|
||||||||
|
PATHOLOGY
Fatty-acid Imbalance May Boost Inflammation in CFThe search for signs of life on Mars will be focusing on the ancient lakebeds and riverbeds that crisscross the red planet, and for good reason. Water is the currency of life. Cells are awash in it both inside and out. They also secrete fluids like saliva, tears, sweat, mucus, and digestive juices through their many membrane channels. Usually these secretions are aqueous and slippery, but in people with cystic fibrosis, a genetic defect in one of the membrane channels upsets the water and chemical composition of the secretions, making them pathologically viscous and sticky.
Steven D. Freedman believes that correcting fatty-acid imbalances may someday be used with other therapies to treat cystic fibrosis patients. (Photo by Bruce Wahl, BIDMC) It now appears that the cystic fibrosis mutant gene may cause disease by altering the balance of another set of primordial molecules, the fatty acids. The discovery, reported by Steven D. Freedman and colleagues in the Feb. 6 New England Journal of Medicine, could lead to a new understanding, and possible treatments, not just of cystic fibrosis, but of a host of related diseases such as pancreatitis, chronic sinusitis, and male infertility. Too Hot to HandleFor years, blame for the symptoms of cystic fibrosis was pinned on the viscous secretions, which clog up and produce life-threatening infections of the lungs. Over the past decade, it has become evident that the severity of these infections is the result of another culprit, an overenthusiastic inflammatory response. "It is not the bacteria so much as it is the host's exuberant response to the bugs that are just stuck there in the tenacious secretions. Your body is just attacking them, almost out of control, and the lung tissue is being destroyed as a kind of innocent bystander," said Freedman, HMS associate professor of medicine at Beth Israel Deaconess Medical Center. But it was unclear how a mutation in a single channel protein, the cystic fibrosis transmembrane conductance regulator (CFTR), could produce two such divergent responses--viscous secretions and an overly reactive immune system.
Perhaps most compelling, Freedman and his colleagues found that they could correct the fatty acid imbalance and reverse disease by giving the mice huge doses of DHA. Inspired by the findings, Freedman--along with Juan Alvarez, HMS associate professor of obstetrics, gynecology and reproductive biology at BID, Michael Laposata, HMS professor of pathology at Massachusetts General Hospital, and colleagues--analyzed samples of CFTR-expressing cells from the plasma and nasal and rectal passages of 38 patients with cystic fibrosis, recruited by Brian O'Sullivan of the University of Massachusetts Medical School, Worcester. As they report, patients produced twice as much arachidonic acid, which belongs to the omega-6 family of fatty acids, and one half as much DHA, a member of the omega-3 family, as those unaffected by the disease. People carrying only one copy of the mutant cystic fibrosis gene, who typically show no signs of disease, fell somewhere in the middle, suggesting the mutant CFTR was directly affecting the fatty-acid ratio. Importantly, the researchers did not find a dramatic fatty-acid imbalance in people with other forms of inflammation such as inflammatory bowel disease, colitis, and certain forms of asthma. "So inflammation alone does not lead to the fatty-acid abnormalities to the degree we see in cystic fibrosis," said Freedman. Therapeutic ApproachesIt is not clear how a defect in an ion channel protein causes the fatty-acid imbalance. The channel pumps ions out of the cell, particularly chloride, yet CFTR is thought to participate in many other aspects of cell function. "That is what has made it, in part, so problematic to come up with a treatment for cystic fibrosis," said Freedman. The researchers have not yet tried to right the fatty-acid imbalance in patients as they did in mice. "One problem is that the dose of DHA we gave the mice is very high. If we extrapolate to humans, it would be six to seven grams of pure DHA. That is 30 or more over-the-counter capsules, and those are not that pure," said Freedman.In cystic fibrosis, the combination of viscous secretions and overexuberant inflammatory response wreaks havoc on the enzyme-producing pancreas and bile-producing liver. The approximately 30,000 Americans affected by the disease have a hard enough time digesting even modest amounts of nutrients and often must take massive doses of enzymes. "They could never absorb that amount of DHA no matter how many pancreatic enzyme pills you gave them," said Freedman. He is talking with pharmaceutical companies about the possibility of developing a more concentrated and absorbable form. Cystic fibrosis patients and their families would gain most from such a formulation. Though their average life span has doubled in the past few decades thanks to a combination of diet and physical therapy, it still is only 31 years--less than half the national average. Other patients might benefit, as well. Freedman and his colleagues have found that 50 percent of people with pancreatitis carry mutant versions of the CFTR protein. The mutant gene has also been found in 40 percent of people with chronic sinusitis and 30 percent with unexplained male infertility. Freedman, however, cautions all patients about rushing to self-medicate with over-the-counter omega-3 formulations. "I would be especially careful about supplementing in the cystic fibrosis population," he said. "It is obviously a devastating disease. But we need to learn more about the role of DHA here. In particular, could there be side effects of high doses?" --Misia Landau |
