Oxygen Free Radicals – Mechanisms of Cellular Injury

00:01 So clearly, we've seen this before, not enough oxygen is a bad thing.

00:06 We don't make enough ATP, we go to anaerobic glycolysis.

00:12 We don't want to do that unless we absolutely have to.

00:14 So too little oxygen a bad thing, too much oxygen in various forms can lead to damage as well.

00:23 And so, it turns out that inflammation as we talk about radiation we will talk about just increased oxygen levels.

00:34 Toxins and chemicals reperfusion injury will all lead to increased levels of oxygen and more importantly, oxygen metabolites.

00:43 These are reactive oxygen species and you need to hang on to this term ROS or reactive oxygen species because we're going to see this many, many, many times over the course of talking about pathology.

00:55 And ROS includes superoxide free radicals, hydroxide radicals and hydrogen peroxide.

01:02 And these, in high amounts or even moderate amount can cause significant damage.

01:09 And so you can have to low oxygen causing damage.

01:13 We can have ROS reactive oxygen species causing damage and there's reactive oxygen species come from that inflammation radiation oxygen toxicity etc.

01:22 So what's a free radical? It's an unpaired electron in an outer orbital.

01:27 So you have in the outer orbital one extra electron and it is very, very, very reactive.

01:36 That's the whole point.

01:37 For the chemist in the audience, that's a very simplified explanation.

01:40 For everybody else, it's a very reactive electron.

01:44 A nd it will affect every component of the cell, lipid, protein, nucleic acid.

01:50 So here's an example what it does to lipid, we're looking at a very simplified in the top right.

01:54 A membrane with the phospholipid, the tails, hydrophobic interacting with each other and the hydrophilic heads pointing out.

02:03 And you see that there are a lot of unsaturation in most of the phospholipids, that's the double bond, it's indicated there.

02:09 Along comes your not-so-friendly superoxide free radical or any of the other free radicals and it will break at those double bonds or it will cause peroxidation.

02:22 That's the oxygen looking like a little triangle across the double bond.

02:26 Or it will cause peroxy links, that's the double oxygen between various lipid tails.

02:35 The end result is that we turn a lipid bilayer into a detergent.

02:41 We've fragmented all of those lipid tails and it's now very, very soluble.

02:48 So the membrane integrity is lost as a result of the oxygen free radical damage.

02:54 So that's effect on lipids.

02:56 It also affects nucleic acids.

02:59 There was oxygen free radicals will cause thymine dimers as indicated on the right hand side.

03:04 And if we do excision repair, it's possible that we will get breaks or we will get defective genetic repair.

03:12 And we can also cause DNA breaks.

03:15 So just by having those oxygen free radicals, we can lose genome genetic integrity.

03:22 And proteins, same thing happens, we get breaks.

03:25 You can see that a normal protein with all of its folds is on the left hand side and then we get protein cross-linking and breaks and you can see gaps in the protein structure.

03:36 And you can also see cross-linking, so we can toward and distort the normal architecture.

03:41 And when that happens that protein, that was previously doing something important maybe enzyme activity or a structural protein is not able to do its job.

03:50 So for oxygen free radicals, radicals of any kind will cause damage to all three of those components and you can imagine that that has fairly dramatic effects on the cell.

04:02 Kind of another important point about free radicals besides the fact that it's the, you know, the unpaired electron in the outer orbital.

04:10 They are autocatalytic.

04:12 So nasty little buggers that they are, once they're formed, they tend to as they go about their business of breaking lipids or cross-linking proteins or causing thymine dimers.

04:23 They generate more free radicals.

04:25 So at each step, you not only do your thing, but you make another free radical.

04:32 So it's autocatalytic.

04:33 They just keep going.

04:34 It's like lighting a match to a bit of dry grass and it just keeps expanding.

04:42 An important other point is that we use this, so these are not just evil things that happen because of bad engineering.

04:50 This is happening normally, it's a normal component of inflammation.

04:54 So what's being shown on the right hand side is a neutrophil.

04:57 It's engulfing a bacteria.

04:59 How do we kill it? Once we've engulfed it, we douse it with reactive oxygen species.

05:05 It's very effective.

05:06 And that's how we, as we will see in subsequent topic discussions.

05:10 That's how we kill things that we internalize.

05:13 It's also very important for killing tumors.

05:15 So we use it as a normal component inflammatory cascade.

05:20 It's important also that you understand that reactive oxygen species, ROS free radicals contribute to the radiation injury.

05:27 So when we get zapped with gamma rays or any any radiation, that is one of the major toxicities.

05:35 It also has to do with increased oxygen toxicity of already mentioned in a previous topic discussion, that if if I put you in a hyperbaric chamber for a week, you will get pulmonary fibrosis.

05:45 Well, that's because you're generating too many oxygen free radicals.

05:49 And cellular aging, cellular senescence happens, because we have oxygen free radical damage that's happening at a low level and we may not completely, accurately repair that.