91, 2004.
Article in English | MEDLINE | ID: mdl-15648605

ABSTRACT

The pathogenesis of diffuse connective tissue diseases (DCTD) is still unknown and has been extensively studied regarding its autoimmunity aspects related to extracellular matrix (ECM) remodelling, with an emphasis on the collagens at the inflammatory site. The present paper describes the pulmonary architectural and repair/remodelling responses to injury after immunization of rabbits with human type V collagen. The animal model consisted of rabbits immunized with collagen mixed with Freund's adjuvant and sacrificed 7, 15, 30, 75, and 120 days after the first of four doses of antigen. Pulmonary architecture remodelling response was evaluated by histology, morphometry, and the immunofluorescence method, according to compartments of reference (parenchyma and interstitium) and injury: 1 inflammation (polymorphonuclear and mononuclear cells); 2-repair (fibrosis) and 3-ECM remodelling (collagen system). The results showed an intense inflammatory involvement of the pulmonary vascular and bronchiolar parenchyma, characterized by increased wall thickness in small arteries, infiltrations by pseudoeosinophils, and mononuclear cells. Progressive remodelling of the pulmonary ECM was characterized by collagen deposition in the septal and bronchovascular interstitium, especially in rabbits sacrifices at 75 and 120 days. The ECM remodelling process was not reproduced when rabbits were inoculated with collagen types I and III. We conclude that the model reproduces morphologic changes similar to those observed in many DCTD, encouraging realization of other experiments to gain a better understanding of the pathogenesis of these diseases.


Subject(s)
Collagen Type V/immunology , Connective Tissue Diseases/pathology , Disease Models, Animal , Extracellular Matrix/pathology , Immunization , Lung/pathology , Animals , Connective Tissue Diseases/immunology , Female , Humans , Lung/immunology , Rabbits
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