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1.
Proc Natl Acad Sci U S A ; 115(32): 8167-8172, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30038020

RESUMO

Morphogenesis during human development relies on the interplay between physiochemical cues that are mediated in part by cellular density and cytoskeletal tension. Here, we interrogated these factors on vascular lineage specification during human-induced pluripotent stem-cell (hiPSC) fate decision. We found that independent of chemical cues, spatially presented physical cues induce the self-organization of Brachyury-positive mesodermal cells, in a RhoA/Rho-associated kinase (ROCK)-dependent manner. Using unbiased support vector machine (SVM) learning, we found that density alone is sufficient to predict mesodermal fate. Furthermore, the long-withstanding presentation of spatial confinement during hiPSC differentiation led to an organized vascular tissue, reminiscent of native blood vessels, a process dependent on cell density as found by SVM analysis. Collectively, these results show how tension and density relate to vascular identity mirroring early morphogenesis. We propose that such a system can be applied to study other aspects of the stem-cell niche and its role in embryonic patterning.


Assuntos
Padronização Corporal/fisiologia , Linhagem da Célula/fisiologia , Citoesqueleto/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Mesoderma/fisiopatologia , Diferenciação Celular/fisiologia , Células Cultivadas , Células Endoteliais/fisiologia , Proteínas Fetais/metabolismo , Imunofluorescência/métodos , Humanos , Processamento de Imagem Assistida por Computador , Aprendizado de Máquina , Mesoderma/citologia , Pericitos/fisiologia , Nicho de Células-Tronco/fisiologia , Estresse Mecânico , Proteínas com Domínio T/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
2.
Crit Care Med ; 46(1): e49-e58, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29088003

RESUMO

OBJECTIVES: Mechanical ventilation can induce lung fibrosis. This study aimed to investigate whether ventilator-induced lung fibrosis was associated with endothelial-mesenchymal transition and to uncover the underlying mechanisms. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Adult male Institute of Cancer Research, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) knockout and wild-type mice. Primary cultured mouse lung vascular endothelial cells. INTERVENTIONS: Institute of Cancer Research, NLRP3 knockout and wild-type mice were subjected to mechanical ventilation (20 mL/kg) for 2 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 24 hours. MEASUREMENTS AND MAIN RESULTS: Mice subjected to mechanical ventilation exhibited increases in collagen deposition, hydroxyproline and type I collagen contents, and transforming growth factor-ß1 in lung tissues. Ventilation-induced lung fibrosis was associated with increased expression of mesenchymal markers (α smooth muscle actin and vimentin), as well as decreased expression of endothelial markers (vascular endothelial-cadherin and CD31). Double immunofluorescence staining showed the colocalization of CD31/α smooth muscle actin, CD31/vimentin, and CD31/fibroblast-specific protein-1 in lung tissues, indicating endothelial-mesenchymal transition formation. Mechanical ventilation also induced NLRP3 inflammasome activation in lung tissues. In vitro direct mechanical stretch of primary mouse lung vascular endothelial cells resulted in similar NLRP3 activation and endothelial-mesenchymal transition formation, which were prevented by NLRP3 knockdown. Furthermore, mechanical stretch-induced endothelial-mesenchymal transition and pulmonary fibrosis were ameliorated in NLRP3-deficient mice as compared to wild-type littermates. CONCLUSIONS: Mechanical stretch may promote endothelial-mesenchymal transition and pulmonary fibrosis through a NLRP3-dependent pathway. The inhibition of endothelial-mesenchymal transition by NLRP3 inactivation may be a viable therapeutic strategy against pulmonary fibrosis associated with mechanical ventilation.


Assuntos
Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Inflamassomos/fisiologia , Pulmão/irrigação sanguínea , Mecanotransdução Celular/fisiologia , Mesoderma/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Fibrose Pulmonar/fisiopatologia , Animais , Células Cultivadas , Células Endoteliais/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout
3.
Cancer Lett ; 390: 176-187, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28007636

RESUMO

The tumor microenvironment is being increasingly recognized as a key factor in cancer aggressiveness. In this study, we characterized the inflammatory gene signatures altered in glioma cell lines and tumor specimens of differing histological and molecular subtypes. The results showed that glioblastoma multiforme (GBM) shows upregulation of a subset of inflammatory genes when compared to astrocytomas and oligodendrogliomas. With molecular subtypes of GBM, the expression of inflammatory genes is heterogeneous, being enriched in mesenchymal and downregulated in Proneural/GCIMP. Other inflammation-associated processes such as tumor-associated macrophage (TAM) signatures are upregulated in mesenchymal, and a subset of 33 mesenchymal-enriched inflammatory and TAM markers showed correlation with poor survival. We found that various GBM tumor-upregulated genes such as IL6, IL8 and CCL2 are also actively expressed in glioma cell lines, playing differential and cooperative roles in promoting proliferation, invasion, angiogenesis and macrophage polarization in vitro. These genes can be stimulated by pathways typically altered in GBM, including the EGFR, PDGFR, MEK1/2-ERK1/2, PI3K/Akt and NFκB cascades. Taken together, the results presented herein depict some inflammatory pathways altered in gliomas and highlight potentially relevant targets to therapy improvement.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioblastoma/fisiopatologia , NF-kappa B/metabolismo , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Glioblastoma/imunologia , Humanos , Mesoderma/fisiopatologia , NF-kappa B/genética , NF-kappa B/imunologia , Reação em Cadeia da Polimerase , Transdução de Sinais/efeitos dos fármacos
7.
Pathology ; 45(4): 371-81, 2013 06.
Artigo em Inglês | MEDLINE | ID: mdl-23594691

RESUMO

Most research into the biology of carcinoma has focused on the epithelial cells therein; the inherent assumption has been that the tumour arises from epithelial cells 'gone bad', and that the surrounding stroma is simply an 'innocent bystander'. However, there is increasing evidence that there is a complex interplay between tumour cells and their surrounding microenvironment, and that the latter may be just as important in determining the development and clinical behaviour of a given tumour. Similarly, traditional oncological practice has been predominantly aimed at a perceived ideal goal of killing all the tumour epithelial cells, with only a few recently developed therapies seeking to affect other components (such as tumour vasculature); but identifying stromal factors involved in tumour growth and survival may well lead to the development of novel therapies. This review examines current understanding of the interplay between tumour epithelial cells and their microenvironment, and enumerates various stromal factors which appear to play a role in tumour progression and/or metastasis.


Assuntos
Carcinogênese/patologia , Células-Tronco Mesenquimais/patologia , Mesoderma/patologia , Neoplasias/patologia , Microambiente Tumoral/fisiologia , Progressão da Doença , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Mesoderma/fisiopatologia , Neoplasias/fisiopatologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-22125178

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in infants born extremely preterm, typically before 28 weeks' gestation, characterized by a prolonged need for supplemental oxygen or positive pressure ventilation beyond 36 weeks postmenstrual age. The limited number of autopsy samples available from infants with BPD in the postsurfactant era has revealed a reduced capacity for gas exchange resulting from simplification of the distal lung structure with fewer, larger alveoli because of a failure of normal lung alveolar septation and pulmonary microvascular development. The mechanisms responsible for alveolar simplification in BPD have not been fully elucidated, but mounting evidence suggests that aberrations in the cross-talk between growth factors of the lung mesenchyme and distal airspace epithelium have a key role. Animal models that recapitulate the human condition have expanded our knowledge of the pathology of BPD and have identified candidate matrix components and growth factors in the developing lung that are disrupted by conditions that predispose infants to BPD and interfere with normal vascular and alveolar morphogenesis. This review focuses on the deviations from normal lung development that define the pathophysiology of BPD and summarizes the various candidate mesenchyme-associated proteins and growth factors that have been identified as being disrupted in animal models of BPD. Finally, future areas of research to identify novel targets affected in arrested lung development and recovery are discussed.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Doenças do Prematuro/fisiopatologia , Mesoderma/embriologia , Mesoderma/fisiopatologia , Proteínas/metabolismo , Transdução de Sinais , Animais , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/metabolismo , Doenças do Prematuro/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos
9.
Ann Dermatol Venereol ; 139 Suppl 4: S148-52, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23522630

RESUMO

Hyperpigmentation of the skin is a common dermatologic condition in all skin types but most prominent in brown-skinned population. In skin of color any inflammation or injury can be accompanied by alterations in pigmentation (hyper/hypo-pigmentation). Postinflammatory hyperpigmentation (PIH) can be observed in many skin conditions including acne, eczema, and contact dermatitis. In the control of skin pigmentation, parallel to the cross-talk between keratinocytes and melanocytes, increasing evidence has underlined the crucial role exerted by the interactions between mesenchymal and epithelial cells through the release of fibroblast-derived growth factors. Among these factors, the keratinocyte growth factor (KGF), alone or in combination with interleukin-1α, induces melanin deposition in vitro and hyperpigmented lesions in vivo. Furthermore, a moderate increase of KGF and a high induction of its receptor have been shown in solar lentigo lesions, suggesting the involvement of this growth factor in the onset of the hyperpigmented spots. Several studies highlight the possible contribution of the fibroblast-derived melanogenic growth factors to the hyperpigmentated lesions, in the context of the mesenchymal - epithelial interactions modulating melanocyte functions.


Assuntos
Hiperpigmentação/etiologia , Inflamação/complicações , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/fisiologia , Técnicas de Cocultura , Colforsina/farmacologia , Citocinas/fisiologia , Epitélio/fisiopatologia , Fator 7 de Crescimento de Fibroblastos/fisiologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Hiperpigmentação/fisiopatologia , Queratinócitos/metabolismo , Lentigo/etiologia , Lentigo/fisiopatologia , Melaninas/metabolismo , Melanócitos/metabolismo , Mesoderma/fisiopatologia , Comunicação Parácrina , Fagocitose , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/fisiologia , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/fisiologia , Pigmentação da Pele/efeitos da radiação , Fator de Células-Tronco/fisiologia , Luz Solar/efeitos adversos , alfa-MSH/farmacologia
10.
Int J Exp Pathol ; 92(3): 151-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21314743

RESUMO

The need for novel insights into the mechanisms of progression of renal disease has become urgent during the last several years because of the increasing incidence of chronic renal disease worldwide. Independent of the underlying disease, the subsequent progression of renal fibrosis is characterized mainly by both an exaggerated synthesis and abnormal accumulation of extracellular matrix proteins produced by mesenchymal cells within the kidney. These cells are mainly myofibroblasts deriving from a variety of renal cells such as vascular smooth muscle, mesangial, resident stem, tubular epithelial, vascular endothelial cells or pericytes. The appearance of myofibroblasts is a reversible process, as suggested by studies in experimental models showing regression of renal fibrosis during therapy with antagonists and/or blockers of the renin-angiotensin system. An additional factor that can also affect the mechanisms of progression/regression of fibrosis is the plasticity of podocytes controlling glomerular filtration.


Assuntos
Glomérulos Renais/patologia , Túbulos Renais/patologia , Rim/patologia , Músculo Liso Vascular/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Humanos , Rim/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Mesoderma/patologia , Mesoderma/fisiopatologia , Camundongos , Músculo Liso Vascular/fisiopatologia
11.
Birth Defects Res A Clin Mol Teratol ; 88(8): 619-25, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20589882

RESUMO

BACKGROUND: Over 200 mouse genes are associated with neural tube defects (NTDs), including Cecr2, the bromodomain-containing subunit of the CERF chromatin remodeling complex. METHODS: Gene-trap mutation Cecr2(Gt45Bic) results in 74% exencephaly (equivalent of human anencephaly) on the BALB/c strain. Gene expression altered during cranial neural tube closure by the Cecr2 mutation was identified through microarray analysis of 11-14 somites stage Cecr2(Gt45Bic)embryos. RESULTS: Analysis of Affymetrix Mouse 430 2.0 chips detected 60 transcripts up-regulated and 54 transcripts down-regulated in the Cecr2(Gt45Bic) embryos (fold > 1.5, p < 0.05). The Cecr2 transcript was reduced only approximately 7- to 14-fold from normal levels, suggesting the Cecr2(Gt45Bic) is a hypomorphic mutation. We therefore generated a novel Cecr2 null allele (Cecr2 (tm1.1Hemc)). Resulting mutants displayed a stronger penetrance of exencephaly than Cecr2(Gt45Bic) in both BALB/c and FVB/N strains, in addition to midline facial clefts and forebrain encephalocele in the FVB/N strain. The Cecr2 transcript is reduced 260-fold in the Cecr2(tm1.1Hemc) line. Subsequent qRT-PCR using Cecr2 (tm1.1Hemc) mutant heads confirmed downregulation of transcription factors Alx1/Cart1, Dlx5, Eya1, and Six1. CONCLUSIONS: As both Alx1/Cart1 and Dlx5 mouse mutations result in exencephaly, we hypothesize that changes in expression of these mesenchymal/ectodermal transcription factors may contribute to NTDs associated with Cecr2.


Assuntos
Ectoderma/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mesoderma/metabolismo , Mutação , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fatores de Transcrição/genética , Animais , Regulação para Baixo/genética , Ectoderma/fisiopatologia , Encefalocele/metabolismo , Ossos Faciais/anormalidades , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Mesoderma/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Defeitos do Tubo Neural/fisiopatologia , Gravidez , Prosencéfalo/anormalidades , Fatores de Transcrição/metabolismo , Transcrição Genética , Regulação para Cima/genética
12.
Anat Rec (Hoboken) ; 293(5): 747-53, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20091891

RESUMO

For over a half century, the ACI (August x Copenhagen) rat has been a primary model for studying renal agenesis and ipsilateral hypoplasia (IHP) of the Wolffian-derived structures (WDS). Because the ACI rat is also used as a model for prostate research, it is important to examine the relationship of IHP and urogenital sinus (UGS) development. The prostate is dependent on androgens for proper growth and differentiation. Alteration in androgen production and/or delivery to the UGS has the potential to perturbate normal development. In this study, we investigate whether the ipsilateral loss of the WDS is associated with altered prostate development. Digital images of serial-sectioned fetal ACI rat UGS were used to create three-dimensional (3-D) surface-rendered models of the developing prostate, seminal vesicle, vas deferens, and utricle on gestational day 21. The number and volume of prostate ducts developing from the UGS were calculated from the 3-D model data. Animals exhibiting IHP had a significant decrease in total fetal prostate volume (40%; P < 0.005) with significant regional specific differences when compared with normal male ACI rats. Anatomical and histological differences in the utricle, abnormal histology of the ipsilateral testes, and a truncation of the ipsilateral Wolffian ductal mesenchyme were also seen in the animals with IHP. Additional research is needed to further understand the mechanisms and consequences of IHP on prostate growth and development. Alterations to normal prenatal development of the male accessory sex organs can have important consequences for the growth and morphology of the adult gland.


Assuntos
Androgênios/deficiência , Próstata/anormalidades , Próstata/fisiopatologia , Anormalidades Urogenitais/fisiopatologia , Ductos Mesonéfricos/anormalidades , Ductos Mesonéfricos/fisiopatologia , Androgênios/metabolismo , Animais , Modelos Animais de Doenças , Imageamento Tridimensional/métodos , Masculino , Mesoderma/anormalidades , Mesoderma/metabolismo , Mesoderma/fisiopatologia , Modelos Anatômicos , Organogênese/fisiologia , Próstata/metabolismo , Ratos , Ratos Endogâmicos ACI , Diferenciação Sexual/fisiologia , Testículo/anormalidades , Testículo/metabolismo , Testículo/fisiopatologia , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/metabolismo , Ductos Mesonéfricos/metabolismo
13.
Proc Am Thorac Soc ; 6(8): 678-82, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20008875

RESUMO

The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the epithelial-mesenchymal trophic unit to control the local microenvironment and help maintain tissue homeostasis. However, in asthma, chronic perturbation of these homeostatic mechanisms leads to alterations in the structure of the airways, termed remodeling. Damage to the epithelium is now recognized to play a key role in driving airway remodeling. We have postulated that epithelial susceptibility to environmental stress and injury together with impaired repair responses results in generation of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Many types of challenges to the epithelium, including pathogens, allergens, environmental pollutants, cigarette smoke, and even mechanical forces, can elicit production of mediators by the epithelium, which can be translated into remodeling responses by the mesenchyme. Several important mediators of remodeling have been identified, most notably transforming growth factor-beta, which is released from damaged/repairing epithelium or in response to inflammatory mediators, such as IL-13. The cross talk between the epithelium and the underlying mesenchyme to drive remodeling responses is considered in the context of subepithelial fibrosis and potential pathogenetic mechanisms linked to the asthma susceptibility gene, a disintegrin and metalloprotease (ADAM)33.


Assuntos
Remodelação das Vias Aéreas/fisiologia , Asma/fisiopatologia , Brônquios/fisiopatologia , Mucosa Respiratória/fisiopatologia , Asma/genética , Humanos , Mesoderma/fisiopatologia , Fatores de Crescimento Transformadores/fisiologia
14.
J Pathol ; 219(2): 222-31, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19644956

RESUMO

DNA methylation is important in cancer development and is a promising biomarker for cancer detection. An epigenomic approach used in our previous work showed that LMX-1A is methylation-silenced in cervical cancer. LMX-1A, a LIM-homeobox gene, is known to participate in developmental events; however, there are at present no data on the role of LMX-1A in cancers. In this study, we characterized the function of this transcription factor by examining cell lines, animal models and human cervical neoplastic tissues, and found that over-expression of LMX-1A does not affect cell proliferation or the cell cycle of cervical cancer cell lines but significantly inhibits colony formation and invasion in vitro. Analysis of changes in epithelial-mesenchymal transition (EMT) markers, such as CDH1, CDH2, VIMENTIN, SNAIL, SLUG and TWIST, revealed involvement of the EMT in LMX-1A-mediated cancer invasion; this result was validated in a stable transfectant over-expressing LMX-1A with RNA interference. Xenograft studies using immunocompromised mice confirmed the suppressor effects of LMX-1A on tumour formation and distant metastasis in cervical cancer cell lines. LMX-1A immunohistochemical staining of tissue arrays containing the full spectrum of cervical neoplasms, including normal cervix, low-grade cervical intra-epithelial neoplasia (CIN), high-grade CIN, locally invasive and distant metastatic cancers, demonstrated the critical role of LMX-1A in invasion and metastasis. Furthermore, we found by analysing TGFbeta-BMP signalling that BMP4 and BMP6 are down-regulated by LMX-1A. The results of this study suggest that LMX-1A suppresses cancer invasion and metastasis in cervical cancer through an incomplete EMT.


Assuntos
Proteínas de Homeodomínio/fisiologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Neoplasias do Colo do Útero/patologia , Animais , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 6/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Células Epiteliais/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes Supressores de Tumor , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas com Homeodomínio LIM , Mesoderma/fisiopatologia , Camundongos , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Fenótipo , Lesões Pré-Cancerosas/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição , Transplante Heterólogo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
15.
J Natl Cancer Inst ; 101(8): 554-9, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19351920

RESUMO

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality in the United States and worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. The presence of COPD increases the risk of lung cancer up to 4.5-fold. To investigate commonalities in disease mechanisms and perspectives for disease chemoprevention, the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) held a workshop. The participants identified four research objectives: 1) clarify common epidemiological characteristics of lung cancer and COPD; 2) identify shared genetic and epigenetic risk factors; 3) identify and validate biomarkers, molecular signatures, and imaging-derived measurements of each disease; and 4) determine common and disparate pathogenetic mechanisms. These objectives should be reached via four research approaches: 1) identify, publicize, and enable the evaluation and analysis of existing datasets and repositories of biospecimens; 2) obtain phenotypic and outcome data and biospecimens from large studies of subjects with and/or at risk for COPD and lung cancer; 3) develop and use animal and other preclinical models to investigate pathogenetic links between the diseases; and 4) conduct early-phase clinical trials of potential chemopreventive agents. To foster much needed research interactions, two final recommendations were made by the participants: 1) incorporate baseline phenotyping and outcome measures for both diseases in future longitudinal studies of each disease and 2) expand collaborative efforts between the NCI and NHLBI.


Assuntos
Pesquisa Biomédica/organização & administração , Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Ensaios Clínicos como Assunto/tendências , Comportamento Cooperativo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Necessidades e Demandas de Serviços de Saúde , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Mesoderma/metabolismo , Mesoderma/patologia , Mesoderma/fisiopatologia , Mutação , National Cancer Institute (U.S.) , National Heart, Lung, and Blood Institute (U.S.) , Neovascularização Patológica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Estados Unidos
16.
Cir. plást. ibero-latinoam ; 35(2): 135-140, abr.-mayo 2009. ilus
Artigo em Espanhol | IBECS | ID: ibc-85478

RESUMO

Los defectos abdominales congénitos de la línea media inferior, como la extrofia cloacal, se producen por fallos en el mesodermo entre la región umbilical y la membrana cloacal provocando severos defectos viscerales, musculares y óseos. Los reiterados intentos para la reconstrucción de los tractos intestinal y génitourinario en este tipo de malformaciones, pueden ocasionar secuelas graves en la pared malformada. La complejidad de esta malformación y los numerosos procedimientos a los que deben ser sometidos estos pacientes, requieren de un abordaje interdisciplinario desde el inicio del tratamiento y en cada una de las etapas reconstructivas a fin de evitar, al máximo, las lesiones delos tejidos abdominales para lograr, al final, una pared adecuada. Presentamos 2 casos de reconstrucción de la pared abdominal en sendos pacientes de sexo femenino con secuelas importantes de extrofia cloacal, utilizando tejidos expandidos, colgajos musculares y complementando el tratamiento en una de las pacientes con una malla protésica. En ambos casos, y a pesar de la falta de tejido provocada por la malformación y las secuelas de múltiples cirugías, obtuvimos un buen resultado funcional y estético (AU)


Abdominal congenital defects of the middle line have their origin in developmental faults of mesoderm between the umbilical region and the cloacal membrane, originating visceral, muscular and osseous defects in the abdominal wall. Repeated attempts to reconstruct the intestinal and genitourinary tract here and in other malformations, can cause serious sequeals in the previously deformed abdominal wall. We present 2 cases of abdominal wall reconstruction inpatients with serious sequelae of cloacal extrophy. Complexity of this malformation calls for an interdisciplinary treatment to avoid the severe damage that may becaused during reconstructive attempts. In spite of lack of tissue because of the malformation and the sequelae of multiple surgeries we obtain a functional and aesthetic result thanks to the adequate utilization of the expanded tissue and of the remnant tissue complemented in one patient with a prosthetic mesh (AU)


Assuntos
Humanos , Feminino , Adolescente , Cloaca/anormalidades , Parede Abdominal/anormalidades , Procedimentos Cirúrgicos Reconstrutivos/métodos , Cloaca/cirurgia , Mesoderma/fisiopatologia , Parede Abdominal/cirurgia , Anormalidades da Pele/cirurgia
17.
Biochemistry (Mosc) ; 73(5): 528-31, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18605977

RESUMO

Complete and incomplete transitions of epitheliocytes into cells of mesenchymal type, so-called epithelial-mesenchymal transitions (EMT), take place in many types of normal morphogenesis and in epithelial carcinogenesis. Connective tissue cells (fibroblasts) also undergo considerable morphological changes during normal morphogenesis and carcinogenesis, but their dynamics are less known. It is suggested that EMT and fibroblast dynamics may have some common step that is some united precursor cell type. The program for normal EMT can be activated in the course of multistep progression of epithelial carcinogenesis; this activation can be supported by cell selection as it provides a basis for dissemination of neoplastic cells from original tumor.


Assuntos
Transformação Celular Neoplásica , Células do Tecido Conjuntivo/citologia , Células do Tecido Conjuntivo/patologia , Células Epiteliais/citologia , Células Epiteliais/patologia , Morfogênese , Neoplasias/patologia , Animais , Humanos , Mesoderma/citologia , Mesoderma/crescimento & desenvolvimento , Mesoderma/patologia , Mesoderma/fisiopatologia , Neoplasias/fisiopatologia
18.
J Urol ; 180(2): 461-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18550128

RESUMO

PURPOSE: Tubulointerstitial fibrosis is the final common pathway to end stage renal disease. The pathophysiology of renal fibrosis involves fibroblast proliferation, macrophage infiltration, the elaboration of cytokines and other proinflammatory mediators, and an imbalance in extracellular matrix deposition and degradation. Although the exact origin of activated fibroblasts remains uncertain, emerging evidence indicates that mature tubular epithelial cells are capable of transforming into myofibroblasts under pathological conditions, a process that is called epithelial-mesenchymal transition. MATERIALS AND METHODS: We reviewed the pertinent literature from January 1980 through June 2007 with regard to the contribution of epithelial-mesenchymal transition to renal fibrogenesis. RESULTS: Epithelial-mesenchymal transition is an orchestrated, highly regulated process that proceeds in stepwise fashion and appears to contribute significantly to renal fibrosis and the progression of chronic renal disease. Several cytokines and growth factors regulate epithelial-mesenchymal transition, of which transforming growth factor-beta1 is the most studied. CONCLUSIONS: Epithelial-mesenchymal transition is a cellular mechanism that has long been recognized as a central feature of normal development. However, increasing evidence implicates epithelial-mesenchymal transition in the pathophysiology of tubulointerstitial fibrosis and chronic renal disease. Recent insights into the molecular events and intrinsic signaling pathways that are active during epithelial-mesenchymal transition have evoked novel therapeutic strategies aimed at halting the onset and progression of chronic renal fibrosis.


Assuntos
Citocinas/metabolismo , Falência Renal Crônica/etiologia , Falência Renal Crônica/patologia , Túbulos Renais/patologia , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Progressão da Doença , Epitélio/patologia , Epitélio/fisiopatologia , Feminino , Fibrose/etiologia , Fibrose/patologia , Humanos , Interleucina-18/metabolismo , Falência Renal Crônica/fisiopatologia , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Mesoderma/patologia , Mesoderma/fisiopatologia , Nefrite Intersticial/fisiopatologia , Prognóstico , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
19.
Allergol Int ; 57(1): 1-10, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18209502

RESUMO

Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.


Assuntos
Asma/imunologia , Asma/fisiopatologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/fisiopatologia , Animais , Asma/etiologia , Asma/patologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Mesoderma/imunologia , Mesoderma/patologia , Mesoderma/fisiopatologia , Polimorfismo Genético , Mucosa Respiratória/patologia , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Sistema Respiratório/fisiopatologia , Células Th1/imunologia , Células Th2/imunologia
20.
Curr Opin Crit Care ; 13(6): 652-5, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17975385

RESUMO

PURPOSE OF REVIEW: The kidney has the ability to restore the structural and functional integrity of the proximal tubule, which undergoes extensive epithelial cell death via necrosis and apoptosis after a prolonged ischaemic insult. This review focuses on the recent advances in this area, and discusses the possible therapeutic interventions that might be derived from these insights. RECENT FINDINGS: Interest has recently been focused on the possible role of bone marrow originating stem cells in endogenous repair of the injured tubule, the identification of a resident population of progenitor cells in the kidney, and the potential therapeutic role of growth factors including erythropoietin and hepatocyte growth factor to stimulate these processes. SUMMARY: Advances in the understanding of the early processes that initiate and control the proliferation of surviving tubular epithelium and vascular structures are ready to be translated into clinical trials in acute kidney injury.


Assuntos
Lesão Renal Aguda/fisiopatologia , Epitélio/fisiopatologia , Isquemia/complicações , Túbulos Renais Proximais/fisiopatologia , Rim/patologia , Lesão Renal Aguda/complicações , Lesão Renal Aguda/terapia , Apoptose , Eritropoetina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Mesoderma/fisiopatologia , Necrose , Células-Tronco
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