What makes red chili peppers peppery is a versatile 11-amino-acidpeptide called substance P., which is released by the chemical,capsaicin. This is the prime pungent ingredient of hot sauce, salsa andTex-Mex cuisine. The peptide also is the soothing secret of currentlypopular over-the-counter anti-pain creams and ointments.

Substance P is the premier member of the tachykinin family ofneuropeptides, explained biochemist and molecular biologist CraigGerard of Harvard School of Medicine in Cambridge, Mass. Theseact via specific cell-surface receptors, coupled to a "G protein," hetold BioWorld Today, "which operates an intracellular signalingmechanism that transduces signals inside the cell.

"These seven-transmembrane-spanning substance P receptors,"Gerard said, "belong to the largest class of cell-surface receptors inall biology." They make smells smelly, sights visible, and some painspainful.

"Substance P," he pointed out, "is actually a very powerful pro-inflammatory mediator. It's found all over the brain and centralnervous system, in several immune-system cells, and in the lining ofsome blood vessels."

Inflammation, Gerard observed, is a bodily phenomenon known andstudied "for the past 2,000 years." Early physicians knewinflammation by its four cardinal signs _ dolor (pain), rubor(reddening), calor (fever) and tumor (swelling). "All four," hepointed out, "can be precipitated by injecting a little substance P intothe skin. In the joint fluids of rheumatoid arthritis patients there's alot of substance P.

"People have been wondering for some time," Gerard continued,"about the link between tachykinins and their receptors with a certaintype of inflammation called neurogenic inflammation. It's believedthat neuropeptides participate in certain types of nerves, called C-fibers, that line joints and tissues."

He and his co-senior author, Norma Gerard, who run a laboratory ofinflammation and host defenses at Harvard, report in today's Scienceon "Neurogenic amplification of immune-complex inflammation."

Gerard explained: "We made a knockout mouse lacking the gene forsubstance P receptor and challenged it with an immune complex.This is a classical inflammation-inciting mechanism that bringstogether antigens and their antibodies in a complex.

"Immune complexes," he added, "can hurt your kidneys, bloodvessels [by causing vasculitis], skin [in terms of lupus]. Lyme diseaseis an immune-complex disease."

Gerard and his co-authors chose to form an immune complex in thelung, a focus of their lab, which studies asthma and cystic fibrosis.They injected the antigen ovalbumin (egg white) into the tail veins ofnormal and knockout mice, from which it circulated throughout thebloodstream.

Then they put anti-ovalbumin antibody down the animals' windpipes."The two came together in the microvasculature of their lungs."

As a result, he recalled, "in normal mice we got a big inflammation,with leakage from blood vessels made permeable, and recruitment ofwhite blood cells, polymorphonuclear neutrophils, which are puscells.

"In the substance-P-receptor knockouts, there was no inflammation.Their lungs were completely protected from the immune complex.That meant that somehow the substance P receptor was an essentiallink between formation of the immune complex and the subsequentinjury _ pulmonary edema, vascular leak and pus."

He observed: "No one ever anticipated that there was anamplification step in the middle, with substance P and its receptor."

This work suggests to Gerard "that substance P receptor antagonists,which have been developed, may have some role in particular typesof inflammatory states. These are on the verge of human drug trials atseveral major pharmaceutical companies."

Potential Market: From Asthma To Nausea

He sees potential applications of such antagonists in protecting thelungs of asthma and cystic fibrosis patients from inflammation. "Soobviously," he said, "we now want to test these knockouts withadditional models of lung injury."

Looking to a much larger potential market, Gerard went on, "It turnsout that several pharmaceutical companies are extremely interestedbecause antagonizing the substance P receptor appears to be anexciting way to treat nausea."

When a person _ or pet _ ingests a harmful substance, the gut sendsa message to the brain's emesis (vomit) center to up-chuck thethreatened poison.

This center in the brain stem, Gerard said, "appears to utilize thesubstance P receptor as a critical emesis mediator or bottleneck.Antagonism of the receptor may be an extremely powerful anti-emetic, which would obviously be an interesting market for air-, sea-and car-sickness, as well as the nausea side effects of cancerchemotherapy.

"Major pharmaceutical companies," he concluded, "are investigatingthis clinically." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.