The long arm of inflammation
There is no “one size fits all” mechanism underlying inflammation, which means there isn’t a “one size fits all” way to treat it.
By now you’ve probably heard of the steady increase in the number of reported cases of measles in the United States. Perhaps you’ve also heard about the rise in the number of Ebola virus disease (EVD) cases in the Democratic Republic of the Congo. And you might have also known that last week we observed World Malaria Day, and that 2019 will see more than 1.7 million new cancer diagnoses in the US. Perhaps you’ve been following the recent basketball playoffs and watched players tending their sore muscles while on the bench. All these diverse instances share a common feature — inflammation.
What is inflammation?
The word “inflammation” has its origins in Latin, and implies setting fire. In biology, the word describes phenomena which result in an increase in size of a site in the body. In the case of measles, the rash is a result of discrete sites of inflammation and children who contract measles can experience cerebral inflammation, often several years after the incidence of the disease; in the case of EVD, there is massive internal inflammation throughout the body; malarial infection results in inflammation of the liver and other organs; some cancers like stomach and liver cancers have been linked to long-lived existing inflammations of those organs; and muscle injury and repair is associated with inflammation — have you ever noticed what a sprained ankle looks like?
In western medicine, the history of inflammation dates back centuries. In fact, Hippocrates is credited with introducing the word “edema” in the 5th century, to describe swelling. He described inflammation as an essential component of the healing cycle when there was injured tissue. But it is only since the last century that research has yielded a better understanding of the body’s immune system, and how it mounts an inflammatory response. The findings have resulted in a burgeoning in medications such as those to treat inflammation that might occur as a consequence of muscle injury, or various kinds of arthritis.
One size does not fit all
Despite a few shared characteristics, inflammation in each disease can be fairly unique, which means treating all types of inflammation requires a large tool-box. This is underscored by the fact that inflammation often occurs in a much later step in a disease; or there is a low level of inflammation that is sometimes not easily detectable and that might be the reason for a disease. Pink eye, or conjunctivitis is an example of the former — a virus or bacterium establishes itself in the eye and the body’s immune system detects the invader and mounts an assault to annihilate the invader. Put very simply, this war manifests as an inflammation.
Key facilitators of inflammation
In those instances where inflammation can be reduced by over-the-counter medications like ibuprofen or other non-steroidal anti inflammatory drugs (NSAIDs), the mechanism of action of the drugs is relatively straightforward, although overuse of NSAIDs can sometimes be deleterious.
COX-1 and COX-2, or cyclooxygenase-1 and cyclooxygenase-2 (or PTGS1 and 2, prostaglandin-endoperoxide synthase 1 and 2), are two very similar enzymes with similar yet distinct roles in the body. While COX-1 is found in almost all tissues, COX-2 is more restricted. These enzymes catalyze a reaction, the products (prostaglandins) of which in some instances promote inflammation, and in others, help in the maintenance of tissue integrity. NSAIDs reduce inflammation by binding to the COX enzymes, preventing the formation of prostaglandins.
Biochemical pathway maps outdo subway maps
In a 2016 study, Gallotti and colleagues looked at the representation of transportation on city maps. They concluded among other things, (a) that New York City subway maps were perhaps the most complicated maps, and (b) “Multimodal transportation systems in large cities have thus already exceeded human cognitive limits and, consequently, the traditional view of navigation in cities has to be revised substantially”
Maintaining a robust signalling system in the complex New York subway system is no small feat. Now, add several orders of complexity to that and you have the complex map of biochemical pathways that keep you fit in the best of times, and make you sick in the worst. The complexity of biochemical pathways compared to the most complex transportation maps that “exceed human cognitive limits” is nothing short of awe-inspiring. For several decades, researchers have taken on the challenge of dissecting these biochemical pathways to develop tools to address situations where the pathways are disrupted.
Zoom and awe
The enzymes that catalyze the synthesis of prostaglandins inhabit a tiny portion of the biochemical pathways map, yet play a key role in wellness.
Noting the level of complexity, it is easier to appreciate why inflammation is such an important process, and why fine-tuning cyclooxygenases is critical. Equally important are attempts to fine-tune the steps that precede the action of cyclooxygenases. Of course, all without disrupting the numerous other processes that feed into or out of these steps. It’s like working on a Jenga game that is inconceivably complicated — move one piece a smidgen incorrectly, and the entire stack crashes.
Viewing these images of the biochemical pathways also makes it easier to appreciate that although a drug can inhibit a cyclooxygenase and thus reduce inflammation, too much of it can be counterproductive, because prostaglandins have been shown to play a role in some normal biological processes including maintenance of some tissues such as the lining of the stomach and intestines.
Gout — inflammation’s poster child
Gout is the most common form of inflammatory arthritis, and its incidence is increasing across the globe. It is caused by the deposition of uric acid crystals in and around the joints. When dietary intake of some purine-rich foods is high, the biochemical pathway that breaks down purines has to work overtime. In susceptible individuals, this results in an accumulation of uric acid crystals formed by the enzyme xanthine oxidase (XO)’s action in the penultimate step in the breakdown of purines. Uric acid accumulation initiates an inflammatory response resulting in the characteristic pain and inflammation unique to gout.
In the 1950s, right about the time when there was a flurry of activity as the structure of DNA was being sorted out, researchers like Gertrude Elion and George Hitchings were studying purine metabolism in an effort to treat cancers: two of the four nucleic acids in DNA are purines (the other two are pyrimidines). Their research led to drugs to treat childhood leukemia, two of which are in use even today — 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG). But in the course of these studies, they also discovered allopurinol, a drug that binds to XO, preventing it from catalyzing the formation of uric acid crystals, and thus reducing the chances of a gout attack.
The long arm of inflammation thus reaches beyond a minor inflammation resulting from a paper-cut, to chronic diseases like arthritis. In fact, as we learn more about diseases, we are likely to find that inflammation rears its head in some form or other in almost all of them. However, because of the complexity and interconnectedness of biochemical pathways, we will need to have exquisitely refined and targeted ways to intercept or temper the process of inflammation while keeping the rest of the pathways intact.
