Welcome to the lecture on inflammation. Some of you may think of inflammation as a bad thing and I will try to point out that in many cases, it's a very good thing indeed. I'm going to use yet another metaphor. In this case, the metaphor for being under a state of inflammation is like being under a state of full red alert, and they're very, very comparable. That is, you're in a situation where you have sensed a danger and you're marshaling your defenses to protect you from that danger. That's the good news. The bad news is that while you are on full red alert, your resources are taken away from other kinds of functions. If a military base is under full red alert, there's certain kinds of things it can't do, probably things that involve resupply or building new buildings. So, indeed, if you have some condition that puts you in a state of acute inflammation, you're not going to feel well, you're not going to be able to grow as well, you're not going to want to do things like think or any other positive things that require energy. So, inflammation is something that you want to raise up when there's a threat to be dealt with and when it's dealt with, you want to damp it back down again and use your resources in ways that again will advance your interests. Now, this process is actually fundamental to all forms of immune defense. All of the things that we've done for adaptive immune responses will not be upregulated if there's not an inflammatory response that sets in motion. This kind of response that you make to disease, to injuries, to any environmental insult is something that has been recognized since Roman times. The doctors of the Roman Empire were very good at what they did, and what they did was patch up soldiers in battle. In the Roman army, if you join the army, you retired with a full pension at age 40. Most Roman soldiers actually lived to be 40 years old and would retire to the provinces on a full pension. They were able to do that in part because the Roman army was really good at treating them when they were injured and feeding them and doing other things as well. So, from very early on, they recognize the effects of an injury and this is still described from Roman physicians today. Rubor, if you're injured the area gets red, calor, it gets hot, tumor, its swells, dolor, it hurts and finally later on, functio laesa, that is, you don't want to use it. All of these hallmarks of inflammation are still recognized today and we still honor the Roman physicians for having discovered them. On the other hand, we're also finding out about a lot more about what brings them out and how they're upregulated and how the whole thing works. Indeed, most of the signs, symptoms, hallmarks identified by the early Romans, come from vascular changes that make the local endothelium, the lining of the blood vessels, leaky and sticky. That causes fluid to leak out, it makes the area red and swollen, the signals responsible for that make you hurt and make you not want to use the injured part. That's a good thing. If you've got a nice new acute injury it really is better if you don't go back into the game and make it even worse. On the other hand, sometimes you have injuries that hurt long after they seem to have been healed and that's something that's not a good thing, and we'll look at that as chronic inflammation. All right. Something I've mentioned before, something that people have known since antiquity, when you get sick, you run a fever, and sometimes that very, very high fever is a sign that you're about to die. So, in antiquity, they thought, well, if we could just lower the fever, we could save people's lives. They're mixing up cause and effect here. One of the techniques that they used for lowering a fever was bleeding, and it works. You bleed somebody, their fever goes down, well, they die anyway sometimes but that bleeding will really will lower the inflammatory response because it lowers the body's ability to essentially shunt fluid and stuff into various sites of infection. All right. Now, here is the weird thing, and this is something we're going to look at later on, while I'm not recommending bleeding for most diseases, chronic inflammatory responses are often mitigated by a variety of things that involve increasing bleeding. That is and many things that are known to be anti-inflammatory increase bleeding as a secondary effect, and that's going to be things like statins and aspirins and fish oils and a huge variety of things that essentially, they are sometimes called thinning the blood. They don't really make the blood thinner, but they make it less likely to clot, and this makes sense too. If you're going to raise your inflammation, in many cases you're doing that in response to an injury, it makes sense to raise your clotting. If you're not going to do that or if you're going to lower your inflammation, the chances are you want to lower your ability to clot. So, this is the kinds of themes that I'm going to develop in a variety of ways throughout this lecture. Inflammation is good under certain circumstances and a royal pain in the other. Inflammation involves a series of changes that are helpful in some situations and a royal pain in the other. The things that lower inflammation often also have a number of side effects that you might not anticipate but if you think about it, it's going to make a lot of sense. So, let's go into some of the first mechanisms for raising inflammation and signaling.