Fundamentals I: 11:00 - 12:00 Scribe: Melissa Precise

Fundamentals I: 11:00 - 12:00 Scribe: Melissa Precise

Thursday, November 12, 2009 Proof: Matthew Davis

Dr. Anderson Acute and Chronic Inflammation Page 1 of 7

I. Chronic Inflammation [S31]

a. Talked about Acute inflammation in the first hour. Remember that is vascular changes and neutrophil recruitment.

i. Want everything to be fine and the neutrophils just come out and clean everything up so that everything goes back to normal. This is what we call Resolution.

1. The organ works fine – there is no scar tissue – there is nothing left behind.

b. Acute Inflammation can leave behind some damage.

i. Remember talked about slopping eating and there was collateral damage due to the overzealous lysosome.

c. If cannot kill right away, or if have a splinter or something that causes more and more recruitment of cells to that area, then cannot just go and clean up and be gone when so many cells come in.

i. There tends to be a formation of an area that is permanent tissue damage.

1. This would be like an abscess formation or liquefactive necrosis.

ii. The underlying tissue dissolves away (is not there anymore). How do you heal something when there is nothing there?

1. Heal by forming a scar.

a. Scar tissue formation is fibrous connective tissue formation

d. Either get resolution or get abscess formation or liquefactive necrosis type formation followed by scar tissue.

II. Figure of Chronic Inflammation Starting [S32]

a. One of the first things that happens in acute inflammation is fluid.

i. Fluids are followed by proteins.

ii. Proteins are followed by neutrophils.

iii. Finally have macrophages coming out.

b. Now going to transition to later when macrophages come in after neutrophils have died primarily of apoptosis.

i. That is what call chronic inflammation.

c. After chronic inflammation, body has to heal the mess that is made which is the wound healing process.

III. Outcomes of Acute Inflammation [S33]

a. We have injury and then have acute inflammation.

i. Either resolves or can have abscess formation.

ii. Then have healing and scarring.

IV. Outcomes of Acute Inflammation [S34]

a. If acute inflammation hangs on for a long time – it cannot kill the bacteria.

i. If acute inflammation just keeps going on and on – it is going to become a chronic inflammation.

b. As shown in the diagram, certain things can cause to directly go to the chronic inflammation bypassing acute inflammation.

i. Examples include fungal infections, which take a while to clear and usually induce chronic inflammation from the get-go.

V. Chronic Inflammation [S35]

a. What is Chronic Inflammation?

i. Proceeded directly to next slide.

VI. Cell Types in Chronic Inflammation [S36]

a. The main thing about chronic inflammation is that it is the same process as acute inflammation except that the main mediator cells are macrophages.

i. With acute inflammation – get burst of fluids, proteins, and neutrophils with macrophages coming in later.

b. When macrophages come in – chronic inflammation begins

c. The macrophages are not just circulating macrophages. A lot of the tissues in the body have resident or fixed macrophages.

i. Kupffer cells reside in the liver – these are macrophages

ii. Pulmonary Alveolar Macrophages – stay in the alveolar lung region and stay there all of the time. They do not have to be recruited – it is just where they live.

iii. Histiocytes – reside in the connective tissue

iv. Microglia – in the brain

1. So when see tiny cells in the brain – these are macrophages

2. These are phagocytic cells from the macrophage line

v. Osteoclasts – cells that chew up bone for remodeling

1. Lineage of macrophages

vi. Spleen/Lymph Nodes – Have reservoirs of macrohages all over the body

vii. Langerhans cells in the epidermis

1. Whenever in contact with anything (any outside allergen or protein) will bind to the protein and interacts with T cells to elicit antibody reaction or cell mediated immune reaction.

viii. So these are all resident or fixed tissue macrophages.

VII. Figure of What Happens When Macrophages are Recruited to an Area? [S37]

a. What happens if want to recruit macrophages to an area?

i. Same paradigm dealt with neutrophils in acute inflammation.

1. Inside the blood vessel – have circulating monocytes (monocytes when in bloodstream)

2. Go through the same process of rolling and pavementing with the eventual immigration through the wall of the vessel out into the tissue.

3. Once inside tissue – known as a macrophage.

a. So macrophages are circulating monocytes that come out of the blood vessels into the tissue

4. Once out into the tissue – have a variety of non-immune activators

5. One of the most important regulators of macrophage function is activated T lymphocytes

a. Primarily CD4 lymphocytes

b. Where else are CD4 T cells a big deal?

i. AIDS

ii. Why such a big deal?

1. Because the HIV virus kills the cells that regulate macrophage function

2. Activated CD4 T cells are the main activator or regulator of macrophage function to end up with an activated macrophage

ii. In activated macrophages, Nucleus tends to get bigger and is darker staining because DNA is actively making RNA. There is a lot of RNA in there and the RNA is coming out of the nucleus into the cytoplasm to produce proteins.

iii. Once the cell is activated – it is starting to do its job

1. A lot of it’s job is to produce cytokines that modulate and regulate inflammatory reactions

2. A lot of the things that it does is related to tissue injury and how modulates tissue injury in the process of cleaning up the mess from the inflammatory process.

3. As beginning process of cleaning up the mess, it is beginning the groundwork for the healing process.

b. So get acute inflammation followed by chronic inflammation followed by wound healing.

c. Macrophage is between finishing up cleaning component and starting the wound healing process.

VIII. Other Cell Types [S38]

a. Other cells types involved in Chronic Inflammation

i. Lymphocytes

1. Talked about CD4 lymphocytes but also B cells are important in chronic inflammation

ii. Plasma cells

1. Are important in making antibodies

iii. Eosinophils

1. Either acute inflammation or chronic inflammation

2. As could imagine with parasitic infections or allergies, those usually have sort of an acute exacerbation. Also kind of last a long time, so eosinophils can kind of be considered in the chronic inflammation.

a. If have parasite, chances are that you are not going to be able to kill it right away and therefore have the parasite for a period of time. So going to have a chronic inflammatory reaction.

iv. Mast Cells

1. Also components in the chronic inflammatory response

IX. Granulomatous Inflammation [S39]

a. Sequenon of chronic inflammation is granulomatous inflammation

b. Granulomatous inflammation

i. Type of chronic inflammation in which see focal accumulations of activated macrophages with an epithelial like appearance.

1. We call these epithelioid macrophages

a. These are activated macrophages that are out there for a while and instead of moving around like we saw earlier in the video- they just kind of sit there.

b. Under the microscope, they look like epithelial cells – so call epithelioid macrophages.

ii. The focal accumulation is what we call granulomas

1. These have specific morphology and will show examples later

2. Just like inflammation itself, they are a microscopic aggregation of epithelioid macrophages surrounded by a collar of lymphocytes and occasionally plasmid cells

c. So chronic inflammation often has accumulations of activated macrophages which are called granulomas and when have chronic inflammation with granulomas in it – we call that granulomatous inflammation

X. Recruitment Stage of Macrophages [S40]

a. Recruitment stage – when monocytes are floating in the blood stream and come out into tissues because of chemotaxis

b. Unlike the neutrophils that just come out and die – macrophages can divide.

i. So once monocyte is out of blood stream and becomes a macrophage. It can go through cell division.

1. So now have a bunch of macrophages dividing.

2. When activated, produce cytokines.

a. One of the cytokines produced is an immobilization factor.

i. So recruit macrophages to site and once there they produce cytokines that prevent them from running away.

ii. If it is a big bad bacteria that looks really ugly – they cannot run away so have to stay there and attack.

iii. As sits there since it cannot go anywhere, it keeps dividing. This is where get granulomas/ focal accumulation/ collection of macrophages

XI. Healing and Repair [S41]

a. Once have recruited the monocytes in to be macrophages and developed granulomas, then phagocytose the material and clean up the mess.

i. After this want to repair the tissue that has been damaged by the whole process.

XII. Process from Inflammation to Wound Healing Figure [S42]

a. Talked about acute inflammation to chronic inflammation

b. Finally going to talk about wound healing.

c. Inflammation

i. Part of it is acute and then going onto more chronic inflammation

d. Granulation tissue that occurs in the chronic inflammation is the beginning part of the wound healing process.

e. Granulomatous inflammation is first and then will have granulation tissue – these are two separate things.

i. When macrophages come in – going to start the wound healing process. So a bump in the graph where the wound healing process is starting.

ii. Once wound is healed, it has to mature.

1. The wound contracts and that is the final phase.

a. This occurs several weeks to months after initial inflammation

2. During initial phase of wound healing, have a lot of fibroblasts but not a lot of collagen.

a. Starting to lay down collagen (scar tissue)

b. Farther down the road will get more and more collagen.

f. Initially collagen is a very weak type of collagen.

i. Not very strong so doesn’t have a high tensile strength.

ii. Start out with Type III

1. This is like laying down the mortar to fix the hole that is there

iii. Over time starting to get Type I, which has a lot of cross-linking between the collagen fibers.

1. This is when the tensile strength goes up (due to cross-linking)

XIII. Cell Types with Different Regenerative Capacities [S43]

a. When think about wound repair – need to know what type of tissue was damaged

b. Need to know if tissue can proliferate or not.

c. Three types of cells

i. Continuously dividing cells

1. If get damaged the new ones keep dividing and replenish those that were damaged

ii. Quiescent/Stable cells

1. Usually not dividing, but if damage occurs can start dividing again

2. Ex. Liver cells will start dividing and to replenish the damaged liver

iii. Permanent cells

1. Have permanently left the cell cycle and will not proliferate at all.

2. Ex. If get stroke that damages the brain, the brain cannot proliferate because made up of permanent cells that are outside the cell cycle.

XIV. Extracellular Matrix [S44]

a. One thing about wound healing and the whole process

b. Everyone things that there are lots of empty spaces between all of the cells and between all of the players in the process. This is a common misconception.

c. One thing to remember about the body is that we don’t have a lot of empty space.

d. Likes this diagram because really shows the interstitial space.

i. In the tissue where all of the reactions are happening – there isn’t a whole lot of empty space.

ii. All cells in there are interconnected. There are various interkins and glycoproteins.

iii. More like a sponge in the tissues than individual cells that are separated by space – hardly any space.

e. Everything is hooked onto what is adjacent to it.

i. This is important because there is a lot of regulation that occurs between cell to cell interactions

f. During the healing process, cells don’t just start making a new organ. There has to be signals that control how they grow.

i. This is why the cellular matrix is very important in the wound healing process.

XV. Figure [S45]

a. Interaction between cells and fibrous tissues adjacent is not just by sticking to each other.

i. They are actually talking to each other.

ii. These receptors and cellular components are helping to regulate the nucleus of the cell.

b. Integrin receptors that are on the epithelial cell are interacting with neutrophils which are also interacting with collagen in the extracellular matrix. The collagen is interacting with the nucleus.

c. Depending on what is happening in the extracellular environment, all of the factors will help regulate what cellular messages are sent to the nucleus to determine what parts of the DNA of the nucleus are transcribed into mRNA and proteins.

d. Don’t think of extracellular matrix as just mortar holding bricks together.

i. Think of as an intricate command center that is regulating or manipulating the tissues that they are within.

XVI. Resolution vs. Repair [S46]

a. One of the classic examples.

b. Think of as the resolutions vs. repair by scar tissue.

c. Classical example is the proximal tubule of the kidney (artist rendition)

d. If in a car accident and go into shock – do not have enough blood to supply the kidney.

i. Proximal tubular cells are full of mitochondria and need lots of oxygen to stay alive. So EMT will try to get a catheter in to give fluids.

ii. Proximal tubular cells are not getting enough oxygen and are going to die – so all epithelial cells lining the proximal tubule die.

iii. Come into the hospital and recover. Given blood to survive.

1. Cannot urinate because do not have proximal tubular cells in kidney. So are put on hemodialysis for a few weeks.

2. During hemodialysis, the surviving cells that didn’t die lining the proximal tubule will divide and will repopulate the whole proximal tubule.

a. The reason they can repopulate the proximal tubule is because the basement membrane is still there.

b. The basement membrane with receptors can talk to the epithelial cells.

i. Tells hows to line up the correct way to make a proximal tubule.

e. What happens if instead of going into shock, a chunk of metal rips into flank and damages the kidney?

i. If proximal tubule is broken, then everything is confused and no basement membrane to tell how to line up.

1. Damage to the extracellular matrix and damage to the basal membranes.

2. Cannot make proximal tubules and will be on hemodialysis for life because cannot make new proximal tubule even though cell can still divide.

f. So difference between wound healing:

i. If have underlying structures (extracellular matrix, basement membrane, and a tissue that can divide and re-enter cell cycle or continually dividing), then can make new cells to line basement membrane and everything will go back to normal. This is how get resolution.