JCI table of contents, February 9, 2006


The smoking gun: elastin fragments drive emphysema

Pulmonary emphysema is caused primarily by cigarette smoking, and the underlying cellular mechanisms are thought to involve smoke-induced activation of tissue degrading enzymes known as proteases. Elastases are proteases that specifically degrade the structural protein elastin and include enzymes such as MMP-12 (matrix metalloproteinase –12, also called macrophage metalloelastase), which is secreted by inflammatory cells called macrophages. Now, researcher A. McGarry Houghton and colleagues at Harvard Medical School in Massachusetts, report that elastases cause emphysema in mice through the generation of pro-inflammatory elastin fragments. The study appears online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation. The authors found that mice that had inhaled pancreatic elastase or who were exposed to cigarette smoke developed elastin fragments in their lungs, macrophage accumulation, and emphysema. However, when the researchers blocked the activity of elastin fragments using a specific anti-elastin antibody, the macrophage numbers were reduced, and the emphysema was prevented in both models. Using cultured human monocytes (macrophage precursor cells), the authors demonstrate that elastin fragments are chemotactic, meaning that they are able to attract inflammatory cells. The studies suggest that the degradation products of protease activity, in addition to the proteases themselves, may be promising targets for emphysema therapy.

TITLE: Elastin fragments drive disease progression in a murine model of emphysema


A. McGarry Houghton
Brigham and Women's Hospital, Boston, Massachusetts, USA
Phone: (617) 278-0765; Fax: (617) 232-4623; E-mail: mhoughton@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25617


Blood vessel structural cells can help limit tumor spread

Metastasis, a major cause of cancer-treatment failure and death in cancer patients, occurs when cells of a primary tumor detach and migrate through the bloodstream to grow elsewhere in the body. The complete mechanisms involved in metastasis are unclear, but it is known that blood vessel–stabilizing cells, called pericytes, change their shape and partially detach from tumor vessels, suggesting that they allow the vessel to become leaky and cancer cells to escape. In a new study appearing online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation, researcher Henrik Semb and colleagues at Lund University in Sweden report that pancreatic tumors in mice increase in size and spread to other organs when pericytes are unable to interact with blood vessel cells called endothelial cells. The authors found that the tumors of mice deficient in an adhesion protein known as NCAM (neural cell adhesion molecule) grow leaky blood vessels that allowed tumor cells to metastasize. In addition, mice that were genetically modified to be deficient in a pericyte recruitment protein called PDGF (platelet-derived growth factor), demonstrated metastases to the liver, kidney, and intestines, suggesting that loss of specific interactions between endothelial cells and pericytes are important in tumor cell spread. The authors suggest that NCAM limits tumor cell metastasis through its promotion of pericyte function, thus identifying a new mechanism for tumor cell migration.

TITLE: Pericytes limit tumor cell metastasis


Henrik Semb
Lund University, Lund, Sweden
Phone: 46462223159; Fax: 46462223600; E-mail: Henrik.Semb@med.lu.se

View the PDF of this article at: https://www.the-jci.org/article.php?id=25705


Death-resistant T cells in female mice with lupus
Proper defense of the body against germs requires the actions of specialized cells of the immune system, known as T cells. Activated T cells must eventually be silenced, or autoimmune diseases such as lupus can result. Researcher Alessandra Pernis and colleagues at Columbia University in New York now show that genetically modified mice that do not express a T cell protein called IBP (IFN regulatory factor-4–binding protein) develop spontaneous autoimmunity and lupus-like disease. The study, which appears online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation, found that most of these affected IBP "knockout" mice were females, similar to the higher incidence of lupus in females than males in humans. The researchers noticed that unlike their normal siblings, 60% of the female IBP knockout mice developed enlarged lymph nodes, easily observed as swollen lumps in their necks at 5 months of age. Further analysis revealed that these IBP knockout T cells were resistant to death and failed to produce enough of a critical immune protein called IL-2 (interleukin-2). These animals provide an important model to understand lupus and other autoimmune disorders, and the authors suggest that investigating IBP in human autoimmunity warrants consideration.

TITLE: Loss of IRF-4–binding protein leads to the spontaneous development of systemic autoimmunity


Alessandra B. Pernis
Columbia University, New York, New York, USA
Phone: (212) 305-3763; Fax: (212) 305-4478; E-mail: abp1@columbia.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24096


Preventing the unwanted side effects of autoimmune disease therapy

Treatment for autoimmune and inflammatory disorders such as multiple sclerosis often includes blocking a special cell surface attachment molecule known as alpha4 integrin to prevent migration of white blood cells (WBCs). However, this therapy can cause adverse side effects, such as impaired immunity and hematopoiesis [the process of development of new WBCs in the thymus (T cells) and bone marrow (B cells)]. Now, researcher Mark H. Ginsberg and colleagues at the University of California in San Diego have identified a mechanism to selectively reduce WBC recruitment while sparing hematopoiesis. The study appears online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation. The authors created mutant mice known as "alpha4(Y991A) mice," in which the alpha4 integrin can no longer bind to a signaling protein inside the cell called paxillin. Previously generated alpha4 integrin mutant mice died at birth because too many aspects of alpha4 function were changed. The new alpha4(Y991A) mice have an impairment only in the interaction between alpha4 and paxillin, and thus have fewer side effects from the mutation. The authors noticed that, in contrast to wild-type mice, alpha4(Y991A) mice exposed to an inflammation-inducing compound called thioglycollate recruited fewer circulating T and B cells to the region of exposure. However, the development of new B and T cells was unaffected. The authors suggest that these mice are an important model for the identification of signaling mechanisms specific to inflammation, and that a new class of pharmaceutical agents that target the specific interaction of paxillin and alpha4 integrin could be important future treatments of inflammatory disease.

TITLE: Blocking the alpha4 integrin–paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site


Mark H. Ginsberg
University of California San Diego, La Jolla, California, USA
Phone: (858) 822-6432; Fax: (858) 822-6458; E-mail: mhginsberg@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26091


An unlikely role for the cystic fibrosis gene in the kidney

Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene are known to cause cystic fibrosis (CF) due to impaired fluid and ion transport across cell membranes in the lung. However, little is known about the role of CFTR in the kidney, another important fluid transport organ. Now, researcher Steven C. Hebert and colleagues at Yale University School of Medicine in Connecticut report that CFTR regulates potassium levels via a functional interaction with a special potassium channel (or pore) known as ROMK (renal outer medullar potassium) specifically in kidney cells. The study, appearing online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation, may help explain the few reports of hypokalemia (low blood potassium) and metabolic alkalosis (increased blood pH) in CF patients. The authors studied genetically altered mice that either lacked the Cftr gene or had a mutant form of Cftr, and found that, in contrast to wild-type mice, the ROMK activity of these Cftr-deficient mice was not inhibited by the diabetes drug glibenclamide, a potent inhibitor of normal ROMK in kidney cells. The ROMK channels from Cftr-deficient mice also demonstrated an impaired response to a small energy molecule called ATP (adenosine triphosphate). These data suggest that the CFTR protein is a critical component of ROMK function and potassium homeostasis in the kidney. The authors hypothesize that CFTR acts as a functional switch to modulate potassium channel activity between states of water loss and water retention.

TITLE: CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney


Steven C. Hebert
Yale University School of Medicine, New Haven, Connecticut, USA
Phone: (203) 785-4041; Fax: (203) 785-7678; E-mail: steven.hebert@yale.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26961


Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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