EDITOR'S PICK: Calcineurin helps newborns breathe easy
It is only very late in pregnancy that the lungs of the fetus complete their development so that the fetus will be able to breathe air when it is born. As a result, many premature babies suffer from the potentially life threatening respiratory distress syndrome. The proteins that control the final stages of lung development have not been identified. Now, in a study appearing online on September 21, in advance of publication in the October print issue of the Journal of Clinical Investigation, Vrushank Davé and colleagues from the University of Cincinnati, show that in mice a protein known as calcineurin is essential for complete lung development. Mice lacking calcineurin function in the epithelial cells of the lung were unable to breathe properly and died shortly after birth because their lungs failed to develop fully. These effects of calcineurin were mediated by a protein known as NFATc3, which was shown to activate the expression of many of the genes that need to be activated if the final stages of lung development are to proceed normally. This study describes one pathway controlling the final stages of lung development in mice and might help researchers design strategies to treat respiratory distress syndrome in premature babies.
TITLE: Calcineurin/Nfat signaling is required for perinatal lung maturation and function
AUTHOR CONTACT: Vrushank Davé University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Phone: (513) 636-3323 or (513) 636-8410; Fax: (513) 636-7868; E-mail: davev0@cchmc.org.
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PHYSIOLOGY: Modeling the intimate bond between mother and developing fetus
The formation of the placenta during pregnancy is a complex process that involves both fetal and maternal factors. As part of this process, cells of the fetus -- known as cytotrophoblasts -- invade the wall of the womb and interact with maternal blood vessels to help establish a blood supply to the fetus. It has been difficult to understand how this process is regulated (and therefore how or why it might go wrong in some instances, such as preeclampsia) because there has been no way to study it in vivo. Now, in a study appearing online on September 21, in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from UCSF, have developed an in vivo mouse model of human placental development.
Susan Fisher and colleagues transplanted human placental tissue to mice unable to mount an immune response (and therefore unable to reject human tissue). Cytotrophoblasts were shown to invade mouse tissue and to interact with the mouse blood vessels by causing the cells of the blood vessels to undergo a form of cell death known as apoptosis. The cytotrophoblasts were also shown to stimulate the formation of vessels that carry fluid and cells of the immune system around the body, perhaps helping maintain the correct fluid balance in the placenta and improving surveillance for signs of infection that might damage the growing fetus. Further analysis using this model of in vivo placental development should provide new insight into the processes by which the fetus establishes its own blood supply and therefore new understanding of how defects in this process might lead to complications in pregnancy.
TITLE: Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation
AUTHOR CONTACT: Susan J. Fisher University of California, San Francisco, San Francisco, California, USA. Phone: (415) 476-5297; Fax: (415) 502-7338, E-mail: sfisher@cgl.ucsf.edu.
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IMMUNOLOGY: Lymph nodes and lymph node–like structures: not as similar as they seem
Individuals with Hashimoto thyroiditis, which is an autoimmune disease caused by the immune system attacking and destroying the cells of the thyroid, have structures that resemble lymph nodes in their thyroid. Much is known about the formation of lymph nodes and it has been suggested that the lymph node–like structures in the thyroid form in similar ways. Now, in a study appearing online on September 21 in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from Mount Sinai School of Medicine, New York, have shown that in mice lymph node–like structures in the thyroid are formed in a different way to normal lymph nodes.
Sergio Lira and colleagues showed that the cells that organize the development of lymph nodes (lymphoid tissue–inducer cells) are not required for the development of lymph node–like structures in the thyroid. Rather, mature CD3+CD4+ T cells initiated this process. These T cells entered the thyroid and interacted with a thyroid-resident cell type, the dendritic cell, to induce the formation of lymph node–like structures. The model of the formation of lymph node–like structures in the thyroid described in this study should allow researchers to determine whether these structures are important for disease progression and, if they are, to design strategies to block their formation.
TITLE: Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid
AUTHOR CONTACT: Sergio A. Lira Mount Sinai School of Medicine, New York, New York, USA. Phone: (212) 659-9404; Fax: (212) 849-2525; E-mail: sergio.lira@mssm.edu.
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CARDIOLOGY: MITF finds a new job in the heart
The heart is able to respond to its surroundings; so, if more power is needed to pump the blood around the body, for example in individuals with high blood pressure, it can increase the size of the muscle cells of the heart (a process known as cardiac hypertrophy). Now, in a study appearing online on September 21 in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from Hebrew University, Israel, have found that mice lacking a fully functional form of the protein MITF have smaller hearts than normal mice and that they are at increased risk of death in situations when the heart should respond by increasing the size of its muscle cells.
Although MITF was known to be expressed in the heart, its function there had not been previously studied. So, Ehud Razin and colleagues analyzed the hearts of mice lacking functional MITF. When mice of similar weights, which should have similar sized hearts, were compared, the mice lacking functional MITF had smaller hearts than normal mice. This inability to increase the size of the heart during development was also seen in situations that require a rapid cardiac hypertrophy response, and mice lacking MITF were more susceptible to death in these situations. This study identifies MITF as a regulator of both normal cardiac development and cardiac hypertrophy, but further work will be needed to understand how MITF is controlled during these two distinct processes.
TITLE: Transcription factor MITF regulates cardiac growth and hypertrophy
AUTHOR CONTACT: Ehud Razin Hebrew University Medical School, Jerusalem, Israel. Phone: +972-2-675-8288 Fax: +972-2-675-8986; E-mail: ehudr@cc.huji.ac.il.
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INFLAMMATION: Platelets do the two-step to activate COX2
Chronic inflammation is a feature of many diseases, including heart disease and rheumatoid arthritis. One protein whose overexpression is thought to have a crucial role in maintaining the chronic inflammatory state is cyclooxygenase 2 (COX2). However, the mechanisms regulating COX2 expression have not been well defined. Now, in a study appearing online on September 21 in advance of publication in the October print issue of the Journal of Clinical Investigation, Dan Dixon and colleagues from the University of South Carolina, have shown that in human cells COX2 expression is controlled by a two-step process. The first step is controlled directly by interactions between monocytes (a type of inflammatory cell) and activated platelets, which activate expression of the COX2 gene. The second step is also initiated by interactions between monocytes and activated platelets but it is indirect: activated platelets induce monocytes to produce a soluble factor known as IL-1-beta, which then acts on the monocytes to enable them to produce COX2 protein. Because COX2 is overexpressed in chronic inflammatory conditions, the authors suggest that one, or both, of these two control steps might be dysregulated in disease.
TITLE: Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling
AUTHOR CONTACT: Dan A. Dixon University of South Carolina, Columbia, South Carolina, USA. Phone: (803) 434-3713; Fax: (803) 434-3795; E-mail: ddixon@biol.sc.edu.
Adam Cohen Press Officer Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Phone: (405) 272-7159; E-mail: Adam-cohen@omrf.ouhsc.edu.
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PARASITOLOGY: Brucipain gives parasite open access to the brain
It is estimated that 40,000 people in sub-Saharan Africa die every year of sleeping sickness. Sleeping sickness occurs when individuals become infected with one of two parasites, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. The final stages of the disease are characterized by neurological defects and occur when the parasite leaves the bloodstream and enters the brain. The mechanisms by which the parasites invade the brain have not been well defined. Now, in a study using human cells in culture, which appears online on September 21 in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from Johns Hopkins School of Medicine, have shown that the T. b. gambiense protein brucipain, which can destroy other proteins, enables the parasite to get past the cells that act as a barrier between the blood and the brain.
Dennis Grab and colleagues showed that inhibitors of brucipain prevented T. b. gambiense getting past the cells that act as a barrier to entry into the brain. Conversely, a mixture of the soluble factors produced by T. b. gambiense, which includes brucipain, helped a related parasite T. b. brucei that normally cannot get past these barrier cells cross the barrier. Further analysis showed that brucipain activates the cells that form the barrier to the brain, but exactly how this provides T. b. gambiense access to the brain remains to be determined.
TITLE: Blood-brain barrier traversal by African trypanosomes requires calcium signaling induced by parasite cysteine protease
AUTHOR CONTACT: Dennis J. Grab Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Phone: (410) 614-3917; Fax: (410) 614-1491; E-mail: dgrab@jhmi.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27798
Journal
Journal of Clinical Investigation