Uncovering the biological role and therapeutic promise of hydrogen sulfide...

Roll over the numbers in the interactive diagram below to discover the broad biological repertoire of hydrogen sulfide. Adapted from paper by Wallace and Wang:  Nature Reviews | Drug Discovery.
Scroll through the diagram below to discover more about the many biological roles of hydrogen sulfide. Adapted from paper by Wallace and Wang:  Nature Reviews | Drug Discovery.
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Hydrogen sulfide addresses inflammation via multiple pathways.

Diagram adapted from Nature Reviews | Drug Discovery - Wallace & Wang (2015).

Hydrogen sulfide can suppress adherence of white blood cells to the inner lining of blood vessels. This maintains blood flow.
Hydrogen sulfide can promote anti-oxidant responses (beneficial) to help prevent tissue damage.
The ability of hydrogen sulfide to inhibit the activity of phosphodiesterases (PDEs) can contribute to improved blood flow to damaged tissues.
Hydrogen sulfide can substitute for oxygen in driving cellular respiration, preventing damage associated with reduced blood flow.
Hydrogen sulfide turns on expression of key anti-inflammatory genes, and turns off key pro-inflammatory genes.

In various ways, hydrogen sulfide promotes resolution of inflammation, including by driving a change from an "aggressive" pro-­inflammatory state (Ml) to a less aggressive, pro-healing form (M2).

Biological Origins

More than three billion years ago, hydrogen sulfide acted as the “oxygen” for early life—remaining so today only for those extreme life forms that cluster near super-heated vents on the ocean floor. While hydrogen sulfide has been supplanted by oxygen as the main source of biological energy, the roots of physiology run deep, and it remains an indispensable molecule throughout plant and animal life, even replacing oxygen in cases of temporary cellular hypoxia. (For more about the origin and functions of hydrogen sulfide in biology, see Physiology (2016).)
 

Discovery of Physiological Function

In 2002, Dr. Rui Wang* published research outlining hydrogen sulfide’s crucial role in nerve signaling—a scientific revelation about a substance long-viewed as hostile to life. Since then, hydrogen sulfide has been recognized for its range of key physiological roles, including regulation of energy production and homeostasis in the gastrointestinal, cardiovascular, respiratory, renal, hepatic, and reproductive systems. It also has a central role in managing oxidative stress, acting as a powerful cellular antioxidant in a variety of biological processes. Notably, many diseases feature abnormally increased or decreased hydrogen sulfide production, pointing to potential therapeutic applications.
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* In 2015, Dr. Wang and Dr. John L. Wallace, Antibe’s Chief Scientific Officer, co-authored a paper in Nature Drug Reviews describing therapeutic opportunities for hydrogen sulfide.
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Hydrogen Sulfide’s Role in Gastrointestinal Health

As indicated in the diagram (right), hydrogen sulfide plays several roles in maintaining the health of the digestive system. Within the blood vessels in the stomach lining, hydrogen sulfide acts to maintain blood flow by enabling increased bicarbonate secretion and by suppressing white blood cell (leukocyte) adhesion (also see video below). In the small intestine, hydrogen sulfide prevents injury to mitochondria (the energy source within cells), supports the health of the intestinal microbiome, and increases production of mucus and COX-2. Notably, while COX-2 can act as an inflammation promoter elsewhere in the body, it is required for healthy intestinal function.

Hydrogen Sulfide's Role in Gastrointestinal Health

As indicated in the diagram (below), hydrogen sulfide plays several roles in maintaining the health of the digestive system. Within the blood vessels in the stomach lining, hydrogen sulfide acts to maintain blood flow by enabling increased bicarbonate secretion and by suppressing white blood cell (leukocyte) adhesion (also see video below). In the small intestine, hydrogen sulfide prevents injury to mitochondria (the energy source within cells), supports the health of the intestinal microbiome, and increases production of mucus and COX-2. Notably, while COX-2 acts as an inflammation promoter elsewhere in the body, it is required for healthy intestinal function.

Play Video

Hydrogen Sulfide: A Therapeutic Opportunity

The initial therapeutic breakthrough occurred in Dr. Wallace’s lab, where the role of hydrogen sulfide was demonstrated in preventing ulceration in an animal stomach. (Click on video to start and stop.)

The first video segment begins with blood flowing in a normal venule (blood vessel) in a rat intestine. One can see white blood cells moving through the bloodstream. After the video flashes, the second segment shows the venule after the rat has been treated with glibenclamide, an inhibitor of in-body hydrogen sulfide production. Note how the venule now becomes occluded by sticky white blood cells. Their accumulation can also damage the walls of the blood vessels, further interfering with normal blood flow. This restriction of circulation is one of the first steps in NSAID-driven stomach ulceration.

New Physiological Insight ... Translated Into New Pharmacology

In the mid-2000s, based on a new understanding of hydrogen sulfide’s gastrointestinal-protective and anti-inflammatory properties, biochemical and animal data were collected for a range of hydrogen sulfide-releasing drug candidates. By 2009, the capacity to prevent NSAID-driven gastrointestinal damage had been therapeutically demonstrated, and Antibe was formed to develop its drug platform.