December 2002
From Journal of Clinical Investigation
JCI Table of Contents, December 2, 2002**Please mention the Journal of Clinical Investigation as the source of these articles** Find below two highlighted articles and the full Table of Contents for the December 2, 2002 issue ***************************************************** Restoration of Faulty Blood Vessel Architecture by Angiopoietin-1 Angiogenesis (the growth of new blood vessels) requires complex signaling between multiple cell types, and abnormalities in these pathways results in faulty vessels. During normal vessel formation endothelial cells that comprise the blood vessel communicate, through a number of secreted agents called growth factors, with a family of cells known as mural cells. Endothelial cells secrete the growth factor PDGF B that is bound to mural cells by the PDGF-b receptor. Murals cells are then recruited to the new vessel where upon direct interaction with endothelial cells they secrete angiopoietin-1 (Ang1). Multiple roles in vessel maturation have been designated to Ang1 and they include sprouting, survival and stability of the new vessel. However, the exact nature of its involvement is unclear. The critical interactions between endothelial cells and mural cells facilitate the growth and maturation of new blood vessels. In diseases such as diabetic retinopathy, mural cells are absent from the vessel maturation process, which results in abnormal vessels growing on top of the retina, which can lead to blindness. The complex mechanisms by which mural cells regulate the activity of endothelial cells is also unclear. One way to investigate this relationship would be to develop an experimental system in which mural cells and endothelial cells are separated, yet new blood vessels still develop. As this development usually happens in the early embryo, it has been a difficult experimental system to manipulate. In the December 2 issue of the Journal of Clinical Investigation, Akiyoshi Uemura and colleagues from Kyoto University, Japan, describe such a system in the retinal vasculature of a newborn mouse -- an environment in which this vessel development occurs after birth. The authors demonstrated that when they blocked the PDGF-b receptor, mural cell recruitment to the developing retinal vessels did not occur and the newly formed vessels were leaky and poorly organized. The authors then describe the partial restoration of large vessel structure, in the absence of mural cells, following the addition of angiopoietin-1 modified from its native form (Ang1*). This indicates that Ang1 is a critical regulator of the postnatal development of blood vessels in the mouse retina. In her accompanying commentary, Patricia D'Amore from the Schepens Eye Research Institute and Harvard Medical School notes that "as the authors themselves point out, the rescue affected by the addition of Ang1* of the pericyte-free retinal vasculature was incomplete, indicating involvement of other mural-cell derived molecules in the fine-tuning of vascular networks. Thus, the association of the pericyte with the vessel accomplishes more than local Ang1 delivery". A more clear understanding of the role of pericytes in the maintenance of normal vessel stability will be important for anti-angiogenic therapies aimed at vessel regression, such a diabetic retinopathy. CONTACT:
Akiyoshi Uemura
Kyoto University, Graduate School of Medicine
Department of Molecular Genetics
53 Kawahara-cho
Shogoin, Sakyo-ku Kyoto 606-8507
JAPAN
Phone: 8175-751-4162
Fax: 8175-751-4169
E-mail: auemura@kuhp.kyoto-u.ac.jp View the PDF of this article at: https://www.the-jci.org/press/15621.pdf *****************************************************
ACCOMPANYING COMMENTARY:
Getting Tie(2)d up in angiogenesis CONTACT:
Patricia A. D'Amore
The Schepens Eye Research Institute
20 Staniford Street
Boston, MA 02114
USA
Phone: 617-912-2559
Fax: 617-912-0128
E-mail: pdamore@vision.eri.harvard.edu View the PDF of this commentary at: https://www.the-jci.org/press/17326.pdf ******************************************************
Alternative treatment for secretory diarrhea linked to the cystic fibrosis gene Secretory diarrhea is the leading cause of death in children less than 5 years of age in developing countries, and a frequent and most unwelcome diagnosis for many adults that is made, on average, up to four times each year. Many common causes of diarrhea exist: bacterial or viral infections resulting from consumption of contaminated food or water; food intolerances; reactions to medicines; bowel disorders and intestinal diseases. Diarrhea results when cells lining the intestine secrete an excess of chloride, via a chloride channel within the cell, as well as sodium in reaction to one of these causal agents. The high level of resulting salt in the intestine causes water removed from the blood to be directed to the gut, thereby producing fluid diarrhea. The most serious and life-threatening development during a bout of diarrhea is dehydration due to continued removal of water from the circulation. In 1989 the cystic fibrosis gene was identified and found to encode a chloride channel in cells lining the lung. Recognized as the cystic fibrosis transmembrane conductance regulator (CFTR), no compounds were known to inhibit the activity of this channel - until now. In the December 2 issue of the Journal of Clinical Investigation, Alan Verkman and colleagues at the Cardiovascular Research Institute at the University of California, San Francisco, developed a high-throughput screening assay to identify compounds that inhibit the activity of CFTR. The authors identified an organic compound, thiazolidinone, effective in inhibiting CFTR-mediated chloride secretion. To test the therapeutic value of thiazolidinone the authors investigated it's utility in mice suffering secretory diarrhea. The authors reported a successful reduction of excess intestinal fluid secretion via inhibition of the chloride channel within cells lining the gut. Will this drug, or its derivatives, be useful in the treatment of secretory diarrhea? In his accompanying commentary Dr. Qais Al-Awqati from the Department of Medicine at Columbia University in New York comments that "the use of the new chloride channel-blockers confers some specificity allowing these compounds to be used in the treatment of diarrhea with impunity". Dr. Al-Awqati does however point out that many infections that cause diarrhea are self-limiting and "the aim of medical therapy remains the prevention and treatment of severe dehydration, making oral rehydration the standard of care". Oral rehydration therapy (ORT), officially endorsed by the World Health Organization and UNICEF in 1975, is the oral administration of a sugar and salts solution that reverses the dehydration caused by diarrhea. In this world of high-tech medicine, it is humbling to observe that such a simple recipe is capable of decreasing the mortality rate associated with diarrheal diseases. Perhaps the most promising conclusion drawn from the work by Verkman and coworkers is that as researchers have been unable to adequately define how defective CFTR leads to airway disease in current mouse models of cystic fibrosis, highly specific CFTR-inhibitors such as thiazolidinone should be useful in determining the role of this chloride channel. It should also aid drug-mediated creation of a more suitable animal model of cystic fibrosis that more closely mimics this disease in humans. CONTACT:
Alan S. Verkman
University of California, San Francisco
Cardiovascular Research Institute
Departments of Medicine and Physiology
1246 Health Sciences East Tower, Box 0521
San Francisco, CA 94143-0521
USA
Phone: 415-476-8530
Fax: 415-665-3847
E-mail: verkman@itsa.ucsf.edu View the PDF of this article at: https://www.the-jci.org/press/16112.pdf *****************************************************
ACCOMPANYING COMMENTARY:
Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors CONTACT:
Qais Al-Awqati
Dept. Of Medicine & Physiology
Columbia U. College Of Phys. & Surgeons
630 W. 168th Street
New York, NY 10032
USA
Phone 1: 212-305-3512
Fax 1: 212-305-3475
E-mail: qa1@columbia.edu View the PDF of this commentary at: https://www.the-jci.org/press/17301.pdf ******************************************************
Epimorphin expression in intestinal myofibroblasts induces epithelial morphogenesis
Epimorphin is a mesenchymal protein expressed in the fetal gastrointestinal tract during villus morphogenesis as well as in the adult intestine during villus repair after injury. To study the gene's function, Deborah Rubin and colleagues altered epimorphin expression in a myofibroblast cell line that expresses low levels of endogenous protein and examined the effects both on cocultured gut epithelial cells and in a graft model. The results (pages1629-1641) suggest that epimorphin has a role in gut ontogeny, and that it exerts its function at least in part via secreted factors, including members of the bone morphogenetic protein family. This is consistent with epimorphin's putative cellular function as a member of the syntaxin family of vesicle docking proteins, and provides support to the growing notion that syntaxins affect specific developmental processes. CONTACT:
Deborah Rubin
GI Division
Washington University School of Medicine
660 S. Euclid Ave. Box 8124
St. Louis, MO 63110
USA
Phone: 314-362-8935
Fax: 314-362-8935
E-mail: DRUBIN@IM.WUSTL.EDU View the PDF of this article at: https://www.the-jci.org/press/13588.pdf *****************************************************
Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids Corticosteroids reduce ischemic injury in myocardial infarction and reduce stroke size in focal cerebral ischemia. Having recently shown that nontranscriptional effects of the glucocorticoid receptor (GR) are responsible for the anti-inflammatory cardio-protective effects, James Liao and colleagues report now on the mechanisms of the anti-ischemic neuroprotective effects of corticosteroids. In an article beginning on page 1729, the researchers show that high doses of steroids, given within two hours of transient cerebral ischemia, trigger GR-association with phosphatidylinositol 3-kinase (PI3K) and activation of PI3K and Akt. This in turn activates endothelial nitric oxide synthase, thereby increasing cerebral blood flow by 40--50% and reducing cerebral infarct size by 30%. These effects were rapid and nontranscriptional, and while they required doses at least ten times as high as those required for a genomic response by the GR, they appeared specifically mediated by the receptor. CONTACT:
James K. Liao
Vascular Medicine Unit
Brigham & Women's Hospital
65 Landsdowne Street, Room 275
Boston, MA 02139
USA
Phone: 617-768-8424
Fax: 617-768-8425
E-mail: jliao@rics.bwh.harvard.edu View the PDF of this article at: https://www.the-jci.org/press/15481.pdf ******************************************************
Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency Postmenopausal drops in estrogen levels cause increased bone resorption without compensatory increase in bone formation -- resulting in net bone loss and osteoporosis. The absence of estrogen leads to elevated levels of IL-7, and M. Neale Weitzmann and colleagues have examined the effects of this cytokine on bone metabolism in ovariectomized mice. Their findings (pages 1643--1650) suggest a critical role for IL-7 in the uncoupling of bone resorption from bone formation. High IL-7 levels promote osteoclastogenesis on one hand, and inhibit osteoblast differentiation and activity on the other. By affecting both pathways, IL-7 seems central to the altered bone turnover characteristic of estrogen deficiency. CONTACT:
M. Neale Weitzmann
Barnes-Jewish Hospital
Division of Bone and Mineral Diseases
MS 90-32-656
216 S. Kingshighway Boulevard
Saint Louis, MO 63110
USA
Phone: 314-454-8829
Fax: 314-454-5047
E-mail: nweitzmann@usa.net View the PDF of this article at: https://www.the-jci.org/press/15687.pdf ******************************************************
Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner Cellular senescence is a state of terminal arrest in which cells remain metabolically active for extended periods but can no longer respond to mitogenic stimulation. Several tumor suppressor genes are involved in induction and maintenance of senescence, suggesting that senescence prevents tumorigenesis. Hoping to find a new way to prevent or treat cancer, Heiko Hermeking and colleagues (pages 1717--1727) have searched for agents that induce senescence without inducing DNA damage. As expression profiling associated downregulation of cGMP signaling with senescence, the researchers focused their screen on inhibitors of this pathway. One of them, an inhibitor of guanylate cyclase, induced cellular senescence. The effect was dependent on p21 (which was upregulated in response to the drug), but not on p53. The latter result suggests that the drug does not induce DNA damage, which is responsible for risks and side effects of most other chemotherapeutic agents. CONTACT:
Heiko Hermeking
Max-Planck-Institute of Biochemistry
Molecular Oncology
Am Klopferspitz 18A
Matinstried, Munich, D-82152
GERMANY
Phone: 49-89-8578-2875
Fax: 49-89-8578-2540
E-mail: herme@biochem.mpg.de View the PDF of this article at: https://www.the-jci.org/press/16588.pdf ********************************************************
A monoclonal thyroid-stimulating antibody
Autoantibodies that activate the thyrotropin receptor and stimulate thyroid function cause Graves disease. Such antibodies would be valuable reagents in better understanding the complex molecular biology of receptor activation as well as potential therapeutic thyroid stimulators. An article in this issue (pages 1667--1674) now reports the successful isolation of an activating antibody. Using an Armenian hamster model of Graves disease, Takao Ando and colleagues isolated a monoclonal antibody that is a potent activator of the thyrotropin receptor. Like the autoantibodies, the monoclonal antibody is stimulatory at nanogram concentrations, but whereas binding of the endogenous hormone ligand promotes cleavage of the receptor into two subunits, binding of the antibody did not. This difference suggests a novel mechanism underlying the prolonged overstimulation of the thyroid gland in Graves disease. CONTACT:
Takao Ando
Mount Sinai School of Medicine
One Gustave L Levy Place
Annenberg 23-66A
New York, NY 10029
USA
Phone: 1-212-241-8148
E-mail: takao.ando@mssm.edu View the PDF of this article at: https://www.the-jci.org/press/16991.pdf *********************************************************
CCR4-bearing T cells participate in autoimmune diabetes CONTACT:
Nora Sarvetnick
The Scripps Research Institute
IMM-23
10550 N. Torrey Pines Rd.
La Jolla, CA 92037
USA
Phone: 858-784-9066
Fax: 858-784-9083
E-mail: noras@scripps.edu View the PDF of this article at: https://www.the-jci.org/press/15547.pdf *****************************************************
ACCOMPANYING COMMENTARY:
Fatal attraction: chemokines and type 1 diabetes CONTACT:
Mark A. Atkinson
University of Florida College of Medicine
Dept. of Pathology, Immunology and Laboratory Medicine
ARB-R3-128
1600 SW Archer Road
Gainesville, FL 32610-0275
USA
Phone: 352-392-0048
Fax: 352-392-8464
E-mail: atkinson@ufl.edu View the PDF of this commentary at: https://www.the-jci.org/press/17311.pdf *********************************************************
T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase CONTACT: Mark Musch
Dept. Of Medicine, GI Unit
Univ. Of Chicago School Of Medicine
5841 S. Maryland Ave., Box 400
Chicago, IL 60637-1463
USA
Phone: 773-702-2283
Fax: 773-702-2281
E-mail: mmusch@medicine.bsd.uchicago.edu View the PDF of this article at: https://www.the-jci.org/press/15695.pdf *********************************************************
Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle CONTACT:
Blake B. Rasmussen
University of Southern California
Department of Kinesiology
University Park
PED 107
Los Angeles, CA 90089-0652
USA
Phone: 213-821-2846
Fax: 213-740-7909
E-mail: blakeras@usc.edu View the PDF of this article at: https://www.the-jci.org/press/15715.pdf *****************************************************
ACCOMPANYING COMMENTARY:
Fatty acid oxidation in human skeletal muscle CONTACT:
Michael D. Jensen
Endocrine Research Unit
Mayo Clinic, 5-164 West Joseph
200 First Street, SW
Rochester, MN 55905
USA
Phone: 507-255-6449
Fax: 507-255-4828
E-mail: jensen.michael@mayo.edu View the PDF of this commentary at: https://www.the-jci.org/press/17303.pdf ********************************************************* Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury CONTACT:
Robert Streiter
UCLA School of Medicine
900 Veteran Ave.
14-154 Warren Hall, Box 711922
Los Angeles, CA 90024-1922
USA
Phone: 310-794-1999
Fax: 310-794-1998
E-mail: rstrieter@mednet.ucla.edu View the PDF of this article at: https://www.the-jci.org/press/15849.pdf *****************************************************
ACCOMPANYING COMMENTARY:
Neutrophils and lung injury: getting it right CONTACT:
Thomas R. Martin
Seattle VA Medical Center
1660 S. Columbian Way, Mail Stop 151L
Seattle, WA 98108
USA
Phone: 206-764-2219
Phone 2: 206-764-2568
Fax: 206-768-5289
E-mail: trmartin@u.washington.edu View the PDF of this commentary at: https://www.the-jci.org/press/17302.pdf *********************************************************
NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele CONTACT:
Martin Pollack
Brigham And Women's Hospital
77 Avenue Louis Pasteur
Boston, MA 02115-5727
USA
Phone: 617-525-5840
Fax: 617-525-5841
E-mail: mpollak@rics.bwh.harvard.edu View the PDF of this article at: https://www.the-jci.org/press/16242.pdf *********************************************************
Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1 CONTACT:
Anne K. Soutar
MRC Clinical Sciences Centre
Imperial College Faculty of Medicine
Hammersmith Hospital
DuCane Road
London, Null W12 ONN
UNITED KINGDOM
Phone: +44-208-383-2324
Fax: +44 208-383-2077
E-mail: anne.soutar@csc.mrc.ac.uk View the PDF of this article at: https://www.the-jci.org/press/16445.pdf | 