Leukocyte Mediators: Arachidonic Acid Metabolites

00:01 So Leukocyte Mediators.

00:03 We have proteases. We've talked about that.

00:06 Reactive Oxygen Species. We've talked about that.

00:09 Very briefly, let's talk about Platelet Activating Factor or PAF It's made from membrane phospholipids.

00:16 It didn't causes not only vasodilation increased permeability, but also platelet activation, hence the name.

00:24 It's also an important chemotactic agent.

00:27 Cytokines and we've talked about cytokines giving you a definition talked about some of them.

00:31 Remember the CXC chemokines are part of cytokines but cytokines like interleukin-1 and tumor necrosis factor are also going to be important mediators.

00:42 And then finally, arachidonic acid metabolites.

00:46 And we're gonna spend a bit of time talking about those because those are really important and we have good drugs for those.

00:53 The arachidonic acid metabolites include prostaglandins, leukotrienes, and lipoxins.

00:59 So let's look at these very briefly.

01:02 The AA or Arachidonic acid metabolites are 20-carbon polyunsaturated fatty acids, they usually have four double bonds in this 20 carbon chain.

01:13 They are released from the nuclear membrane, interestingly enough, by the activity of cytosolic phospholipase A2.

01:21 We care about that because things like steroids will have important anti-inflammatory agent by blocking this release of arachidonic acid metabolites.

01:32 Steroids have other effects, but that's one of the things that it does.

01:36 So Arachidonic Acid Metabolites.

01:38 Once we release the 20 carbon polyunsaturated precursor, it is then acted on by number of enzymes in different cell types.

01:48 And there is going to be a major pathway that involves a molecule, an enzyme called cyclooxygenase, abbreviated COX.

01:55 And this is an important pathway because it's pro inflammatory.

01:59 And we can block it with nonsteroidal anti-inflammatory drugs.

02:05 So we can inhibit cyclooxygenase (COX) we things like aspirin, and things like naproxen.

02:13 So we can block this.

02:14 We have really good drugs, and it's very profoundly anti-inflammatory for those of you who have ever taken an aspirin or naproxen or any of those other nonsteroidals.

02:26 There is a separate pathway.

02:28 And we'll show this schematically in just a second.

02:31 The lipoxygenase pathway, and this is going to make leukotrienes which are going to have vasoactive effects.

02:36 They're going to change vascular permeability, and vasodilation.

02:40 But they're also going to be chemotactic.

02:43 And finally, lipoxins.

02:46 So you remember one of those truisms that I told you a long time ago, for every pro there's an anti? Well, at the same time that we're making pro inflammatory mediators like prostaglandins and leukotrienes.

02:58 Similar pathways in parallel are using arachidonic acid to make things like lypoxins, which are anti-inflammatory.

03:06 So it's a beautiful kind of yin and yang counterregulatory pathway.

03:12 Alright, let's get down into some details, because again, we have important molecules, and these molecules may have important inhibitory molecules.

03:23 And moreover, cyclooxygenase, and downstream molecules occur over and over and over again in your clinical care of patients, but also on board exams.

03:35 So arachidonic acid release from the nuclear membrane is then acted on by various enzymes, and the first one we're going to talk about is COX or cyclooxygenase.

03:45 And it makes a variety of downstream mediators.

03:48 These are not important yet.

03:50 I'll get you to the important one in a minute, but they're progressively acted on, and modified to make slightly different structures.

03:58 From cyclooxygenase, we can get prostacyclin, also abbreviated PGI2.

04:05 This is going to cause vasodilation and inhibit platelet aggregation.

04:10 So this is actually an anticoagulant prostacyclin.

04:16 So in the endothelial cells, the final pathways prostacyclin.

04:20 But I can take the same precursor prostaglandin H2.

04:24 And in platelets, I'll make thromboxane A2.

04:28 Same precursors, different cells with different enzymatic activities with completely opposite results.

04:36 Prostacyclin (anticoagulant), Thromboxane A2 (procoagulant) it causes vasoconstriction and it promotes platelet aggregation.

04:46 So again, Yin and Yang, a pro and an anti involving this same pathway.

04:54 Further down, we can also get PGD2 and PGE2.

04:59 These are other kinds of metabolites that happen in other cells and different enzymatic activities.

05:04 And these are pro inflammatory.

05:05 They're going to cause vasodilation, and increased vascular permeability.

05:10 Okay, so that's just one example.

05:11 They're actually, there are many other branch points.

05:13 This is simplified, believe it or not.

05:17 We can inhibit with COX inhibitors, COX-1 and COX-2.

05:20 there are different isoforms in different tissues.

05:23 But basically, aspirin and indomethacin will inhibit cyclooxygenase.

05:28 And then we don't get all of those effects.

05:31 We don't get the same procoagulant or anticoagulant effects.

05:34 We don't get the same inflammatory mediators.

05:37 That's why aspirin is so good at treating inflammation.

05:43 Okay, so that was one pathway, we've now grayed that out.

05:45 We're gonna go another pathway.

05:48 So mainly through the lipooxygenase pathway.

05:50 So a different enzyme in a different pathway.

05:54 And we're going to make now the leukotrienes.

05:57 These are in general pro inflammatory, and pro chemotactic.

06:01 So you can see that the molecules again, don't memorize the names of the words, just let the entire kind of feeling flow over you.

06:13 So some of these are involved in chemotaxis.

06:16 And some are involved in pro inflammatory processes vasoconstriction, bronchospasm, increased vascular permeability.

06:24 So mainly so far, we've been talking about pro inflammatory outcomes from arachidonic acid.

06:31 well, remember that we also have this other pathway making lipoxins And these are going to be anti inflammatory.

06:40 They're going to inhibit neutrophil, adhesion, and chemotaxis.

06:44 So these pathways are really important in driving a variety of inflammatory mediators and driving a number of the inflammatory processes.

06:55 And it's worthwhile kind of at least having a conceptual framework.

06:58 to think about them.

07:01 At that point, now, we've covered how we get inflammatory cells like neutrophils into the sites of injury, what they recognize when they get there, how they know what's a friend and what's a foe, and then how they eat them, and degrade them, and kill them, and some of the mediators that they make.

07:20 So that was a lot, but a very important set of concepts and even details that are going to you're going to encounter every day in your clinical lives.