Inflammation is an essential process that helps protect our body from infection and starts the healing process. When we get an infection or injure ourselves, pro-inflammatory cytokines help attract immune cells to address the threat to our body.

During an infection, this helps alert the immune system and allows immune cells to recognize and eliminate the threat. During an injury, it causes the removal of damaged tissue.

Upon removal of the threat or damaged tissue, the release of anti-inflammatory cytokines resolves the inflammation and repairs collateral damage. As a result, the body returns to homeostasis.

Both of these processes are essential to effective healing. If we lost the ability to create an inflammatory response, we wouldn’t be able to fight infection or heal. But if we lost the ability to regulate inflammation, it could kill us.

Consequently, 6 of the 7 leading causes of death have chronic inflammation as a driver. This includes:

• Heart disease
• Cancer
• Chronic lower respiratory diseases
• Stroke
• Alzheimer’s disease
• Diabetes

Fortunately, there are pathways in place to help us deal with inflammation. One of those pathways is the heme oxygenase-1 pathway. Oddly enough, the product of this pathway that acts as an anti-inflammatory is more commonly associated with death.

The anti-inflammatory molecule that can also kill you

There are 3 types of heme oxygenase in humans, annotated HO-1, HO-2, & HO-3. All 3 forms of HO work in the same way, by breaking down free heme. Heme is an iron containing protein found in hemoglobin, myoglobin, cytochromes, and other important proteins..

Heme is highly inflammatory when released from heme proteins. When this happens, heme oxygenase rapidly converts heme in to biliverdin, free iron, and carbon monoxide.

Biliverdin is then rapidly converted to bilirubin, which you can see as a bruise transitions from red(heme), to green(biliverdin) to yellow(bilirubin). For more on the antioxidant effects of bilirubin, click here.

While the antioxidant effects of bilirubin are interesting, the production of carbon monoxide(CO) is even more interesting. As it turns out, the once feared gas turns out to be a potent regulator of inflammation and is essential to circadian rhythms.

Carbon monoxide as an anti-inflammatory

Our cells are constantly churning out carbon monoxide. HO-2 is always running, and found in endothelial cells, the brain, and testis. HO-1 is inducible, meaning it turns on and off, and found in most cells. It’s a stress response pathway; cells activate it when exposed to stress.

When our cells are exposed to stress, they turn on HO-1. Through the generation of carbon monoxide, HO-1 acts to dampen inflammation and reduce oxidative stress. And the best part is, once you activate HO-1 and create CO, this increases HO-1 activation further.

This effect has garnered the attention of the pharmaceutical industry. Clinical trials are currently underway on the use of low dose inhaled CO or carbon monoxide releasing molecules(CORMs) for a multitude of inflammatory diseases.

The anti-inflammatory benefits of CO occur locally in cells, but may also work systemically as well. In rats, inhaled CO activates the cholinergic anti-inflammatory pathway by stimulating the vagus nerve. If this acts in the lung, it indicates the CO we make may do the same. And there is evidence in humans to indicate this.

Inhaling high levels of carbon monoxide kills people because hemoglobin has a 240x higher affinity for carbon monoxide than it does for oxygen. As a result, during carbon monoxide poisoning, hemoglobin binds carbon monoxide instead of oxygen, essentially suffocating our cells.

But we make such low levels of CO that this high affinity has a purpose. In order to remove it from cells swimming in a sea of oxygen and carbon dioxide, hemoglobin has to have a much higher affinity for it or it would just accumulate to potentially deadly levels.

Carbon monoxide: Essential component of circadian rhythms

In addition to regulating inflammation, CO is also essential to circadian rhythms. Circadian rhythms help regulate a number of physiological processes. At the simplest level, they help separate use from repair so that processes that use the same co-factors or oppose one another occur separately.

The best way to conceptualize this is that we have an active part of our day and a resting part of our day. In humans, we sleep during the night and are active during the day.

Needless to say, we are more likely to encounter a pathogen or experience an injury during the day than at night. As such, oxidative stress is higher during the day and lower at night.

HO-1 is a stress response pathway that’s more active during the day when oxidative stress is high. As a result, CO production increases during the day and helps prevent inflammation from getting out of control.

This, indirectly, affects circadian rhythms. CO also has a direct effect on circadian rhythms by binding to and regulating circadian clock components. Knocking out HO-1 or removal of CO disrupts circadian rhythms.

Conclusion

Carbon monoxide generated from the HO-1 pathway is essential to controlling inflammation and regulating circadian rhythms. Pharmaceutical companies are currently looking at the use of carbon monoxide releasing molecules(CORMs) and low dose inhaled CO in inflammatory conditions such as IBD.

But there are things we can eat and behaviors we can do on a regular basis to get the benefits of HO-1 activation and CO production. We’ll discuss what you can do to enhance HO-1 activation and CO production in the next email coming out tomorrow.