As premature infants often have under-developed lungs, oxygen is administered following birth. One devastating side effect, however, is the development of retinopathy of prematurity (ROP), whereupon oxygen administration to the infant suppresses the expression of essential growth factors that promote the development of retinal blood vessels, resulting in blindness. In the July 1 issue of the Journal of Clinical Investigation, a study by researchers at Harvard Medical School and Children's Hospital, Boston investigating the development of the retinal vasculature in mice demonstrates that specific activation of the receptor VEGFR-1 by the growth factor PlGF-1 protects against oxygen-induced vessel loss.
ROP occurs in two distinct stages. First, exposure to high levels of oxygen causes obliteration of immature retinal vessels. The second phase, initiated upon return to breathing normal air, results in an adverse overcompensation of new vessel growth. The new vessels are excessive in number and often leaky. The inner membrane of the retina can be breached, whereby vessels grow into the vitreous of the eye causing retinal detachment and blindness.
The process of vasculature development is mediated in part by the growth factor VEGF. It had been shown previously that vessels can be rescued by administration of VEGF, suggesting that VEGF might be used in the treatment of ROP. However, this theory presents a double-edged sword as VEGF also stimulates abnormal vessel growth that can ultimately result in leaky vessels.
In order to wisely skirt this catastrophic event, Lois E. H. Smith and colleagues utilized placental growth factor-1 (PlGF-1), which exclusively activates the VEGF receptor-1 (VEGFR-1). The authors demonstrate that the administration of PlGF-1 protects against oxygen-induced vessel loss without provoking neovascularization. Unlike VEGF, which interacts with both forms of the VEGF receptor (VEGFR-1 and VEGFR-2), PlGF-1 only binds VEGFR-1.
These results suggest that PlGF-1 could be harnessed as a therapeutic agent to stabilize vessel growth. "Clearly, the case of ROP is unique, considering the defined nature of the pathogenic insult, its relatively short duration, and its predetermined onset. These characteristics, in conjunction with the fact that the vitreous is a close, immunoprivileged compartment and that the superficial retinal vessels are accessible to injected reagents, increase the likelihood of success" states Dr. Eli Keshet, from the Hebrew University-Hadassah Medical School in Jerusalem, Israel in his accompanying commentary. In addition, as it is the specific activation of VEGFR-1, and not VEGFR-2, that protects against oxygen-induced vessel loss, targeting VEGFR-1 with additional pharmacological activators may also control vessel degeneration in ROP and other retinopathies.
TITLE: Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity
AUTHOR CONTACT:
Lois E. H. Smith
The Children's Hospital, Boston, Massachusetts, USA.
Phone: 617-355-6499
Fax: 617-734-5731
Email: lois.smith@tch.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17808.pdf
ACCOMPANYING COMMENTARY:
Preventing pathological regression of blood vessels
AUTHOR CONTACT:
Eli Keshet
The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Phone: 972-2-6758496
Fax: 972-2-6757195
Email: keshet@cc.huji.ac.il
View the PDF of this commentary at: https://www.the-jci.org/press/19093.pdf
2. Fibroleukin at fault in viral hepatitis
Unlike other virus-induced diseases, acute and chronic liver disease caused by the hepatitis B virus are not the result of direct viral-induced tissue destruction, but rather a consequence of the host immune response to the virus. Two such responses to viral hepatitis B infection are the deposition of fibrin and thrombosis within the small blood vessels of the liver. Activated endothelial cells and macrophages express procoagulants including a novel prothrombinase, Fgl2/fibroleukin, important for the initiation and localization of fibrin deposition. In the July 1 issue of the Journal of Clinical Investigation, Philip Marsden and colleagues from the University of Toronto, Canada, show that mice lacking Fgl2/fibroleukin fail to develop a procoagulant response to infection with hepatitis B. In addition, the authors show that in humans with chronic hepatitis B virus infection, expression of the Fgl2/fibroleukin gene is high and fibrin is deposited in the liver. Collectively, these studies indicate a critical role for Fgl2/fibroleukin in the pathophysiology of viral hepatitis and suggest that inhibition of this prothrombinase may be important for the treatment of inflammatory diseases not only of the liver but also of other tissues.
TITLE: The Fgl2/fibroleukin prothrombinase contributes to immunologically-mediated thrombosis in experimental and human viral hepatitis
AUTHOR CONTACT:
Philip A. Marsden
University of Toronto, Toronto, Ontario, Canada.
Phone: 416-978-2441
Fax: 416-978-8765
E-mail: p.marsden@utoronto.ca
View the PDF of this article at: https://www.the-jci.org/press/18114.pdf
Uncovering the link between obesity and high blood pressure
A decrease in body weight lowers blood pressure in obese hypertensive patients, suggesting a close association between energy balance and blood pressure. The mechanisms underlying hypertension in obesity, however, have not been fully elucidated. Researchers at Harvard Medical School, and the Universities of Edinburgh and Dundee, Scotland have revealed a potential role of the hormone glucocorticoid in fatty tissue in the induction of hypertension in obese individuals.
TITLE: Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
AUTHOR CONTACT:
Jeffrey S. Flier
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-667-9050
Fax: 617-667-9054
E-mail: jflier@caregroup.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17845.pdf
Stem cells repair injured kidney
Researchers have long thought that upon injury to the renal tubule in the kidney, surviving cells in the area of injury migrate to the injury site, multiply, and rebuild damaged tissue. Researchers at Yale University Medical School have now demonstrated that following renal injury in mice, bone marrow-–derived stem cells home to the site of injury, differentiate into cells specific for that area, and comprise the majority of cells repairing the injury. The study challenges the existing theory of kidney repair and suggests that approaches aimed at bone marrow-derived stem cell propagation and delivery to the kidney should be pursued in attempts to treat this disease and possibly the repair of other solid organs.
TITLE: Bone marrow stem cells contribute to repair of the ischemically injured renal tubule
AUTHOR CONTACT:
Lloyd G. Cantley
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-7110
Fax: 203-785-4904
Email: lloyd.cantley@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/17856.pdf
Specific donor cell selection during bone marrow transplant achieves immune reconstitution without recipient rejection
Graft-versus-host disease (GVHD), a common and serious complication of bone marrow transplantation where there is a reaction of donated bone marrow against a patient's own tissue, represents a major cause of morbidity and mortality. A study in mice by researchers at Yale University has now shown that the selective administration of donor memory CD4+ T cells results in immune reconstitution in the recipient without GVHD, a result that if translatable to humans has important clinical implications for stem cell transplantation.
TITLE: Memory CD4+ T cells do not induce graft-versus-host disease
AUTHOR CONTACT:
Warren D. Shlomchik
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-737-2478
Fax: 928-395-8571
E-mail: warren.shlomchik@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/17601.pdf
ACCOMPANYING COMMENTARY:
Pleasant memories: remembering immune protection while forgetting about graft-versus-host disease
AUTHOR CONTACT:
Paul M. Sondel
University of Wisconsin, Madison, Wisconsin, USA.
Phone: 608-263-9069
Fax: 608-263-4226
Email: pmsondel@wisc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19095.pdf
Fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver disease
Researchers at the University of Auckland, New Zealand, and The University of Hong Kong, China, demonstrate that the fat-derived hormone adiponectin modulates sensitivity to both alcohol- and nonalcohol-induced liver injury. Delivery of recombinant adiponectin into mice suffering from fatty liver disease successfully alleviated inflammation, enlargement, and fatty degeneration of the liver. The results suggest a potential clinical application of adiponectin in the treatment of liver diseases.
TITLE: The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice
AUTHOR CONTACT:
Aimin Xu
University of Auckland, Auckland, New Zealand.
Phone: 64-9-373-7599 ext. 87243
Fax: 64-9-373-7416
E-mail: amxu@hkucc.hku.hk or a.xu@auckland.ac.nz
View the PDF of this article at: https://www.the-jci.org/press/17797.pdf
Researchers develop strategy to prevent programmed death of immune cells and increase DNA vaccine potency
DNA vaccines deliver DNA of pathogenic antigens to dendritic cells (DCs), which in turn prime the immune system to produce antigen-specific T cells prepared to fight infection. DCs have a limited life span however, which decreases their long-term ability to prime these T cells. Investigators at The Johns Hopkins Medical Institutions have revealed an innovative strategy whereby co-delivery of DNA vaccines with DNA encoding anti-apoptotic proteins inhibits the programmed self-destruction of DCs and enhances vaccine potency.
TITLE: Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins
AUTHOR CONTACT:
T. -C. Wu
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: 410-614-3899
Fax: 443-287-4295
E-mail: wutc@jhmi.edu
View the PDF of this article at: https://www.the-jci.org/press/17293.pdf
ACCOMPANYING COMMENTARY:
DNA vaccines and apoptosis: to kill or not to kill?
AUTHOR CONTACT:
Nicholas P. Restifo
National Cancer Institute, Bethesda, Maryland, USA.
Phone: 301-496-4904
Fax: 301-402-0922
Email: restifo@nih.gov
View the PDF of this commentary at: https://www.the-jci.org/press/19069.pdf
Cystic fibrosis study reveals second chloride transport abnormality
Cystic fibrosis (CF) is characterized in part by the inadequate absorption of nutrients from the small intestine. A result of genetic defects in epithelial cell chloride channels, it has long been accepted that CF patients suffered from defective chloride secretion. Researchers from Baylor University and the Children's Medical Center, Dallas, Texas and the University of Graz, Austria now present evidence of a second chloride transport abnormality in CF intestine: a strong reduction in passive chloride absorption.
TITLE: Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect
AUTHOR CONTACT:
John S. Fordtran
Baylor University Medical Center, Dallas, Texas, USA.
Phone: 214-820-2672
Fax: 214-820-4837
E-mail: johnfo@baylorhealth.edu
View the PDF of this article at: https://www.the-jci.org/press/17667.pdf
Stem cells hold their breath: Low oxygen levels increase stem cell survival
Researchers at the University of Pennsylvania and the London Research Institute reveal that low oxygen levels, commonly found in the microvasculature of the bone marrow, are important for the survival, self-renewal, and differentiation of human bone marrow–derived hematopoietic stems cells (HSCs). The researchers demonstrated that the use of low oxygen levels in vitro improved bone marrow cell survival compared to survival under normal oxygen levels, and also allowed increased expansion of these cells by more than 4-fold normal levels. These findings represent an important advance in ex vivo expansion of human HSCs and may have important clinical implications.
TITLE: Expansion of human SCID-repopulating cells under hypoxic conditions
AUTHOR CONTACT:
Guénahel H. Danet
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215-573-3705
Fax: 215-573-7049
Email: gdanet@mail.med.upenn.edu
View the PDF of this article at: https://www.the-jci.org/press/17669.pdf
Prostaglandin release in the kidney regulates salt and water balance
Macula densa (MD) cells in the kidney are important regulators of salt and water balance within the body, however the signaling mechanisms underlying this tightly controlled regulation were previously undefined. Collaboration between researchers at the University of Alabama at Birmingham, Vanderbilt University, the Hungarian Academy of Sciences, and Semmelweis University in Budapest has facilitated the development of a novel biosensor tool to measure prostaglandin E2 (PGE2) release from the MD. The study provides the first direct evidence that intact MD cells synthesize and release PGE2 during reduced luminal salt content and suggest that this response is important in the control of salt and water balance during salt deprivation.
TITLE: Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells
AUTHOR CONTACT:
János Peti-Peterdi
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: 205-934-5783
Fax: 205-934-1147
E-mail: petjan@uab.edu
View the PDF of this article at: https://www.the-jci.org/press/18018.pdf
Del-1 drives development of new blood vessels in injured muscle
The development of new blood vessels from an existing network of vessels, known as angiogenesis, occurs during embryonic development, cancer, arthritis, and in response to a lack of oxygen supplied by the blood to surrounding tissue. Researchers at the University of California, Stanford University, and the Scripps Research Institute in California have used the extracellular matrix protein Del-1 to enhance vessel development and accelerate the recovery of tissue function in two models muscle ischemia. This angiogenic matrix protein Del-1 may be a useful tool for the therapy of ischemic disease.
TITLE: Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1
AUTHOR CONTACT:
Judith A. Varner
University of California, San Diego, California, USA.
Phone: 858-822-0086
Fax: 858-822-1325
E-mail: jvarner@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/17034.pdf
Researchers identify a new type of human immunodeficiency syndrome: HIGM type 4
Hyper-IgM syndrome (HIGM) is a primary immunodeficiency characterized by normal to elevated serum levels of IgM and low levels or the absence of IgG, IgA, and IgE. A large collaborative study by researchers in France, Italy, Hungary, Japan, Turkey, and the United Kingdom characterized HIGM type 4, a previously undocumented defect in antibody gene diversification caused by a selective block in class-switch recombination, providing significant insight towards understanding HIGM immunodeficiencies.
TITLE: Hyper-IgM syndrome type 4 with a B lymphocyte–intrinsic selective deficiency in Ig class-switch recombination
AUTHOR CONTACT:
Anne Durandy
ISERM, Hôpital Necker-Enfants Malades, Paris, France.
Phone: 33-1-44-49-50-89
Fax: 33-1-42-73-06-40
Email: durandy@necker.fr
View the PDF of this article at: https://www.the-jci.org/press/18161.pdf
ACCOMPANYING COMMENTARY:
Novel antibody switching defects in human patients
AUTHOR CONTACT:
Frederick W. Alt
Howard Hughes Medical Institute, The Children's Hospital, Boston, Massachusetts, USA.
Phone: 617-355-0290
Fax: 617-738-0432
Email: alt@enders.tch.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19091.pdf
Angiotensin II and its receptor revealed as target for blocking tumor angiogenesis and growth
The renin-angiotensin system (RAS) plays an important role in the regulation of vascular wellbeing, however the role of RAS in the supply of new blood vessels to tumors is not well understood. Researchers from Nagoya University, Japan, and colleagues have demonstrated that mice lacking the angiotensin II (ATII) type 1a (AT1a) receptor exhibit slower growing tumors and an increased survival rate compared to controls. The study indicates that the ATII-AT1 receptor pathway supports tumor-related angiogenesis and growth, which hints at a possible new therapeutic target against tumors.
TITLE: Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth
AUTHOR CONTACT:
Toyoaki Murohara
Nagoya University, Nagoya, Japan.
Phone: 81-52-744-2149
Fax: 81-52-744-2157
E-mail: murohara@med.nagoya-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/16645.pdf
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