JOHN WHITFIELD
Researchers have found a molecular switch that enables the immune system's cells to function without oxygen. Jamming the switch stops inflammation, suggesting a new way to treat arthritis and other diseases in which the body turns on itself.
The switch is in white blood cells, the immune system's special forces. These cells rush into ailing tissues, and form the first line of defence against incoming infection, eating invading bacteria. This influx is one of the causes of inflammation.
Randall Johnson of the University of California, San Diego, and his colleagues have found that a molecule called HIF-1 alters white blood cells so that they can survive without oxygen1 - a trick that is essential to their defensive role, as damaged tissues are often low in the gas.
The team genetically engineered mice to lack HIF-1 in their white blood cells. The modified cells stay away from low-oxygen environments, and destroy few bacteria. "It's as if they can't manage the energetic burst needed to kill bacteria," says Johnson.
The animals' skin does not redden in response to irritating chemicals, and their joints do not develop arthritis when injected with a substance that normally causes swelling.
"This is a very important observation in terms of understanding the biology of inflammation," says cancer biologist Adrian Harris of the University of Oxford, UK.
HIF-1 was known to switch on genes that trigger the production of red blood cells or the growth of blood vessels. "Tying HIF-1 to the biology of white blood cells is a big contribution," says blood specialist Franklin Bunn of Harvard Medical School, Massachusetts.
Cancer researchers are already looking for drugs that block HIF-1 - which they hope will starve tumours of oxygen. Such drugs might also help to treat arthritis, says Johnson.
But without HIF-1, a mouse's immune system is also much weaker. The molecule's many jobs will make it difficult to disable without adverse side-effects. Bunn warns: "You're going to have to work very hard to find a targeted drug."
References
Cramer, T. et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell, 112, 645 - 657, (2003). |Homepage|
Curr Opin Clin Nutr Metab Care 2003 Jan;6(1):87-93
Exercise treatment to counteract protein wasting of chronic diseases.
Zinna EM, Yarasheski KE.
PURPOSE OF REVIEW The objective is to summarize the findings from recent (June 2001-2002) studies that have examined the potential benefits of exercise training for the treatment of wasting associated with sarcopenia, cancer, chronic renal insufficiency, rheumatoid arthritis, osteoarthritis and HIV. In many clinical conditions, protein wasting and unintentional weight loss are predictors of morbidity and mortality. The pathogenesis of protein wasting in these conditions can be different, but the fundamental mechanism is an imbalance between muscle protein synthetic and proteolytic processes. The muscle proteins most affected and the precise alterations in their synthetic and proteolytic rates that occur in each cachectic condition are still under investigation. RECENT FINDINGS Regular exercise, or sometimes just a modest increase in physical activity, can mitigate muscle protein wasting. Aerobic exercise training primarily alters mitochondrial and cytosolic proteins (enzyme activities), while progressive resistance exercise training predominantly increases contractile protein mass. Previous studies indicate that resistance exercise acutely increases the muscle protein synthetic rate more than muscle proteolysis such that the muscle amino acid balance is increased for up to 2 days after exercise. Progressive resistance exercise training increases muscle protein synthesis and muscle mass, but attenuates the increment in proteolysis that results from a single bout of resistance exercise. The cellular mechanisms that produce these adaptations are not entirely clear.SUMMARY In general, patients with wasting conditions who can and will comply with a proper exercise program gain muscle protein mass, strength and endurance, and, in some cases, are more capable of performing the activities of daily living.
