Quemerina e fatores relacionados ao risco cardiovascular em crianças e adolescentes: uma revisão sistemática / Chemerin and factors related to cardiovascular risk in children and adolescents: a systematic review

RESUMO Objetivo: Sintetizar os achados sobre a quemerina e os fatores relacionados ao risco cardiovascular em crianças e adolescentes. Fontes de dados: Realizou-se uma revisão sistemática de acordo com os itens propostos pela diretriz PRISMA nas bases de dados PubMed, Science Direct e Lilacs. Utilizaram-se os descritores chemerin de forma associada a children e adolescent, sem limite de tempo. A pesquisa limitou-se a artigos originais realizados com seres humanos, em língua inglesa, excluindo-se a população adulta e idosa, assim como os artigos de revisão, comunicação breve, cartas e editoriais. Síntese dos dados: Após análise dos estudos por dois revisores, de forma independente, segundo os critérios de elegibilidade, permaneceram na revisão sete artigos, publicados entre 2012 e 2016. Foram incluídos estudos de delineamento transversal, prospectivo, coorte e caso-controle. A importância da adipocina quemerina nos fatores de risco para doenças cardiovasculares é demonstrada por meio de sua associação com obesidade e diabetes melito, assim como com parâmetros clínicos, antropométricos e bioquímicos. Entretanto, a força da evidência dos estudos é relativamente baixa, em função da heterogeneidade das publicações, destacando-se como limitações o número reduzido das amostras e sua ausência de representatividade, a falta de padronização dos métodos de dosagem, o delineamento transversal de grande parte dos estudos e a impossibilidade de extrapolação dos resultados. Conclusões: A desregulação da quemerina provocada pelo aumento de tecido adiposo pode contribuir para o aparecimento de doenças cardiovasculares, sugerindo que tal adipocina tem papel relevante na identificação precoce de indivíduos em risco.

ABSTRACT Objective: To review findings on chemerin and factors related to cardiovascular risk in children and adolescents. Data source: A systematic review was performed, according to the standards proposed by the PRISMA guideline, on PubMed, Science Direct, and Lilacs databases. The descriptor "chemerin" was used in combination with "children" and "adolescent", no time limit applied. The research encompassed only original articles written in English, conducted with human subjects - the adult and elderly populations excluded -, as well as literature reviews, brief communications, letters, and editorials. Data synthesis: After independent analyses of the studies by two reviewers, seven articles meeting the eligibility criteria, published between 2012 and 2016, remained for the review. Cross-sectional, prospective, cohort, and case-control studies were included. The importance of chemerin adipokines on the risk factors for cardiovascular disease is demonstrated by its association with obesity and diabetes mellitus, as well as clinical, anthropometric, and biochemical parameters. However, the strength of evidence from these studies is relatively low, due to their heterogeneity, with several limitations such as small samples and consequent lack of representativeness, lack of standardization in dosage methods, cross-sectional design of most studies, and impossibility of extrapolating results. Conclusions: The deregulation of chemerin caused by increased adipose tissue may contribute to the development of cardiovascular diseases, suggesting that this adipokine may play a significant role in early identification of individuals at risk.

Vías de señalización implicadas en la megacariopoyesis / Signaling pathways involved in megakaryopoiesis

La hematotoxicología es un área poco estudiada en nuestro país y es limitado el conocimiento sobre el efecto que ciertos contaminantes atmosféricos inducen en la sangre y en la médula ósea. La contaminación por partículas suspendidas ha cobrado más interés, por los contaminantes que se adhieren a su superficie. Un ejemplo es el benceno, relacionado con aplasia medular y leucemia. Algunos metales que también están en las partículas inhaladas son hematotóxicos. Uno de ellos es el vanadio, que nuestro grupo ha identificado como un agente inductor de alteraciones en la megacariopoyesis, lo que motivó esta revisión. Las plaquetas desempeñan un papel muy importante en la hemostasia y derivan de la célula más grande de la médula ósea: el megacariocito. Hasta hace algunos años desconocíamos casi todo del megacariocito, pero con la clonación de la trombopoyetina, en 1994, la principal hormona reguladora de la producción plaquetaria, ha existido un desarrollo acelerado en el conocimiento de la megacariopoyesis. Este artículo hace una revisión de la megacariopoyesis y su regulación, con énfasis en las vías de señalización implicadas. Además, se mencionan algunas enfermedades relacionadas y se discuten las perspectivas de investigación de este proceso, con énfasis en la toxicología.

Hematotoxicology has been studied with less interest than other fields associated with atmospheric pollution. There is limited knowledge about on the effects that certain atmospheric pollutants may provoke in the blood and bone marrow. Suspended particle pollution has become an area of scientific inquiry due to the contaminants adhering to its surface. We have identified the association of inhaled vanadium and variations in megakaryopoyesis and thrombopoyesis. Platelets are the smallest elements in the blood, but they play a strategic role in hemostasis. They are derived from the largest cell of the bone marrow, the megakaryocite. This cell size is about 150 microm, with apolyploid nucleus and unknown origin until few years ago. When TPO was cloned in 1994 the knowledge about megakaryocyte began to growth exponentially, elucidating the mechanisms of proliferation, differentiation and release of platelets. More information is still needed in order to translate knowledge into clinical application for diseases such as thrombocytopenia or thrombocytosis. A review of the current concepts of megakaryopoiesis and its regulation, with emphasis on signaling pathways are presented in this paper; a classification in TPO-dependent and TPO-independent is also detailed. In addition, we review some diseases associated with changes in the signaling pathway of megakaryopoyesis, as well as possible perspectives in this field, including toxicology.

Células inflamatórias e seus mediadores na patogênese da DPOC / Inflammatory cells and their mediators in COPD pathogenesis

A doença pulmonar obstrutiva crônica (DPOC) é causada por processo inflamatório crônico que limita o fluxo aéreo, sendo sua principal causa o tabagismo. Conforme dados da Organização Mundial de Saúde (OMS), a DPOC será a quarta causa de mortalidade em 2020, atrás apenas das doenças vasculares, cardíacas e cerebral, além das neoplasias. Apesar do enorme crescimento da prevalência e da mortalidade da DPOC, não existe nenhuma terapêutica que consiga controlar a evolução da doença estabelecida. O processo inflamatório crônico causado pelos gases da fumaça de tabaco desencadeia alterações estruturais que predominam nas pequenas vias aéreas (menores que 2 mm). Essa agressão provoca um processo inflamatório que conta com a participação não apenas de macrófagos, linfócitos e neutrófilos, mas células estruturais como epiteliais, musculares e fibroblastos. Atualmente, a interação entre macrófagos e linfócitos, especialmente CD8+, tem sido implicada na patogênese da DPOC. Quimiocinas como CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC e CCL5/RANTES têm sido descritas como possíveis responsáveis pelo recrutamento de linfócitos T e monócitos sanguíneos, facilitando o aumento de macrófagos alveolares e linfócitos T CD8+ no parênquima dos pacientes com DPOC. Conhecer melhor como ocorre o tráfego de células mononuclerares em direção ao pulmão é fundamental não só para um maior entendimento da patogênese da DPOC, mas para o desenvolvimento de terapêuticas adequadas. Com base nessas evidências tem sido proposto o estudo de moléculas capazes de bloquear de forma específica o recrutamento de células inflamatórias para o pulmão por meio de ação direta nos seus receptores.

Chronic Obstructive Pulmonary Disease (COPD) is considered to be a progressive disease characterized by chronic inflammation and irreversible airflow obstruction, mainly caused by tobacco smoking. Based on World Health Organization data, COPD will be the fourth cause of mortality in 2020, after vascular, cardiac and cerebral diseases and cancer. To date no therapy retards or suppresses progression of COPD. The chronic inflammatory process caused by tobacco smoking promotes structural changes predominantly in the small airways (less than 2mm). Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial and smooth muscle cells. The interaction between macrophages and lymphocytes, especially CD8+, has been implicated in the pathogenesis of COPD. Chemokines such as CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC and CCL5/ RANTES have been described as possibly responsible for recruitment of T cells and blood monocytes increasing the number of macrophages and CD8+ T cells in the lung of COPD patients. The study of the influx of mononuclear cells to the lung is very important not only to promote a better understanding of the COPD physiopathology but also to help identify new targets for treatment. Based on this new evidence, the study of several mediator antagonists that can block the recruitment of inflammatory cells to the lung have been tested in COPD.

O papel das quimiocinas nas uveítes / The role of chemokines in uveitis

A inflamação é parte do processo fisiológico que visa reparar o dano tecidual causado por infecção, trauma, auto-imunidade. Quando este processo fisiológico encontra-se alterado, pode contribuir para o aumento do dano tecidual. As quimiocinas e seus receptores são importantes elementos envolvidos no processo de migração celular para os tecidos inflamados. Nas doenças oculares, principalmente nas uveítes, estas proteínas estão sendo identificadas como importantes mediadores da resposta inflamatória. Esta revisão visa discutir o papel das quimiocinas em diversas doenças oculares, dando ênfase aos processos uveíticos.

Inflammation is part of the physiological process that aims at repairing the damage produced by different causes such as infection, trauma, and autoimmune disease. However, when this physiological process is not regulated, it can contribute to the increase in tissue damage. Chemokines and their receptors are major factors involved in the process of cell migration into inflamed tissues. In the ocular diseases, mainly in uveitis, such proteins have been identified as important mediators of the inflammation process. This review discusses the role of chemokines in several ocular diseases, with emphasis on the uveitic process.

Chemokines and their association with paediatric diseases

The knowledge about chemokines and their receptors activity is an essential need of health care professionals, Chemokines represent a super family of small, inducible, secreted, proinflammatory cytokines involved in a variety of function in leukocyte trafficking, recruiting, and recirculation. The purpose of this review is together and highlights the different studies concerning with chemokines and their potential effects with various diseases. Chemokines play a significant role in many pathophysiological processes such as inflammation, allergic responses, autoimmune diseases, angiogenesis and tumor growth. In addition, particular chemokines have been reported to act on hematopoietic progenitor cells, influence wound healing and have a close association between their receptors and certain human diseases. It is important to know the biological characteristics of chemokines and their receptors activity. It has been also observed that there is a close association between chemokines, chemokine receptors, cells and certain adult and paediatric diseases. In addition, chemokines play a significant role in many pathophysiological processes such as inflammation, infectious, allergic response and autoimmune diseases. For this review we reviewed English-language MEDLINE publications from 1966 through January 2006 for experimental, observational and clinical studies having relation with chemokines with different diseases. Approximately 72 publications were reviewed based on the relevance, strength and quality of design and methods, 54 publications were selected for inclusion

O papel das quimiocinas na neuroinflamação / The role of chemokines in neuroinflammation

Inflamação é parte do processo fisiológico que visa reparar o dano tecidual causado por infecção, trauma, isquemia, autoimunidade. Entretanto, quando o processo inflamatório não é controlado, pode contribuir para o aumento da lesão tecidual. A regulação da resposta inflamatória no sistema nervoso central (SNC) envolve diferentes tipos celulares, como neutrófilos, macrófagos e linfócitos, células da glia, moléculas de adesão, citocinas e quimiocinas. As quimiocinas são uma família de citocinas de baixo peso molecular responsáveis pelo recrutamento seletivo de leucócitos, e subdividem-se em quatro subfamílias de acordo com a posição do resíduo cisteína N-terminal dessas moléculas: C, CC, CXC, CX3C. O objetivo desta revisão é apresentar o papel das quimiocinas na regulação da inflamação em doenças do SNC.

Inflammation is part of the physiological process that aims at repairing the tissue damage produced by infection, trauma, ischemia, autoimmune diseases. However, when this process is not controlled, it can increase the tissue lesion. The regulation of the inflammatory response in the central nervous system (CNS) involves different cell types such as neutrophils, macrophages, lymphocytes, glia cells, adhesion molecules, cytokines and chemokines. Chemokines are a large family of low-molecular weight cytokines associated with the selective trafficking of leukocytes, and are classified into four subfamilies on the basis of the arrangement of cysteine residues located in the N-terminal region of these molecules: C, CC, CXC and CX3C. This review will attempt to describe the role of chemokines in the regulation of inflammation in CNS diseases.

Nitric oxide: a major determinant of mast cell phenotype and function

Mast cells (MC) are important in the numerous physiological processes of homeostasis and disease. Most notably, MC are critical effectors in the development and exacerbation of allergic disorders. Nitric oxide (NO) is a diatomic radical produced by nitric oxide synthase (NOS), and has pluripotent cell signaling and cytotoxic properties. NO can influence many MC functions. Recent evidence shows the source of this NO can be from the mast cell itself. Governing the production of this endogenous NO, through alterations in the expression of tetrahydrobiopterin (BH4), a NOS cofactor, has stabilizing effects on MC degranulation. Furthermore, NO regulates the synthesis and secretion of de novo generated mediators, including leukotrienes and chemokines. These novel observations add to the growing body of knowledge surrounding the role of NO in the MC.

Cellular signaling in tissue regeneration

With recent progress in stem cell-based research, there has been tremendous interest in stem cell-based tissue regeneration. Stem cells can be differentiated into specialized cells/tissues by growth factors and cytokines. These small molecules are thought to play an important role in both wound healing and tissue regeneration. However, their biological activity and signal transduction during tissue regeneration are poorly understood. With recent advances in signal transduction by growth factors, the receptor kinases and G protein-coupled receptors, an understanding in the underlying mechanism of how these factors regulate tissue regeneration beginning to take place. In this review, the potential underlying mechanisms of growth factor signaling in normal tissue regeneration and chronic wound healing is discussed. Thus, it is an aim to provide a basis for designing more specific therapies for tissue regeneration in the near future.

Eosinophil-active chemokines: assessment of in vivo activity

The selective recruitment of eosinophils in tissue is a striking feature of allergic diseases. Recently, a family of chemoattractant molecules, namely chemokines, has been described which potently activates eosinophil function in vitro. We have developed a murine model of eosinophil recruitment to compare the relative potency and efficacy of chemokines in vivo. Of the chemokines tested, only eotaxin and MIP-1alpha induced significant accumulation of eosinophils in vivo, but eotaxin was more effective than MIP-1alpha. Chemokines, especially eotaxin acting via the CCR-3 receptor, may have a fundamental role in determining selective eosinophil recruitment in vivo.

The role of the eosinophil-selective chemokine, eotaxin, in allergic and non-allergic airways inflammation

Blood eosinophilia and tissue infiltration by eosinophils are frequently observed in allergic inflammation and parasitic infections. This selective accumulation of eosinophils suggested the existence of endogenous eosinophil-selective chemoattractants. We have recently discovered a novel eosinophil-selective chemoattractant which we called eotaxin in an animal model of allergic airways disease. Eotaxin is generated in both allergic and non-allergic bronchopulmonary inflammation. The early increase in eotaxin parallel eosinophil infiltration in the lung tissue in both models. An antibody to IL-5 suppressed lung eosinophilia, correlating with an inhibition of eosinophil release from bone marrow, without affecting eotaxin generation. This suggests that endogenous IL-5 is important for eosinophil migration but does not appear to be a stimulus for eotaxin production. Constitutive levels eotaxin observed in guinea-pig lung may be responsible for the basal lung eosinophilia observed in this species. Allergen-induced eotaxin was present mainly in the epithelium and alveolar macrophages, as detected by immunostaining. In contrast, there was no upregulation of eotaxin by the epithelial cells following the injection of Sephadex beads and the alveolar macrophage and mononuclear cells surrounding the granuloma were the predominant positive staining cells. Eotaxin and related chemokines acting through the CCR3 receptor may play a major role in eosinophil recuitment in allergic inflammation and parasitic diasease and thus offer an attractive target for therapeutic intervention.

Description of an in vivo model for assessment of eosinophil chemoattractants in the mouse

Chemokines (chemoattractant cytokines) induce potent and selective chemotaxis of leukocyte subsets in vitro. Here, we review briefly the chemokines shown to induce eosinophil chemotaxis in vitro and describe a novel model for the study of the ability of chemokines to stimulate eosinophil migration in vivo. Eosinophils were purified from the blood of mice over-expressing the IL-5 gene and labelled with 111In. Only the C-C chemokines, eotaxin and MIP-1 alpha, but not RANTES, MCP-1, MCP-3, MIP-1ß. KC and MIP-2, effectively induced the recruitment of 111In-eosinophils in mouse skin. We suggest that this mouse model will be useful in assessing the role of endogenously-generated chemokines in mediating eosinophil migration to sites of allergic inflammation in vivo.

Las quimoquinas : una nueva familia de citoquinas reguladoras del proceso inflamatorio

La respuesta inmune e inflamatoria es regulada positiva y negativamente por medio de la secreción de mediadores solubles denominados citoquinas. Una nueva familia de citoquinas denominadas quimoquinas se compone por lo menos de 18 proteínas. Estas citoquinas presentan 20 a 45 por ciento de homología entre su secuencia de aminoácidos y poseen cuatro cisteínas conservadas que forman enlaces disulfuro en el extremo NH2 de la proteína. Con base en la secuencia de las primeras dos cisteínas, las quimoquinas se han dividido en dos subfamilias; las B-quimoquinas en las cuales las primeras dos cisteínas se encuentran separadas por un residuo no conservado (C-X-C) y las B-quimoquinas en las cuales estas dos cisteínas se encuentran adyacentes (C-C). Dentro de las actividades biológicas que comparten las alfa y las beta-quimoquinas se encuentran el incremento pasajero del calcio intracelular, cambios de la forma celular al interactuar con proteínas de la matriz celular, inducción de degranulación, incremento en la expresión de moléculas de adhesión celular (B2 integrinas), producción de prostaglandinas y leucotrienos e inducción de la explosión respiratoria en neutrófilos, basófilos, linfocitos T y monocitos principalmente. De manera particular, las B-quimoquinas ejercen una modulación de la respuesta inmunológica a través de varias actividades pleitrópicas, las cuales incluyen el reclutamiento de Células T y macrófagos en sitios de inflamación por medio de la regulación de su activación y proliferación. Se ha desmostrado recientemente que estas funciones pleiotrópicas de las quimoquinas juegan un papel importante en la regulación del proceso inflamatorio asociado al desarrollo de la patología de procesos autoinmunes y alérgicos.