Ovulation is triggered by the gonadotropin surge that induces the expression of two key genes, progesterone receptor (Pgr) and prostaglandin-endoperoxide synthase 2 (Ptgs2), in the granulosa cells of ...preovulatory follicles. Their gene products PGR and PTGS2 activate two separate pathways that are both essential for successful ovulation. Here, we show that the PGR plays an additional essential role: it attenuates ovulatory inflammation by diminishing the gonadotropin surge-induced Ptgs2 expression. PGR indirectly terminates Ptgs2 expression and PGE2 synthesis in granulosa cells by inhibiting the nuclear factor κB (NF-κB), a transcription factor required for Ptgs2 expression. When the expression of PGR is ablated in granulosa cells, the ovary undergoes a hyperinflammatory condition manifested by excessive PGE2 synthesis, immune cell infiltration, oxidative damage, and neoplastic transformation of ovarian cells. The PGR-driven termination of PTGS2 expression may protect the ovary from ovulatory inflammation.
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•Successful ovulation requires timely expression of PGR in the ovarian granulosa cells•PGR terminates LH-surge-driven PGE2 synthesis by decreasing PTGS2 (COX-2) expression•Impaired PGR expression leads to hyperinflammation and tissue damage in the ovary
A preovulatory LH surge induces the expression of PGR and the production of PGE2, a proinflammatory prostaglandin, in preovulatory granulosa cells. Park et al. show that PGR then suppresses PGE2 synthesis by decreasing the expression of PTGS2. Such PGR-driven termination temporarily confines ovulatory inflammation within a short period.
Ovulation is preceded by intraovarian inflammatory reactions that occur in response to the preovulatory gonadotropin surge. As a main inflammatory event, leukocytes infiltrate the ovary and release ...proteolytic enzymes that degrade the extracellular matrix weakening the follicular wall, a required step for follicle rupture. This study aimed to quantitatively measure the infiltrating leukocytes, determine their cell types, and localize infiltration sites in the periovulatory rat ovary. Cycling adult and gonadotropin-stimulated immature rats were used as animal models. Ovaries were collected at five different stages of estrous cycle in the adult rats (diestrus, 1700 h; proestrus, 1500 h; proestrus, 2400 h; estrus, 0600 h; and metestrus, 1700 h) and at five different time points after superovulation induction in the immature rats (pregnant mare’s serum gonadotrophin, 0 h; pregnant mare’s serum gonadotrophin, 48 h; human chorionic gonadotropin, 6 h; human chorionic gonadotropin, 12 h; and human chorionic gonadotropin, 24 h). The ovaries were either dissociated into a single cell suspension for flow cytometric analysis or fixed for immunohistochemical localization of the leukocytes. Similar numbers of leukocytes were seen throughout the estrous cycle (∼500,000/ovary), except proestrus 2400 when 2-fold higher numbers of leukocytes were found (∼1.1 million/ovary). A similar trend of periovulatory rise of leukocyte numbers was seen in the superovulation-induced immature rat model, recapitulating a dramatic increase in leukocyte numbers upon gonadotropin stimulation. Both macrophage/granulocytes and lymphocytes were among the infiltrating leukocytes and were localized in the theca and interstitial tissues, where platelet-endothelial cell adhesion molecule-1 and intercellular adhesion molecule-1 may play roles in the transmigration of leukocytes, because their expressions correlates spatiotemporally with the infiltrating leukocytes. In addition, a strong inverse relationship between leukocyte numbers in the ovary and spleen, as well as significant reduction of leukocyte infiltration in the splenectomized rats, were seen, indicating that the spleen may serve as an immediate supplier of leukocytes to the periovulatory ovary.
A comprehensive quantitative measurement of leukocyte infiltration in the ovaries of adult and superovulation-induced immature rats is presented.
Pituitary–ovary–spleen axis in ovulation Oakley, Oliver R; Frazer, Michele L; Ko, CheMyong
Trends in endocrinology and metabolism,
09/2011, Letnik:
22, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Leukocytes are rapidly recruited to the preovulatory ovary and play a crucial role as facilitators of ovulation and luteal formation. In this article, recent findings on leukocyte trafficking to the ...ovary, as well as the physiological role of leukocytes in the ovary, will be summarized and discussed. We then explore the novel hypothesis that the hypothalamus–pituitary–ovary (HPO) axis might include the spleen as a reservoir of leukocytes by summarizing recent reports on this topic, both in the fields of immunology and reproductive biology.
17β-estradiol is a potent sex hormone synthesized primarily by gonads in females and males that regulates development and function of the reproductive system. Recent studies show that 17β-estradiol ...is locally synthesized in nonreproductive tissues and regulates a myriad of events, including local inflammatory responses. In this study, we report that mesenteric lymph nodes (mLNs) and Peyer's patches (Pps) are novel sites of de novo synthesis of 17β-estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17β-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17β-estradiol synthesis. Subsequent immunohistochemistry and tissue culture experiments revealed that aromatase expression was localized to high endothelial venules of these lymphoid organs, and these high endothelial venule cells synthesized 17β-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17β-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17β-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-β had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17β-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17β-estradiol content, or steroidogenic capacity in these lymphoid organs.
Objective To describe the development of a multidimensional conceptual framework capable of drawing out the implications for policy and practice of what is known about public involvement in research ...agenda setting.
Background Public involvement in research is growing in western and developing countries. There is a need to learn from collective experience and a diverse literature of research, policy documents and reflective reports.
Methods Systematic searches of research literature, policy and lay networks identified reports of public involvement in research agenda setting. Framework analysis, previously described for primary research, was used to develop the framework, which was then applied to reports of public involvement in order to analyse and compare these.
Findings The conceptual framework takes into account the people involved; the people initiating the involvement; the degree of public involvement; the forum for exchange; and methods used for decision making. It also considers context (in terms of the research focus and the historical, geographical or institutional setting), and theoretical basis.
Conclusions The framework facilitates learning across diverse experiences, whether reported in policy documents, reflections or formal research, to generate a policy‐ and practice‐relevant overview. A further advantage is that it identifies gaps in the literature which need to be filled in order to inform future research about public involvement.
Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality ...rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle.
The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, synonymous to the initial stages of tissue and organ destruction by T-cell responses in organ rejection and Graft-versus-host disease. Using this approach, we examined the effectiveness of two ribonucleotide reductase inhibitors (RRI), Didox and Trimidox, to inhibit T-cell activation and proliferation.
The compounds caused a marked reduction in the proliferative responses of T-cells, which is also accompanied by decreased secretion of cytokines IL-6, IFN-gamma, TNF-alpha, IL-2, IL-13, IL-10 and IL-4.
In conclusion, these data provide critical information to justify further investigation into the potential use of these compounds post allogeneic bone marrow transplantation to alleviate graft-versus-host disease thereby achieving better outcomes.
Despite the use of antimicrobial prophylaxis, cytomegalovirus (CMV) and
Pneumocystis carinii (
PC) pneumonia (PCP) are both leading causes of morbidity and mortality in immunocompromised patients. It ...has previously been reported that CMV infection modulates host immune responses with a variety of mechanisms which include the suppression of helper T cell functions and antigen presenting cell (APC) functions, both of which are critical for PCP resolution. However, the mechanisms of these interactions and other possible immune regulatory effects are not clearly understood. In this study, we investigated the impact of murine CMV (MCMV) induced immunomodulation on the progression of PCP in a co-infection model. Initial results show that dually infected mice had evidence of more severe
PC disease, which include a greater loss of body weight, an excess lung
PC burden and delayed clearance of
PC from lungs, compared to mice with
PC infection alone. At day 7 post-infection, dually infected mice had reduced numbers of MHC-II expressing cells in the lung interstitium and lymph nodes and reduced migration of CD11c
+ cells to both the tracheobronchial lymph nodes and alveolar spaces. Dual infected mice showed elevated numbers of specific CD8 responses concomitant with a decrease in activated CD4
+ T cells in both the lymph nodes and in alveolar spaces when compared to mice infected with MCMV alone. These data suggest that MCMV infection inhibits the immune responses generated against
PC which contribute to the delayed clearance of the organism.
In this study, we investigated the effect of Didox (DX) on the pathogenicity of and host responses to murine cytomegalovirus (MCMV) infection.
In vitro efficacy of DX against MCMV was determined ...using plaque reduction assays. For in vivo studies, mice infected with a sublethal dose (10(4) PFU) of MCMV were treated daily with DX (200 mg/kg) using either a prophylactic or delayed protocol. At predetermined intervals, target organs were removed for histopathology. Cytokine transcription and viral load were performed using real-time PCR. Serum cytokine levels were determined by ELISA, and T-cell markers by real-time PCR.
DX (0.5-50 μM) inhibited MCMV plaque formation in vitro. However, in vivo, prophylactic DX treatment did not decrease viral load and prolonged hepatic proinflammatory cytokine transcription at days 3 and 5 post-infection, which corresponded with more severe histopathological changes observed in the liver. Significant CD8(+) T-cell marker suppression was seen, in accordance with DX-induced inhibition of lymphocyte proliferation observed in vitro. DX prolonged the recovery of MCMV-infected mice when given after infection was established.
Despite promising MCMV inhibition in vitro, DX had no beneficial effect on MCMV disease in our model and paradoxically had adverse effects when administered prophylactically. The lack of correlation between in vitro activity and in vivo efficacy emphasizes the importance of selecting appropriate antiviral targets and of using animal models when testing new drugs.
Oxygen carriers: A selected review Inayat, Mohammed S.; Bernard, Andrew C.; Gallicchio, Vincent S. ...
Transfusion and apheresis science,
02/2006, Letnik:
34, Številka:
1
Journal Article
Recenzirano
The most common and widely transplanted tissue world wide is blood, which in 2000 resulted in the transfusion of 12.5 million units of blood in the US alone Goodnough LT, Shander A, Brecher ME. ...Transfusion medicine: looking to the future. Lancet 2003;361:161–9. The current use of donated blood products is relatively safe; however, there are inherent problems with allogeneic blood transfusions. The wide spread use of blood in procedures results in problems involving inadequate supply exacerbated in times of war and disasters and by the limited storage life of blood donations (30–42 days). Blood contamination due to patient pre-disposition, poor collection, sterilization, or storage is the second most common cause of death from transfusion in the US Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: joint ASH and AABB educational session in transfusion medicine. Hematology (Am Soc Hematol Educ Program) 2003:575–89. Blood is a complex tissue involved in a plethora of homeostatic roles, including immunity, wound healing and the transport of nourishment, electrolytes, hormones, vitamins, heat, oxygen and the removal of metabolic waste products. However, by far the principle role of blood transfusions is the replacement of red cell volume and the maintenance of oxygen levels within the circulation. Creation of investigational new drugs (INDs) which would function as oxygen carriers and prolong shelf life is now a very active arena of scientific research. Several such IND products are now in clinical trials. This article gives an easy to follow concise evaluation of major areas of focus and current testing for each type of blood substitution molecule.
Pituitary-ovarian-splenic axis in ovulation Oakley, Oliver R.; Frazer, Michele L.; Ko, CheMyong
Trends in endocrinology and metabolism,
05/2011, Letnik:
22, Številka:
9
Journal Article
Recenzirano
Leukocytes are rapidly recruited to the preovulatory ovary and play a crucial role as facilitators of ovulation and luteal formation. In this article, recent findings on leukocyte trafficking to the ...ovary, as well as the physiological role of leukocytes in the ovary, will be summarized and discussed. We then explore the novel hypothesis that the hypothalamus-pituitary-ovarian (HPO) axis might include the spleen as a reservoir of leukocytes by summarizing recent reports on this topic, both in the fields of immunology and reproductive biology.
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