Platelets Play Role in Blood Vessel Growth

Image courtesy of Janka Kisucka Matrigels containing fibroblast growth factor were implanted subcutaneously and recovered on day seven after implantation. Hematoxylin- and eosin-stained Matrigel sections from the platelet-depleted mice (bottom) show numerous extravascular red blood cells and hematomas, whereas those from mice in the control group (top) show few abnormalities.

Much is known about the role of platelets in clot formation, but now new research examining their behavior in the body has linked them, and their special ability to adhere to activated endothelial cell walls, to angiogenesis. The findings appear in the Jan. 24 Proceedings of the National Academy of Sciences.

To examine angiogenesis in vivo, Denisa Wagner, HMS professor of pathology at the CBR Institute for Biomedical Research, and colleagues stimulated blood vessel growth in two experimental models. Janka Kisucka, HMS research fellow in pathology and first author, studied mouse corneas, tissues that normally do not contain a vascular system. “The cornea is a nice visual model,” said Wagner. “Since there are no blood vessels before stimulation, you can see where and how well they have grown.” The second method utilized implanted Matrigel, a kind of sponge that provides a scaffold on which vessels can grow, that were injected with fibroblast growth factor to artificially stimulate angiogenesis.

Several mouse models helped researchers zero in on the role of platelets in angiogenesis. In wild-type mice injected with an antibody that depletes platelets, the few blood vessels that grew were leaky though a control group grew plenty of sturdy vessels. Mice lacking proper glycoprotein Ib-alpha (GPIb-alpha), the von Willebrand factor receptor that mediates platelet adhesion, also formed vessels with increased hemorrhage when compared to wild-type mice; mice genetically engineered to lack glycoprotein VI (GPVI), a collagen receptor, did not leak. The results show that platelets and the expression of GPIb-alpha together contribute to normal blood vessel growth and maturation to prevent hemorrhage.

Future research will further explore the role of platelet adhesion in angiogenesis using inhibiting agents instead of genetic mutations, said Wagner. Because tumor growth, metastasis, and atherosclerosis all require blood vessel growth to progress, a better understanding of the mechanisms of angiogenesis may eventually lead to novel treatments.

—Elizabeth Dougherty

Molecular Findings Show Fish Oil Is Not Just Snake Oil

Scientists have known about the benefits of dietary omega-3 fatty acids, prevalent in fish oils, for more than half a century, yet an understanding of their effects on the body remained elusive. A new study, in the Dec. 30 Journal of Biological Chemistry, details part of the biochemical path of a major omega-3 fatty acid, docosahexaenoic acid (DHA), resulting in a potent anti-inflammatory agent.

Using lipid-mediator bioinformatics, a new technique for identifying and profiling small molecules, Amiram Ariel, HMS research fellow in anesthesia at Brigham and Women’s Hospital and the paper’s first author, found that human blood cells convert DHA into protectin D1 (PD1). Thousands of times more potent than its precursor, PD1 triggers several anti-inflammatory effects. The study is the first characterization of a DHA--originated molecular pathway in an immunological setting, focusing on how the lipid-mediator PD1 regulates inflammatory responses.

Some diseases, such as atherosclerosis, asthma, and arthritis, cause the natural inflammation control system to break down. Anti-inflammatory medications used to artificially suppress the immune system and control inflammation include COX-2 inhibitors and glucocorticoids, both of which have undesirable side effects. “Our modus operandi is to find out how inflammation is normally controlled by the body,” said co-author Charles Serhan, the Simon Gelman professor of anesthesia at BWH. “We’re searching for new ways to enhance or use the body’s own molecules as templates for therapy. PD1 looks like a very good template.”

It has long been accepted that essential fatty acids such as DHA are important for maintaining organs, neuronal development, and the immune system. Previous epidemiological and clinical studies showed that high doses of fish oils had a significant impact, for example, in decreasing the risk of a second heart attack and reducing the inflammation of arthritis. In 2003, Serhan and colleagues identified PD1 and, in molecular terms, described novel roles for it in the resolution of acute inflammation in the brain.

Their latest research reveals that PD1 plays a more wide-ranging and long-lasting anti-inflammatory role. Ariel and collaborators found that T helper type 2 cells, which regulate allergic reactions and responses to parasites and counteract inflammation-promoting T helper type 1 cells, also selectively produce PD1 from DHA. The anti-inflammatory actions of PD1 include blocking T cell migration to inflamed sites and promoting T cell apoptosis. PD1 also suppresses the T cell secretion of TNF-alpha and IFN-gamma, cytokines involved in the development of chronic inflammatory disorders such as arthritis and inflammatory bowel disease.

Future research will focus on understanding in more detail how PD1 regulates immune responses and on developing new analogs that behave like PD1, but have increased duration and potency.

While PD1 may serve as a launch point for the design of new therapies for disease, this study also underscores the critical role of omega-3 polyunsaturated fatty acids in disease prevention. Because the body does not make DHA on its own, it is an essential nutrient whose best dietary source is fish and omega-3–enriched eggs. “We’ve defined in molecular terms,” said Serhan, “why eating foods like fish lipids that are rich in DHA is so important to a healthy immune system.”

—Elizabeth Dougherty

More Limited Screening May Increase Efficiency Of West Nile Prevention

Screening all blood donations for West Nile virus is extremely costly and provides only marginal health benefits when compared with more isolated screening, reports a study in the February 2006 Public Library of Science Medicine. “With West Nile virus, infection through the blood supply is rare and many infections won’t result in death,” said Megan Murray, HSPH assistant professor of epidemiology. “Screening everyone is a really expensive way of prevention.”

After West Nile virus appeared in the United States in 1999 and caused deaths in those infected directly and through blood transfusions, the Food and Drug Administration mandated that all blood donations during the May through October epidemic season be screened for the virus using a nucleic acid test. Rather than screening all donations, Murray and colleagues conclude that screening only blood destined for immunocompromised individuals is more cost-effective than the mandated approach in regions with high infection rates.

The high costs of comprehensive screening eclipse the benefits, according to this analysis. Screening individual donations adds one quality-adjusted life year (QALY) among everyone receiving donated blood compared with using the alternative of screening only blood intended for immunocompromised patients, but at a cost of $1.7 million. Although there is no consensus on an acceptable cost per QALY gained, other well-accepted interventions are cited as being between $50,000 and $100,000 per QALY in the United States. Such imbalances in spending are not logical, said Caroline Korves, lead author and former HSPH doctoral candidate now at Columbia University. “We’re investing public health dollars in things that have little benefit in the end.”

In regions with low infection rates, the authors maintain, a simple questionnaire provides as much benefit as screening assays, but with greatly reduced costs. A different approach not analyzed in this study involves funding programs that prevent vector-borne disease. Such programs might include determining the ecological niche of West Nile virus, finding ways to control transmission through mosquito control, and informing the public about the risks of mosquito bites.

The costs of prevention are rarely weighed against those of screening, however, because no single agency or funding source ties these different approaches together. “No one is making a rational decision about what types of programs to pursue,” said Murray. “We need to think about cost-effectiveness and use systematic approaches to prioritize interventions.”

—Elizabeth Dougherty

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