Published online: 2 August 2006
Protein discovery reveals mechanism of anaphylactic shock.
Richard Van Noorden
For some people, it just takes a taste of peanut to induce a sudden and possibly fatal allergic reaction. Now researchers have unpicked the mechanism behind this anaphylactic shock, and have managed to protect mice against the condition.
Anaphylactic shock is estimated to affect up to 15% of the US population. It can be triggered by a wide array of allergens, including bee stings, latex, medications and certain foods (such as peanuts or shellfish). Those struck have trouble breathing, find their face, neck and throat swelling up, and may eventually lose consciousness as their blood pressure drops — the cause of death if the symptoms are not treated.
Many allergic reactions settle down of their own accord, or respond to antihistamine treatment. Should severe anaphylactic shock kick in, however, the only effective treatment is a quick injection of adrenaline (epinephrine).
"This is a supportive, booster treatment," explains co-author Peter Brouckaert of the Flanders Interuniversity Institute for Biotechnology in Ghent, Belgium. "The adrenaline contracts blood vessels and increases heart rate, combating low blood pressure. But it doesn't interfere with the mechanism of the anaphylactic shock."
That mechanism, however, has been a bit of a mystery. An allergic reaction occurs when an allergen, such as a peanut protein, triggers the release of histamines and other molecules that cause swellings and pain. But the biochemical pathways that then lead to severe anaphylactic shock have been unknown.
Presumed innocent
Previous research in mice, which have a similar immune system to humans, had hinted that extreme amounts of nitric oxide (NO) throughout the body might be responsible. So Brouckaert and colleagues took a closer look. They induced anaphylactic shock in mice in two ways: by injecting a molecule to deliberately lower blood pressure, and by creating an allergic reaction much like that experienced in humans.
By injecting nitric-oxide blockers into some of the mice before attempting to give them anaphylactic shock, the researchers were able to confirm that nitric oxide was indeed the culprit. But, they report in the Journal of Clinical Investigation1, it was coming from an unexpected source.
Researchers had previously assumed that a protein called iNOS was the top suspect for anaphylactic shock. But instead, Brouckaert and his team found eNOS to be to blame — a protein previously thought to produce only small amounts of nitric oxide in order to regulate the body's normal blood pressure variations.
Mice genetically engineered to lack eNOS were immune to potentially fatal allergens, whereas mice missing iNOS fell victim to them. "eNOS was always presumed innocent," says Anje Cauwels of the Flanders Interuniversity Institute for Biotechnology, who headed the study.
Stop the shock
Doctors could potentially use nitric-oxide blockers to help treat the condition, the researchers say. The team managed to prevent anaphylactic shock by injecting drugs known to block proteins in the eNOS production pathway before trying to induce a shock. These mice experienced just a brief drop in blood pressure followed by a quick recovery.
Unfortunately, these types of drugs are very slow-acting against anaphylaxis as they need time to accumulate in the body, so would presumably not do much good as an emergency response. "But a patient sensitive to penicillin, anaesthetics, or latex could be pre-loaded with these drugs before an operation," says Cauwels.
Charles Lowenstein, cardiologist and professor of pathology at Johns Hopkins University in Baltimore, Maryland, finds the research very encouraging. "Lots of people get anaphylaxis, but we don't understand the pathways involved, so it's impossible to give them targeted therapies," he says. "This certainly suggests a specific therapy."
He warns, though, that the researchers mainly concentrated on the shock induced in mice by injection, rather than by a true allergic reaction. It's not clear how well this part of their experiment mimics the human condition.
J Clin Invest. 2006 Aug 1;116(8):2244-2251. Links
Anaphylactic shock depends on PI3K and eNOS-derived NO.Cauwels A, Janssen B, Buys E, Sips P, Brouckaert P.
Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University and Flanders Interuniversity Institute for Biotechnology (VIB), Ghent, Belgium. Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCalpha1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis. |
