Foie Gras (7) What do you mean by inflammation?

This paper contains a very superficial and bullet point overview of the inflammatory cascade. It omits swathes of anti inflammatory pathways and many of the boxes on the chart could be massively expanded. The paper is interested in using phytotoxins (mis-termed phytonutrients) as anti inflammatory agents, so all I take from the paper is their doodle

Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals

A legible version of the diagram is in the paper if anyone would like to actually read it.

We can simplify the process slightly with the red arrow. In addition I've circled in blue the component that is being used as a marker of inflammation in the Vaughan paper:

We can now consider the basic process a little more carefully. This massive review (no, I've not read it all) brings to prominence the central role of ROS in inflammation

Reactive Oxygen Species in Inflammation and Tissue Injury

and has this nice illustration featuring mitochondria as sources of ROS. Superoxide generation is never accidental. It is a tightly controlled and highly specific process to achieve certain ends. Mitochondria and NOXs are not making mistakes or having accidents:

BTW MPO is the myeloperoxidase we've seen recently in Vaughan's paper. HOCl is bleach, it's an inflammatory tool. We use it to kill germs.

So this lets us redraw this doodle of inflammation with a small modification:

Right up at the top of the inflammation doodle is a small red circle labelled PLA2, phospholipase A2. Its job, in the event of tissue injury, signalled by ROS and derivatives, is to release arachidonic acid from lipid membranes which then allows the generation of a raft of inflammatory mediators using cyclooxygenase and lipoxygenase enzymes.

Corticosetroids are potent suppressors of PLA2. They also releases both glucose and FFAs from the liver and adipocytes in to the blood stream. Physiological cortisol does this to deal with the sort of situation where you and a bunch of your mates are about to go and drive an angry mammoth into a bog, to kill it and butcher it. But high FFAs and high glucose together generate metabolic ROS, which are pro inflammatory.

You want raw energy, not to be crippled by an acute inflammatory reaction. So cortisol also down regulates the inflammatory cascade which *should* have been triggered, via ROS from the ETC, while flooding mitochondria with large amounts of substrate in anticipation of incipient need.

So cortisol floods your metabolism with calories, simultaneously controlling inflammation, and your mitochondria convert those calories in to the ability to successfully kill a mammoth, ie obtain food for a month for you and your tribe. Those calories get used successfully. Nothing is overloaded, nothing is damaged. Glucose and FFAs get used up during the hard work involved, facilitated by AMP-kinase rather than insulin. There is no generation of bulk inflammation, and what minor ROS mediated lipid peroxidation does occur has the routine inflammatory response suppressed. 

Evolution sets the levels correctly. It may be blind but it recognises functionality when it sees it.

Now imagine you're an Homo modernus visiting your bank manager in the 1960s to get a mortgage with a borderline adequate income and a just passable deposit, for the house of your dreams. The manager is a local petty Hitler and, even if he intends to grant the mortgage, he's going to really make you suffer, mentally, for it. Because he can.

You're stressed pre interview. So cortisol floods your system. Glucose and FFAs are made plentiful to allow you to fight at your hardest during a necessary mammoth kill. But there are consequences to killing the bank manager and most people, understandably, decide not to do so. Much as they might wish to. Especially if he refuses to grant you the debt you can barely afford. For your safety. There is no energy usage, no AMPK activation, just a serious availability of calories.

If the levels are high enough they will flood your mitochondria and provide substrate well in excess of what is needed for current ATP demand. If ATP synthase refuses to turn because ATP is high and ADP is low, while NADH and FADH2 keep supplying electrons to the ETC at the CoQ couple, delta psi will rise above that safe figure in the region of 170mV and ROS will be produced in large amounts from multiple sites, giving both insulin resistance and tissue damage.

You can use pharmaceuticals to inhibit phospholipase A2 as much as you like to avoid any response to this damage, classically using prednisolone or dexamethasone, but there is still the flood of calories generating ROS at tissue damaging levels. You might feel okay because the whole inflammatory cascade is suppressed, but cells are still dying from high ROS levels. If these happen to be endothelial cells lining your coronary arteries you are in trouble. Some will be.

So I would posit that the increased risk of CVD under corticosteroids could be (in part, there are many other issues) an effect of acute ROS injury. Under corticosteroids the inflammatory response is suppressed but the excess calories are still generating excess ROS. The damage is still done.

Of course the same applies to metabolic syndrome.

I define metabolic syndrome as the inability to shut down FFA availability in the presence of insulin and elevated glucose. FFAs are high from basal lipolysis at the same time as glucose from the diet causes hyperglycaemia. If substrate supply is high enough ROS will be generated and damage will be done. This time there will be an actual inflammatory response, no corticosteroid involved, and people can make statements like "obese people are chronically inflamed". They are producing mitochondria mediated ROS to physiologically resist insulin. If they are forced to continue to accept calories despite resisting insulin, the ROS become simply damaging. Inflammation follows. 

If you do not link this "inflammation" back to ROS then you would, logically, treat it with dexamethasone. Which would be a booboo, as we say in the UK. You would suppress inflammation while supplying even more ETC input, so worsening ROS mediated damage. Those poor coronary artery endothelial cells. In the absence of slaughtering a mammoth of course.

It's also worth thinking about the role of 4-HNE. Just a skim of the abstract of this book chapter is worth a moment:

Oxidative Stress-Induced Lipid Peroxidation: Role in Inflammation

4-HNE is, in itself, a product of ROS damage. It is also a generator of ROS per se. Much of the inflammatory cascade is self amplifying (which is why we have systems to turn inflammation off as well as on). Taking exogenous 4-HNE has profound effects on ROS mediated signalling in the insulin cascade, at low dose by injection to enhance, at high dose (with other lipid peroxides) orally to inhibit. It matters in the inflammatory cascade as much as in the insulin cascade.

My interest, getting back to Vaughan's obese mice without hepatic inflammation, is rooted in the factors which generate 4-HNE in situ around the ETC and which factors stop this. I'm talking about ROS generation.

Back to those mice and their non-inflamed hepatocytes and adipocytes.

Peter