By David N. Leff
A do-it-yourself, Kevorkian-inspired individual goes into the garage, shuts the door, shoves one end of a length of garden hose into the car¿s exhaust pipe, leads the other end into the automobile¿s interior, hits the starter, and breathes deeply.
In this scenario, the suicidal agent is a colorless, odorless, tasteless gas ¿ carbon monoxide (CO). Depending on its concentration and duration in that garage, death can occur in minutes to a few hours.
But suppose that auto-execution is interrupted if the subject¿s spouse unexpectedly enters the garage, takes in the scene, quickly opens the doors, shuts off the motor and dials 911. Help arrives in time to rush the wannabe victim to the hospital. What then?
¿Depending on the CO levels in the person¿s blood,¿ said cardiovascular specialist David Pinsky, at Columbia University in New York, ¿the most effective treatment we have today is hyperbaric oxygen. So the patient is put in under high-pressure, super-high oxygen concentrations, which drives the CO off the blood, off the hemoglobin, and then replaces it with oxygen.¿
Pinsky is senior author of an article in the May 2001 issue of Nature Medicine, titled ¿Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis.¿ In other words, CO¿s white hat covers a beneficial clot buster.
¿The mechanistic finding in the paper,¿ Pinsky told BioWorld Today, ¿is that CO, which is known to be made in the body, was thought to be an incidental byproduct of the breakdown of heme molecules. Now, rather, it appears that CO actually has a very important physiological role ¿ to maintain blood flow, and prevent clots from accumulating in vessels that have been injured, either by ischemia or inflammation.¿
Pinsky explained: ¿Carbon monoxide binds to heme, an iron molecule that¿s encompassed within hemoglobin. This red blood cell transports oxygen from the lungs to the body¿s tissues ¿ notably the heart and brain. It¿s actually the iron in the heme ring that binds oxygen, but can also bind CO. So what happens,¿ he went on, ¿is that CO displaces and reduces the amount of oxygen delivered to tissues. And that¿s how CO at elevated levels can be lethal.¿
What¿s Toxic CO Doing In Human Blood?
How then can CO confer benefit? ¿This iron-containing heme molecule isn¿t found only in hemoglobin,¿ Pinsky elaborated. ¿It also occurs in various enzymes of the body, one of which is called guanylate cyclase. That¿s responsible for making within cells a second messenger ¿ an internal signaling molecule ¿ called cGMP [guanosine cyclic monophosphate].
¿The guanylate cyclase is normally in an inactive state,¿ he continued, ¿but as soon as CO binds to the heme within that enzyme, it activates it ¿ turns it on ¿ and then starts churning out cGMP. Nitric oxide [NO],¿ Pinsky added, ¿activates that very same enzyme ¿ so that¿s how CO is in a sense taking over NO¿s functions.
¿One of the other new links we show in our paper,¿ he observed, ¿is that by causing formation of cGMP, CO sets in motion a cascade of events that leads to the breakdown of clots. It does so via a cGMP intermediary ¿ plasminogen activator inhibitor. This protein suppresses clot formation or accumulation, and reduces fibrinolysis. So CO-generated cGMP has a number of these beneficial effects, which maintain normal blood vessel function and prevent clots from accumulating, among other things.¿
The co-authors tested these CO effects in vivo:
¿What we did,¿ Pinsky narrated, ¿was tie off the blood supply to the left lung of a mouse, and left that ligature in place for an hour or an hour and a half. Then we released it so the blood flow came back to the lung. We administered CO by inhalational therapy prior to the ligation. Also ¿ because it was very important if we ever anticipate using CO clinically ¿ we gave it during that ischemic event. We found, surprisingly, that too was quite effective.
¿Paradoxically,¿ Pinsky said, ¿blood oxygen levels following the procedure were higher after CO inhalation then after the same procedure in the absence of that treatment. The overall results were that animals that inhaled the gas exhibited significantly better survival and lung function than those that had the identical surgical procedure, but without the CO gas ¿ and rather were breathing just room air. We also studied knockout mice lacking the normal gene that makes the CO. We were able to rescue those carbon monoxide-minus animals.¿
Pinsky noted one report in the literature ¿of a patient who lacked the gene to produce CO under stress conditions. And that patient had a lot of problems ¿ anemia, extreme susceptibility to environmental stress, and all the other pathologies you might predict. I don¿t think that¿s a very widespread condition ¿ only one report of a single patient that I¿m aware of. But it¿s something that might be investigated.
¿In medicine,¿ Pinsky observed, ¿we use a lot of toxic molecules for a lot of things. Most chemotherapeutic agents for instance are highly toxic agents, but if we give them judiciously at the right doses, they can be quite effective under the right circumstances. It wouldn¿t be the first instance of having something that is toxic at one level prove useful at another level.¿
Gas Of All Gigs Packs Clinical Potentials
¿I think we have to be sanguine ¿ no pun intended,¿ he went on, ¿about the fact that CO may or may not ultimately be useful. Certainly our studies, which may be provocative, suggest that we should test further. Ultimately, it may find its way into a clinical use.
¿In situations where blood flow is compromised,¿ Pinsky continued, ¿maybe myocardial infarction, maybe stroke, maybe in organ transplantation, right after implantation when an organ is put in, there can be considerable compromised blood flow. And there might be something such as sepsis. These are conditions where there may be a use for CO. When inhaled in very low doses, it might have some therapeutic value. And that was not previously recognized.
¿This is the first time,¿ he concluded, ¿that a group has shown that CO can protect blood vessels and organs from ischemic injury.¿