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Considering lack of target‐specific antiviral treatment and vaccination for COVID‐19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID‐19‐infected patient outcomes. In a follow‐up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up‐regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID‐19 and many other pathologic conditions.

Many studies have confirmed the merits of metformin to treat type 2 diabetes, but few studies have addressed its effect on the respiratory system. Moreover, vascular endothelial growth factor (VEGF) is critical to many lung functions. In this way, we evaluated the metformin impact on the lung in treated obese Swiss mice, induced by postnatal overnutrition. Glucose and insulin were detected and the insulin resistance index (HOMA) was calculated; inflammatory cells and nitrite/nitrate concentration (NOx) was quantified from bronchoalveolar lavage, collagen and lung VEGF-a was analysed in the lung tissue and lung mechanics were evaluated by methacholine-induced bronchoconstriction. Values of glucose, insulin, HOMA; VEGF-a and collagen demonstrate the partial ability of metformin to improve the effects of obesity. However, metformin is ineffective in re-establishing the inflammation, shows no effects on NOx and does not restore bronchoconstriction in obese mice. In conclusion, metformins beneficial effects on lung are questionable in the postnatal overnutrition model of obesity.

Introduction Although uterine Natural Killer (uNK) cells have cytoplasmic granules rich in perforin and granzymes, these cells do not degranulate in normal pregnancy. DBA lectin + uNK cells produce angiogenic factors which stimulate remodeling of uterine arterioles to increase blood flow within the growing feto-placental unit. We sought to investigate the importance of COX-2 on mouse pregnancy inoculated with Gram-negative bacteria Lipopolysaccharide (LPS) by treating with a selective COX-2 inhibitor (nimesulide). Methods We have combined histochemical, immunohistochemical, stereological, morphometric, behavioral, and litter analyses to investigate mouse pregnancy inoculated with LPS with or without pre-treatment with nimesulide 30 min before LPS injections, focusing on DBA + uNK cell response and viability of the pregnancy. Results LPS caused sickness behavior, an immature DBA + uNK influx, decreased mature DBA + uNK cell numbers, and triggered a new DBA low uNK appearance. These effects of LPS, except the sickness behavior, were prevented by nimesulide. COX-2 inhibition also prevented the down-regulation of uNK perforin and spiral arteriole α-actin expression stimulated by LPS. While the litter size from Nimesulide + LPS-treated mothers was significantly smaller compared to those from LPS-treated group, nimesulide alone showed no effect on the offspring. Discussion Collectively, our data indicate that COX-2 changes angiogenic DBA + uNK cells in order to protect mouse pregnancy after LPS injection.

One of the most abundant immunologic cell types in early decidua is the uterine natural killer (UNK) cell that despite the presence of cytoplasmic granules rich in perforin and granzymes does not degranulate in normal pregnancy. UNK cells are important producers of angiogenic factors that permit normal dilation of uterine arteries to provide increased blood flow for the growing feto-placental unit. Gram-negative bacteria lipopolysaccharide (LPS) administration can trigger an imbalance of pro-inflammatory and anti-inflammatory cytokines impairing the normal immune cells activity as well as uterine homeostasis. The present study aimed to evaluate by immunohistochemistry the reactivity of perforin and α-actin on UNK cell from LPS-treated pregnant mice. For the first time, we demonstrate that LPS injection in pregnant mice causes α-actin down regulation, concomitantly with perforin loss in UNK cells. This suggests that LPS alters UNK cell migration and activates cytotoxic granule release.

Uterine natural killer (uNK) cells are the dominant lymphocytes of pregnant mammals' uterus. Studies have identified four differentiation stage of mouse uNK cells based on Dolichos biflorus lectin cytochemistry, and their distribution showed preferential domain in the uterus through out the pregnancy. This work was done to investigate the expression of alpha5, alpha6, and beta7 integrins on uNK cells and their ligands distribution. Section of mouse uterus from sixth to seventeenth gestational days were submitted to immunocytochemistry and positive reactions for alpha5, alpha6, and beta7 integrins were found on uNK from eighth to tenth gestational days but not after twelfth gestational days. Fibronectin reactions were seemed from sixth to tenth gestational days around uNK from the myometrium and endometrium close to the myometrium. No reaction for fibronectin was seen in the decidualized and nondecidualized endometrium near the placenta. Laminin reaction was seen just in the antimesometrial side. beta7 integrin seems to be the active receptor to bind with VCAM-1 or MAdCAM-1 of endothelial cells, promoting the uNK cross through the vessels. The absence of laminin in an uNK domain suggests these cells are not dependent of laminin and alpha6 integrin for their establishment. However, fibronectin seems to support uNK migration, proliferation, differentiation, and survival in the uterus by binding with alpha5 integrin. The loss of alpha5 integrin ligation by the down regulation of fibronectin could inhibits these events and further studies are need to investigate whether unligated alpha5 can actively and initiate apoptosis, maybe in a caspase 8-dependent way that has been called integrin-mediated death.

This study investigated behavioral responses to an immune challenge among animals with fructose-induced metabolic disorders. Adult male Wistar rats were provided either water or a fructose solution (10%) for 5 weeks. Sickness behaviors were assessed 2h following the injection of either a lipopolysaccharide (LPS) or vehicle. The rats were subjected to an open field test, a social interaction test, a food intake test and a fever evaluation. Cytokine expression was assessed in both adipose tissue and hypothalamus samples. The neural response was assessed in the forebrain immunohistochemistry for c-Fos. Compared with the control group, the fructose diet induced dyslipidemia and significantly higher plasma total cholesterol, HDL-cholesterol, triglyceride, and glucose levels as well as both epididymal and retroperitoneal adiposity. Furthermore, in response to LPS (1 mg/kg), the rats subjected to a fructose diet exhibited exacerbated sickness behaviors and accentuated febrile responses. LPS induced Fos protein expression in several areas of the brains of the control rats; however, higher numbers of Fos-positive cells were observed in the brains of the rats that were fed a fructose diet. Moreover, larger increases in cytokine expression were observed in both the hypothalamus and the adipose tissue of the obese rats compared with the control rats in response to LPS. In this study, fructose diets played an important role in both the induction of metabolic disorders and the modulation of sickness behaviors in response to an immunological challenge, most likely through the induction of cytokines in the hypothalamus.

Problem Enrichment of uterine natural killer (uNK) cells occurs during pregnancy in many species. However, functions of uNK cells and regulation of their uterine homing are not fully defined. In mice and women, uNK cells contribute to angiogenesis, a role reviewed here and now addressed in a mammal with an alternative placental type. Methods of study To address lymphocyte functions, RNA from murine or porcine endometrium and lymphocytes purified from endometrium were analyzed using real-time or reverse transcription PCR. To address homing potential, human blood CD56+ lymphocytes were evaluated using both RNA and functional adhesion to endothelium presented under shear force in frozen sections of gestation day 7 C57Bl/6J implantation sites. Women were serially sampled over a menstrual cycle or a clinical preparatory cycle for embryo transfer. Results Activation of murine uNK cells is associated with much greater increases in transcription for Eomes than for T-bet (Tbx21). Lymphocytes from normal porcine implantation sites transcribe vascular endothelial growth factor, placental growth factor, interferon-gamma and hypoxia-inducible factor (HIF)-1α. In fertile women, increases in L-selectin- and α4-integrin-mediated interactions between CD56+ cells and endothelium occur at luteinizing hormone (LH) surge (cycling women) to oocyte pick up or embryo transfer, then return to pre-LH levels. Conclusions Uterine lymphocytes may universally promote pregnancy-associated endometrial angiogenesis. Recruitment of uNK precursor cells from blood appears to occur in a window promoted by rising plasma estrogen and LH and limited by rising progesterone.

During human and rodent uterine decidualization, transient but abundant numbers of uterine natural killer (uNK) cells appear, proliferate, and differentiate. uNK cells share features with peripheral NK cells but are specialized to promote interferon-γ (IFN-γ)-mediated, pregnancy-associated, structural changes in maternal placental arteries. In CD8+ T cells and NK cells, the transcription factors T-bet and eomesodermin (Eomes) regulate maturation and effector functions, including IFN-γ production. No studies are reported for uNK cells. Implantation sites in T-bet null mice, which have a defect in NK cell maturation, had uNK cells normal in morphology and number and normally modified spiral arteries. As Eomes null mice are not viable, real-time polymerase chain reaction comparisons between C57Bl/6J (B6) and alymphoid (Rag20/0γc0/0) mice were used to assess uNK cell expression of T-bet, Eomes, and the target genes IFN-γ, granzyme A, and perforin. Gestation dated (gd) uterine tissues (mixed cell composition) and 200 morphologically homogeneous, laser-capture, microdissected uNK cells of different maturation stages were used. In uterus, Eomes transcripts greatly outnumbered those of T-bet, whether donors were nonpregnant or pregnant, and increased to gd10. In uNK cells, transcripts for T-bet, Eomes, and IFN-γ were most abundant in mature stage cells, and transcripts for granzyme A and perforin were lower at this stage than in immature or senescent cells. Thus, Eomes dominance to T-bet discriminates regulation of the uNK cell subset from that observed for peripheral NK cells.

The hypoxia-inducible factor-1alpha (HIF-1alpha) is expressed in response to hypoxia and has been recently demonstrated in a variety of cells such as tumor cells and tumor-associated macrophages. Several characteristics of leishmanial lesions in humans and in animal models, such as microcirculation impairment, metabolic demand for leukocyte infiltration into infected tissue, parasite proliferation, and secondary bacterial infection, are strong indications of a hypoxic microenvironment in the lesions. We evaluated HIF-1alpha expression in the cutaneous lesions of BALB/c mice during Leishmania amazonensis infection. Immunohistochemical analyses of the lesions demonstrated, only in the later stages of infection when the lesion size is maximal and parasite burden is enormous and massive numbers of recruited macrophages and ulcers are observed, positive HIF-1alpha-infected cells throughout the lesions. HIF-1alpha is expressed mainly in the cytoplasm and around parasites inside the parasitophorous vacuoles of macrophages. This is the first evidence that macrophages in the microenvironment of lesions caused by a parasite produce a hypoxia-inducible factor.

Virgin adult C57Bl/6J mouse uterus contains a population of small, non-granulated Natural Killer (NK) cells with balanced expression of NK cell activating and inhibiting LY49 receptors. Coincident with blastocyst implantation and decidualization, uterine (u)NK cells become activated. The surface glycoslyation of uNK changes, the cells proliferate and they induce production of interferon (IFN)gamma, perforin, serine esterases and other molecules, including angiogenic factors. Mouse strains genetically ablated in uNK cells fail to undergo modification of spiral artery segments that branch from the uterine artery and feed into the placenta and these mice do not sustain a robust decidualization response. IFN-gamma is thought, from bone marrow transplantation and therapeutic studies, to be the key uNK-cell derived mediator regulating gene expression in vascular and decidual tissues. Here, we review recent studies showing that IL-15 is the critical cytokine controlling uNK cell differentiation and that uNK cells are activated by either IL-12 or IL-18 and by other factors when both IL-12 and IL-18 are genetically absent from implantation sites. We address possible roles of the IFN-gamma regulated gene alpha2-macroglobulin (alpha2-M) in regulation of the position of fetal trophoblast within the walls of the spiral arteries, and we discuss approaches that have been successful in evaluating mechanisms involved in homing of mouse uNK cell precursors to the uterus. These approaches maybe applicable to studies in women. Our studies show that complex immuno-physiological events contribute to spiral artery modification by mid-gestation in mice.

Uterine Natural Killer (uNK) cell differentiation in vivo requires oestrogen (E) priming prior to progesterone (P). Hybridomas between uNK precursor and SP2/0 cells express message for E receptor (ER)alpha but nor PR. However, mature, rodent and human uNK cells lack these receptors. To functionally assess requirements for uNK cell expression of ERalpha or ERbeta during precursor differentiation, marrow was transplanted from either ERalpha(o/o) (alphaERKO) or ERbeta(o/o) (betaERKO) mice into alymphoid RAG-2(o/o)/gammac(o/o) females. Recipients were mated and their implantation sites were examined by light microscopy, morphometry and ultrastructure. High numbers of uNK cells were established from each donor strain. Graft-derived uNK cells were similar in number and morphology to uNK cells of normal mice, suggesting that neither alpha- nor beta-ER is required for uNK precursor cell differentiation. Induction of spiral artery modification in the transplant recipients indicated that graft-derived uNK cells had functional properties. A novel technique for rapid isolation of highly purified uNK cells from normal mice using Dolichos biflorus agglutinin (DBA) lectin-conjugated magnetic beads was employed to obtain RNA. Expression of alpha- and beta-ER was absent by RT-PCR from NK cells isolated from the uterus, supporting the conclusions from the in vivo study.

Chapter Summary After blastocysts cross the uterine epithelium and begin interstitial implantation, the critical process of establishing the chorioallantoic placenta begins. This precedes the stage of rapid fetal growth that depends upon the placenta accessing maternal arterial blood, which provides adequate nourishment and oxygen supplies for fetal growth. The key events in the placental development process occur in the mesometrial endometrium. This tissue region experiences complete remodeling of its components. This chapter discusses the changes in the cellular and tissue biology of uterine epithelium that support receptivity for blastocyst implantation and support development of the utero-placental circulation. This chapter is complementary to Chapter 11 (decidua reaction) and provides a synthesis of content from Chapters 10 and 12 Chapter 10 Chapter 12 (ectoplacental and placental trophoblast), with the integration of new information and emphasis on the differences between mesometrial and antimesometrial decidua. It also gives an introduction to content in Chapters 15, 16 (uterine and utero-placental vasculature), and 19 Chapter 15 Chapter 16 Chapter 19 (uterine leukocytes).

Chapter Summary This protocol chapter outlines the technical knowledge necessary to conduct correct sample handling for electron microscopic analysis of mouse reproductive organs during pregnancy. Some basic knowledge of the physics of images generated by electromagnetic waves is discussed in order to distinguish between light and electron microscopy. Detailed standard protocols using the pregnant mouse uterus as a reference for ultrastructural analysis and ultrastructural immunocytochemistry are described. This protocol has supported the work cited in Chapters 10, 11, 13 and 34 Chapter 10 Chapter 11 Chapter 13 Chapter 34 .

Lipopolysaccharide (LPS), produced by gram-negative bacteria, mediates vasodilatation, changing the action of contractile smooth muscle by increasing expression of nitric oxide synthase and prostaglandin. For the first time we demonstrate, by immunohistochemical methods, that administration of LPS to pregnant mice causes α-actin-mediated down-regulation of contractile filaments in uterine blood vessels, thereby potentially increasing vessels permeability, blood supply, and immune cells homing to this environment, culminating in the reestablishment of uterine homeostasis.

Uterine natural killer (uNK) cells are the dominant lymphocytes found in pregnant mammals that develop uterine decidualization. Four stages of mouse uNK cell differentiation are recognized using Dolichos biflorus agglutinin (DBA) lectin histochemistry. Each uNK cell subtype has a preferential domain. In human and mouse normal pregnancies, uNK cells are activated interferon gamma-producing cells that promote angiogenesis and development of the decidua and placenta. Murine transplant models suggest that uNK cells differentiate from self-renewing progenitors found in peripheral secondary lymphoid tissues, particularly spleen and lymph nodes. In this work, the spleen was removed 7 days before mice were mated to address whether absence of the spleen reduced uNK cell numbers or altered the distributions of maturing uNK cell subsets using quantitative lectin histochemistry. Splenectomy delayed uNK cell maturation within implantation sites. This coincided with delayed decidual and placental development and a significant (48 hr) lengthening of gestation without loss of viability. These studies characterize spleen as a biologically important progenitor tissue for uNK precursor cells.

Aim of the study Averrhoa carambola L. (Oxalidaceae) leaves are used in Brazilian traditional medicine to treat hypertension. This study was conducted to evaluate the hypotensive effect of the aqueous extract of Averrhoa carambola (AEAc) and its underlying mechanisms in the isolated rat aorta. Materials and methods The effect of AEAc on the mean arterial pressure (MAP) was determined in vivo in anesthetized rats. In vitro , thoracic aortic rings were isolated and suspended in organ baths, and the effects of AEAc were studied by means of isometric tension recording experiments. In HPLC analysis, the fingerprint chromatogram of AEAc was established. Results In normotensive rats, AEAc (12.5–50.0 mg/kg, i.v.) induced dose-dependent hypotension. In vitro , AEAc caused a depression in the E max response to phenylephrine without a change in sensibility. Also, in a depolarized Ca 2+ -free medium, AEAc inhibited CaCl 2 -induced contractions and caused a concentration-dependent rightward shift of the response curves, indicating that AEAc inhibited the contractile mechanisms involving extracellular Ca 2+ influx. Conclusions These results demonstrate the hypotensive effects of AEAc, and these effects may, in part, be due to the inhibition of Ca 2+ , which supports previous claims of its traditional use.

Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56(bright) uterine (u)NK cells. Key findings are reviewed in this article. In mice, uNK precursor cells are recruited from secondary lymphoid tissues and are activated coincident with their uterine arrival. uNK cells proliferate, produce cytokines (interferon gamma (IFN-gamma) and interleukin 18 (IL-18) and IL-27), and terminally differentiate into granulated lymphocytes. Many uNK cells proliferate within the myometrium at each implantation site forming a structure, the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds blood vessels servicing each placenta. Post-mitotic uNK cells are abundant within decidua basalis; frequently (

Uterine Natural Killer (uNK) cells are a transient lymphocyte population found in the pregnant uteri of human and rodents. The pregnant uterine environment appears to influence migration, differentiation and suppression of the cytolytic activation of uNK cells but the mechanisms involved in these processes are not well understood. Similarities to circulating NK (cNK) cells are limited. The present study sought to discrimate uNK cells from cNK cells in mice by identification of a unique uNK cell marker. Dolichos biflorus (DBA) lectin, which has high selectivity for glycoconjugates containing N-acetyl D-galactosomine in the terminal position, reacted with the plasma membranes of mouse uNK cells. DBA lectin did not react with other uterine lymphocytes or with cNK cell surfaces in Swiss, CBA-J, C57BL/6, SJL, BALB/c, DBA-2 mice strains. DBA lectin staining was useful for both light and electron microscopy and distinguished 4 uNK cell subtypes that appear to be stages of differentiation. Quantitative evaluation of these 4 uNK cell subtypes over early to late gestational times showed dynamic changes between immature and mature forms in different compartments of the implantation sites and indicated the occurrence of microdomains in the uterus capable of controlling uNK cell proliferation and differentiation. This is the first report showing mouse uNK cells expressing specific molecules not found in other NK cells. Use of this reagent should enhance studies of earlier, non-granulated forms of uNK cells and provide new strategies for purification of mouse uNK cells for functional and molecular studies.

Orientadores : Aureo Tatsumi Yamada, Paulo Pinto Joazeiro Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: As células natural killer uterinas (NKu) constituem uma população linfocitária transitória, presente no útero de humanos e roedores durante a gestação. O ambiente uterino, no início da gestação, parece ser determinante na migração e diferenciação, assim como, na supressão da atividade citolítica destas células, que atuam em outras localidades na resposta imune inata. Porém, os fatores ou os mecanismos envolvidos nestes processos celulares, das NKu, não foram ainda elucidados. As características fenotípicas e constitutivas asseguram a similaridade das NKu com as NK circulantes (NKc), porém, diversos ensaios apontam a primeira como sendo uma provável subclasse de células NK. No presente estudo, estabeleceu-se um método cito químico utilizando-se a lectina DBA (Dolichos biflorus) como um marcador altamente seletivo para as células NKu de camundongos, que permite distingui-Ias das células NK circulantes e das demais populações linfocitárias, por não apresentar reatividade cruzada. Com este marcador, foi possível identificar morfologicamente os subtipos correspondentes aos estágios de maturação, bem como, estabelecer de forma precisa a incidência e localização das NKu no útero ao longo da gestação. Ao contrário dos imunomarcadores utilizados até então, que apresentavam limitações (restritas a algumas linhagens de camundongos, ou que reconheciam apenas as formas maduras ou imaturas), a lectina DBA mostrou ser um marcador universal para as células NKu de camundongos, além de reagir com formas imaturas e plenamente diferenciadas destas células. Com o intuito de se elucidar a ação do estrógeno diretamente sobre as células NKu, utilizou se animais geneticamente modificados juntamente com métodos imunocitoquímicos e moleculares para identificar a possível expressão de receptores de estrógenos (ERa e ERJ3) nestas células. A medula óssea de animais deficientes em receptores de estrógenos a e J3 (ER-KO ae 13) foi transplantada em camundongos imunodeficientes B6-Rag-2-/- /yc-/- (T,B-, NK} O isolamento e purificação das células Nku pelo método lectina DBA-biomagnético, tornou-se possível após ter sido constatado que a mesma reage de forma específica com o glicoconjugado presente na superfície das células NKu. Os testes de RT-PCR realizados com as NKu isoladas demonstraram a ausência de receptores de estrógeno (X e 13 nas células NKu de camundongos, revelando que o hormônio estrógeno não seria o indutor que atua diretamente na migração, proliferação ou diferenciação destas células no ambiente uterino Com o fito de investigar se as NKu constituem um subtipo especializado de células NK, avaliou-se as expressões dos genes de 14 receptores LY49 e do DAP12, através do RT-PRC em tecidos mesometriais dissecados de camundongos virgens, prenhes, normais e geneticamente modificados deficientes em linhagens de linfócitos. Úteros virgens de C57Bl/6J (B6), randombred (predominante H-2b) scid/scid, B6-IL-1Y/- e B6 nu/nu expressaram DAP12 e um repertório parcial de Ly49. A prenhez induziu a expressão de receptores inibitórios adicionais em todas as linhagens estudas. No útero de camundongo B6 virgem os receptores de ativação L Y 49D e L Y 49H foram co expressos com os inibitórios L Y49 I, J e Q. No início da gestação (dg6), foi observada a expressão de genes para um repertório extenso de Ly49, que prossegue até a metade da gestação, os quais devem estar relacionados com a diferenciação e comportamento das NK no útero. O conjunto destes experimentos e os respectivos resultados foram organizados em três capítulos distintos, redigidos na forma de três artigos científicos já submetidos para publicação em revistas especializadas da área. Saliente-se que partes deste trabalho foram desenvolvidas no laboratório da Profa. Dra. Bárbara Anne Croy, University of Guelph, ON, Canada Doutorado Histologia Doutor em Biologia Celular e Estrutural