Top 10 Things to Know about Acute and Chronic Inflammation

1. Inflammation: what’s the point?

You'll notice as you go through pathology that you'll hear the word "inflammation" about every other minute. No kidding.

Inflammation is a pretty complex series of events by which white cells (mostly neutrophils and lymphocytes) get from the blood into the tissues where they are needed. What's the point of it all?

The main reason we have inflammatory reactions is to get rid of damaged tissue and foreign invaders (like bacteria). It's a protective mechanism...getting rid of the root problem (a microbe, say) and the resulting damage (dead tissue).

That's all well and good, but often inflammation gets triggered when it shouldn't be - and it ends up harming tissues rather than doing something protective. This happens in everything from atherosclerosis, to lupus, to stomach ulcers. For more on inflammation, see Robbins, page 44.

2. Four Latin words you should know

Okay - there are definitely more than four Latin words you should know. There are a few important phrases that would be good to have at the ready, such as:

Raptus regaliter. (Royally screwed.) Visne saltare? Viam Latam Fungosam scio. (Do you want to dance? I

know the Funky Broadway.) Cogito, ergo doleo. (I think, therefore I am depressed.) Magister Mundi sum! (I am the master of the universe!) ...and one that almost always works: Ita erat quando hic adveni. (It was

that way when I got here.)

Anyway. Four medically important Latin words that you should add to your repertoire were penned by Celsius in the first century AD and describe the cardinal signs of inflammation:

1. Rubor (redness)2. Tumor (swelling)3. Calor (heat)4. Dolor (pain)

For more historical tidbits on inflammation, see Robbins, page 44.

3. Exudate vs. transudate

I guarantee someone will ask you this on a test at some point: "What's the difference between an exudate and a transudate?"

Here's the answer:

An exudate is a fluid that has a lot of protein and cellular debris, and a high specific gravity (>1.020). It's formed during inflammation, when vascular permeability increases, and fluids, proteins and blood cells escape from vessels and pour into interstitial tissues or body cavities. Exudates are usually cloudy.

A transudate is a fluid with a small amount of protein (most of it being albumin), no cellular debris, and a low specific gravity (<1.012). It occurs when there is increased hydrostatic pressure (or decreased oncotic pressure) within the vessel; fluid gets filtered out of the vessel without any change in vascular permeability. Transudates are usually clear.

Bottom line: Exudates have a lot of protein and are usually caused by inflammation. Transudates have little protein and are usually caused by osmotic or hydrostatic pressure change.

For more on transudates and exudates, see Robbins, page 46.

4. Leukocyte recruitment

In order for leukocytes to fight infection or help clean up after an injury, they need to get out of blood vessels and into the affected tissue. The name for this process is "recruitment," and it consists of a series of steps:

Margination (the white cells start lining up along the vessel walls instead of just floating along in the blood)

Rolling (they then adhere briefly to the endothelium, detach, and adhere again, rolling along the wall until they reach a good stopping point)

Adhesion (finally, they stick firmly to the wall) Migration through the vessel wall Migration (by chemotaxis) through the tissue to the place they are needed

For more on recruitment of leukocytes, see Robbins, page 48.

5. Sometimes our white cells behave badly.

Examples of diseases caused by our own white cells are numerous:

ARDS (neutrophils) Transplant rejection (lymphocytes) Asthma (eosinophils) Septic shock (cytokines) Arthritis (lymphocytes, macrophages) Atherosclerosis (macrophages, maybe lymphocytes too) Pulmonary fibrosis (macrophages)

For more on white cells behaving badly, see Robbins, page 55.

6. How do you turn off acute inflammation?

Okay - so the neutrophils have shown up and done their job – now there needs to be a way to stop the process before all those enzymes start damaging host tissue. It turns out there are several ways that acute inflammation gets turned off:

The mediators of inflammation (like histamine, cytokines, chemokines) die off (they have short half lives and are degraded quickly).

Neutrophils themselves die off (they die by apoptosis a few hours after leaving the blood).

Arachidonic acid production switches from pro-inflammatory leukotrienes to anti-inflammatory lipoxins.

Macrophages release anti-inflammatory cytokines (like TGF-beta and IL-10).

Anti-inflammatory mediators called resolvins and protectins (they sound like household cleaners to me) are produced.

For more on termination of the acute inflammatory response, see Robbins, page 56.

7. The cytokine secret

Here's something I learned in medical school that has never failed me. You can't do this all the time, or people will catch on...but if used judiciously, it can get you out of a tight spot.

If anyone asks you the mechanism of some disorder (whether it's inflammatory, immunologic, neoplastic, or infectious) and you don't know the answer, you can say it's a cytokine-mediated mechanism and list off a few of the following cytokines and their functions, effectively overwhelming the question-asker, and boring him or her to tears. Done!

There are 6 main cytokines that are involved in inflammatory responses. Not a bad idea to try to remember these:

1. TNF (tumor necrosis factor): stimulates expression of endothelial adhesion molecules; stimulates release of other cytokines

2. IL(interleukin)-1: similar to TNF; big role in fever3. IL-6: secreted by macrophages; has systemic effects4. IL-12: secreted by macrophages; increases production of IFN gamma 5. IFN (interferon) gamma: secreted by T cells; tells macrophages to go kill

bugs and tumor cells6. IL-17: secreted by T cells; calls in neutrophils and monocytes

For more on cytokines, see Robbins, page 61…but be prepared with a pot of coffee, or at least several Monsters.

8. The dude abides

The macrophage is considered to be the dominant dude in chronic inflammation. Macrophages help get rid of the inciting cause of injury (such as a bug), and they initiate the process of repair.

There are several other cell types, though, that also play important roles:

Lymphocytes (activate macrophages, participate in antibody-mediated and cell-mediated immune reactions)

Plasma cells (make antibodies) Eosinophils (contain major basic protein which is toxic to parasites - but

also damaging to epithelial cells) Mast cells (bind IgE, release mediators like histamine and prostaglandin;

secrete other cytokines too)

For more on the cells in chronic inflammation, see Robbins, page 72.

Jeff Bridges as The Dude in The Big Lebowski.

“You can call him The Dude or His Dudeness, or uh, Duder, or El Duderino if you’re not into the whole brevity thing.”

Macrophage eating Mycobacterium tuberculosis bacilli.

You can call it the macrophage, or his macrophagenificence, or uh, mϕ, or El macrophagerino if you’re not into the whole brevity thing.

9. The six major granulomatous diseases

Can you list the 6 major granulomatous diseases? If you want to try, read no further...and scroll down when you're ready.

Here they are:

1. Tuberculosis2. Leprosy3. Syphilis4. Cat-scratch disease 5. Sarcoidosis6. Crohn disease

For more on granulomatous disease, see Robbins, page 73.

10. What exactly is the acute-phase response?

Here's a term that gets thrown around a lot, but is rarely defined: acute-phase response. It's discussed very nicely in a readable section in Robbins on page 74. Basically, the acute-phase response is the body's reaction to acute inflammation.

It consists of several features:

1. Fever. This is mediated by cytokines like IL-1 and TNF, which stimulate the production of prostaglandins, which in turn stimulate neurotransmitters that reset the body's temperature set point to a higher level. Fever probably helps you kill bugs - though the mechanism hasn't been found.

2. Increased acute phase proteins. The most well known of these are C-reactive protein, fibrinogen, and serum amyloid A protein. These things are made by the liver, and they have multiple actions that help the body locate and destroy bacteria.

3. Leukocytosis. Usually the count goes up to 15 or 20 (normal being 4-11) - but sometimes it can go as high as 100,000 (pretty uncommon).

4. A bunch of clinical findings including: increased pulse and blood pressure decreased sweating (redirection of blood from surface to deep capillary

beds) anorexia sleepiness chills, rigors (shivering) general malaise.

For more on the acute-phase response, see Robbins, page 74.