杏吧原创

HERE鈥橲 a breathtaking idea: carbon monoxide might be good for your health.
The deadly gas kills thousands of people each year, yet some scientists believe
it could be a lifesaver. They say it could improve transplant patients鈥� chances
of survival, or even help people with asthma breathe more easily.

Carbon monoxide is fast gaining a reputation for its health-giving
properties. Earlier this year, a team of medical researchers showed they could
prevent rats rejecting a mouse heart transplant by giving them a trickle of the
gas to breathe. Another team reported that carbon monoxide stops mice dying
after surgery designed to mimic a lung transplant. There鈥檚 even evidence the gas
can prevent heart attacks.

We鈥檝e known since the 1960s that the body naturally produces small amounts of
carbon monoxide when an enzyme called haem oxygenase-1 (HO-1) breaks down
haem鈥攖he iron-containing pigment in red blood cells. HO-1 is a well-known
part of the body鈥檚 defences against injury and infection, called into action
when tissues are damaged by toxins, ultraviolet radiation, hormones, excessively
high or low oxygen levels and drugs. It鈥檚 HO-1鈥檚 job to clear away toxic haem
molecules released from damaged red blood cells. But everyone assumed the carbon
monoxide produced in the clean-up was nothing more than an inconsequential
by-product.

However, in 1993, Solomon Snyder at Johns Hopkins University in Baltimore
proposed a more meaningful role for carbon monoxide. His team had been following
research on another gas, nitric oxide, one of the body鈥檚 signalling molecules.
They had a hunch that nitric oxide was not alone, and that other gases could
wear similar hats. One of Snyder鈥檚 students pointed out that carbon monoxide was
a simple gas like nitric oxide, so why couldn鈥檛 it act as a biological messenger
too?

Snyder and other researchers have since produced evidence that carbon
monoxide helps nitric oxide regulate some of the body鈥檚 housekeeping functions,
such as contraction of the intestines, emptying the stomach, and erection of the
penis. But despite considerable efforts, researchers have found it difficult to
work out carbon monoxide鈥檚 precise role in the body.

The new research looks set to put that right. Earlier this year, a team led
by Augustine Choi, an associate professor at Yale University School of Medicine,
and Fritz Bach, a professor of surgery at Harvard Medical School, published a
paper suggesting that small doses of carbon monoxide could help prevent organ
rejection. The team transplanted mouse hearts into rats dosed with a chemical,
tin protoporphyrin, that blocks HO-1. The rats rejected the transplants within a
week. But the grafts survived if the rats were kept in an atmosphere that was
between 250 and 500 parts per million (ppm) carbon monoxide. It looked as though
carbon monoxide was a vital cog in the biochemical machinery keeping the rats
alive.

The team later found that simply exposing the donated heart to carbon
monoxide 鈥渋n transit鈥� between the mouse and the rat would do the trick. 鈥淭his is
an amazing gas,鈥� says Bach.

That conclusion was echoed later in the year when medical scientist David
Pinsky of Columbia University, New York, along with colleagues at Columbia and
the Brigham and Women鈥檚 Hospital in Boston, reported that a trickle of carbon
monoxide could also help with lung transplants. Pinsky genetically altered mice
so they lacked the gene for HO-1. Then he subjected them to a surgical procedure
designed to simulate some of the effects of a lung transplant, clamping off the
blood supply to their left lungs for an hour and then allowing the flow to
resume. Nine out of ten normal mice survive this operation. All of the
genetically modified mice died, killed by blood clots in their lungs. But when
Pinsky gave the genetically modified mice a whiff of carbon monoxide to
breathe鈥攁 mere 500 to 1000 ppm鈥攁round half escaped death. What鈥檚
more, ordinary mice given carbon monoxide survived the procedure in greater
numbers than normal.

Maybe, then, carbon monoxide would improve the success of lung transplants in
people. Although thousands of these are carried out every year, they鈥檙e much
riskier than other organ transplants. Around 3 in every 10 fail, compared with
about 1 in 10 kidney transplants.

Christoph Thiemermann, professor of pharmacology at the William Harvey
Research Institute at St Bartholomew鈥檚 and the Royal London School of Medicine
and Dentistry, says carbon monoxide looks 鈥渧ery promising indeed鈥� as a drug to
prevent lung damage following transplants. 鈥淭he effects of carbon monoxide are
striking compared with the few other medications that we have available,鈥� he
says.

That doesn鈥檛 mean you鈥檒l see cylinders of carbon monoxide in emergency rooms
anytime soon. The main obstacle is carbon monoxide鈥檚 bad reputation, says Choi.
The gas causes 5000 to 6000 accidental deaths each year worldwide because of
faulty heating or cooking appliances and car exhausts. Carbon monoxide kills
because it binds tenaciously to haemoglobin in red blood cells, forming
carboxyhaemoglobin, which can鈥檛 ferry oxygen around the body. 鈥淭he public knows
that it can be lethal,鈥� says Choi. 鈥淏ut at low concentrations it has beneficial
effects鈥攊t is a Jekyll and Hyde gas.鈥�

Another problem is the very narrow margin of safety between a dose of carbon
monoxide that kills and one that cures. The benefits of carbon monoxide aren鈥檛
felt until around 25 per cent of the body鈥檚 haemoglobin is converted to
carboxyhaemoglobin, but nausea, vomiting and dizziness kick in at 20 per cent,
and you die when levels reach 40 per cent.

What鈥檚 more, Pinsky鈥檚 studies showed that you could reproduce the protective
effects of 500 to 1000 ppm of carbon monoxide with just 65 ppm of nitric oxide.
And nitric oxide is far less toxic than carbon monoxide. 鈥淚f you have an
alternative that is potentially less toxic, then that is a better alternative,鈥�
says Thiemermann.

But Bach says the medical community should not be so quick to reject the
therapeutic potential of carbon monoxide. 鈥淣itric oxide is a chemically more
reactive species than carbon monoxide, and so it could be harmful for it to
remain around for too long.鈥� He says it鈥檚 worth noting that many people
voluntarily expose themselves to higher-than-normal levels of carbon monoxide:
鈥淢any smokers have levels of carboxyhaemoglobin of around 15 per cent, and
non-smokers who live in polluted cities such as Tokyo have levels of around 8
per cent.鈥� Regularly inhaling carbon monoxide at low levels might be an
acceptable risk. And if carbon monoxide offers the slightest of benefits, it
could still improve the lives of millions of transplant patients, who must take
costly immunosuppressants for the rest of their lives. Pinsky adds that carbon
monoxide treatment could be the best thing in emergencies, for example when
treating patients seriously ill with adult respiratory distress syndrome, which
can develop rapidly after an infection.

An alternative strategy could use gene therapy to deliver the
carbon-monoxide-producing enzyme HO-1 to the target. Choi has shown he can
protect lungs against damage caused by excessive levels of oxygen using HO-1
gene therapy. More recently, Elizabeth Nabel and colleagues at the National
Heart, Lung and Blood Institute in Bethesda, near Washington DC, delivered the
gene for HO-1 to pig arteries damaged by an angioplasty. The treatment relaxed
the vessels and made them less prone to thickening again, making a heart attack
less likely. Nabel has also done preliminary studies that suggest doses of
carbon monoxide might do the same.

Even if the gas doesn鈥檛 make it as a medicine, we now have a better idea how
carbon monoxide might work鈥攁nd whether it鈥檚 part and parcel of the body鈥檚
protective system. Pinsky found that carbon monoxide activates soluble guanylate
cyclase鈥攖he same enzyme nitric oxide turns on鈥攚hich switches off the
manufacture of a protein called fibrin, the scaffold for blood clots. When blood
flow to a lung dries up during a transplant operation, fibrin builds up and
blocks its narrow blood vessels. When the flow is restored, blood floods into
the blocked vessels and pressure builds up like water in a garden hose when
someone has trodden on it. This leads to serious injury. Unwanted fibrin is also
a problem during strokes and heart attacks, and carbon monoxide therapy might
help here too.

Choi and Bach鈥檚 team, meanwhile, believes that carbon monoxide works by
dampening down the body鈥檚 inflammation response. It activates anti-inflammatory
molecules and suppresses pro-inflammatory factors. 鈥淐arbon monoxide knows
exactly how to tickle the immune system,鈥� says Bach. Choi, now professor of
medicine at the University of Pittsburgh School of Medicine, is looking at how a
small dose of carbon monoxide might help control inflammatory lung disorders
such as asthma, emphysema and cystic fibrosis.

For Pinsky, there鈥檚 only one conclusion: the production of carbon monoxide by
HO-1 is an intrinsic part of the body鈥檚 biochemical armour. But not everyone
agrees and several questions remain. It鈥檚 debatable whether the body can
manufacture enough of the gas to make it an important protective agent, and it
is unclear whether HO-1 can be turned on and off at will to provide the
necessary level of control.

鈥淭he jury is still out,鈥� says Michael Marletta, an enzymologist at the
University of California, Berkeley. 鈥淚 don鈥檛 think that the right experiments
have been done yet.鈥� He鈥檇 like to see direct measurements of the gas in tissues.
But researchers do not have the necessary tools.

杏吧原创s may not have dispelled the clouds of controversy over whether the
protective effects of carbon monoxide are part of the body鈥檚 grand design, or
just biological artefacts. But maybe that鈥檚 of secondary importance. 鈥淚 would
prefer if it was a physiological process,鈥� says Bach. 鈥淏ut if it helps patients
then I don鈥檛 care.鈥�