Pathology, Lecture 7 (lecture Notes)

Inflammation

General pathology is a very important subject that you need to understand very well before proceeding to systemic pathology. So you should understand basic mechanisms of inflammation, injury + the main aspects of inflammation. After that it will be very easy for you to understand the subsequent courses (cardiovascular module, respiratory module ….. etc).

I think you have ready study the mechanisms of cell injury and today will start discussing the inflammation.

As you know any organism to survive need to eliminate the invaders from their body or from their tissues. And these invaders are made from infectious agents (microbes or dead tissues or …..). So the main process (mechanism) that these organisms beat harmful agents is what we called INFLAMATION. The inflammation is a dynamic process of chemical or physiological or cellular interactions that occur in response to stimuli that cause cell injury in the vascularized tissue. So you should know types of cell injury, the causes of cell injury .

Inflammation has beneficial and harmful effects on the body or cells.

Inflammation results in accumulation of leucocytes (white blood cells) and fluids in the extra vascular spaces or

tissues .

What is the effect of the inflammation? It is the elimination of the cause of cell injury (microbes, viruses, infectious agents)

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And after that this inflammation process will eliminate such agent (By diluting or neutralizing) and this will lead to necrotic cells (or dead tissues), also the process itself is taking care of this to eliminate such necrotic or dead or abnormal tissues or cells. After that it paves the way for proper repair (subsequent events of inflammation), we need to repair the tissue because inflammation of dead cells will lead to some kind damage, after this damage to the cells (blood vessels) we need to repair and this process will set the seam for subsequent repairing and other regeneration effect .

How do we call different kinds of inflammation of different body, (prefix pr suffix) (prefix which come before the word. or suffix after the word)For inflammation process we use the suffix –it is after the tissue nameFor example :-If we have inflammatory process in the appendix we call this inflammatory Appendicitis.

For the Dermis (of the skin) we call it Dermatitis.

For the Gallbladder we call it Cholecystitis.

For the Meninges (the membranes around brain and spinal cord) we call it Meningitis.

So what are the possible causes of inflammation?

(usually any cause that make cell injury will trigger an inflammatory response)

1 -Microbial infections: bacteria, viruses, fungi, parasites.

2 -Immunologic: hypersensitivity (contact with some substances that cause irritation like allergy) autoimmune reactions (in which the immune system attack the body antigens).

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3- Physical agents: trauma, heat, cold, ionizing radiation.

4- Chemical agents: acids, alkali, bacterial toxins, metals.

5- Foreign materials: sutures (surgical sutures in the operation. We usually see that the body attacks the sutures material), dirt.

6- Tissue necrosis: ischemic necrosis. Tissue necrosis, will lead to inflammatory process because the necrotic tissue (dead cell) must be removed from the bodySo who are the players in this process (the participants)? So there are different players from different categories which all together come to play this kind of inflammatory process:

All of them will be discussed in details later on-:

1- White blood cells and platelets (Neutrophils, monocytes, lymphocytes, eosinophils, basophils).

2- Plasma proteins: Coagulation, fibrinolytic system, kinin system, complements system.

3 -Endothelial cells and smooth muscles of vessels (The components of blood vessels).

{So we need to get some sort of endothelial damage and endothelial cell contraction to allow the increase of permeability of blood component to get out of blood vessel}

4- Extracellular matrix and stromal cells (stroma means the matrix or supporting tissue of an organ, as distinguished from its parenchyma or functional element.) :Mast cells, fibroblasts (a modified macrophages) , macrophages & lymphocytes - Structural fibrous proteins, adhesive glycoproteins, proteoglycans, basement membrane.

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You know the extra cellular matrix interaction is one of the most important things in pathogenesis of either inflammation (or any other reaction process) because the extra cellular matrix is directly controlling process or body on the growth of inflammation (interaction or different process).

So I will summarize the component of inflammation, you will see hereBlood vesselsSmooth musclesBasement membrane

In the normal situation there is just a little space between the cells and it allows only minimum escape some fluids (or proteins) outside to the extracellular matrix, and in these blood vessels we have different components, we have the plasma, plasma proteins and different kinds of white blood cells including (monocyte, neutrophiles, eosinophiles and basophiles, lymphocytes) also we have

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red blood cells and platelets in addition to this we have clotting factors (Kininogens and complement components) And out of this we have the connective tissue cells (fibroblast and macrophages and mast cells),Fibroblast is term of modified macrophages and it has the heredity to differentiate into fibrous tissue to rebuild damaged tissue and that is why we call it fibroblast.

We have the Matrix which contains the extracellular cells. And this matrix consists of a lot of fibers like elastic fibers, collagen fibers or proteoglycans. Anf the interactions between these cells and this matrix is very important to inflammatory process.

Is all inflammation is same (same type or same kind), the answer to this is No.Of course we have different kinds of inflammation, the main two types are:

Acute Inflammation and Chronic InflammationSo from the names Acute means (something that resolve rapid or quickly) and Chronic means (it takes longer time to be prepared) So what is the main difference here?

Acute Inflammation:

Duration: very short here (minutes to days)It is characterized by the Predominance of neutrophils (the

first arrivals) .

We have more exudation (Fluid & plasma protein) into the connective tissue,so it exudates because it has higher protein content .

Chronic Inflammation:

Duration: days to years.

It is characterized by the Predominance of lymphocytes and macrophages.

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Tissue destruction by the products of inflammatory cellsVascular proliferation and fibrosis (new blood vessels production) low exuadationWe are going to explain the two types in more details.

Acute Inflammation

Definition: Early response of vascularized tissue to injury.

The Aim of Acute Inflammation:

1 -Recruitment of neutrophils (white blood cells) in the first three days initially, and monocytes (after 3 days) to clear the cause of injury and remove necrotic cells.

2 -Deliver plasma proteins: antibodies, complement systems, others (which can help in counter acting and remove the infectious agents we have).

: The Two Components of Acute InflammationWe have two main components: the vascular changes & the cellular events

1 - The Vascular Changes :

We have three main mechanisms:

A- Vasodilatation (To deliver more blood and inflammatory cells to the site of infection to make more destruction of infectious agents)

B- Increased vascular permeability (which means we need to get proteins and components outside the blood to reach the site if inflammation or infection)

C- Stasis (Stasis means slowing down in the stream, it is immunological to have more leakage of the plasma and it's component. When a lot of plasma proteins go out the concentration of rbc's will increase so the blood will

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become more viscous and it will slow down. This will lead to margination of leukocytes because it's larger than rbc's.

2- The Cellular Events :

A- Emigration of cells from microvessels to outside.

B- Accumulation of these cells at sites of injury.

So the process is orchestrated by release of chemical mediators such two events (vascular and cellular) and the way that vascular changes happen or initiated and then the migration of cells are fully controlled and in a very good harmony by what we called chemical mediators and cytokines (are released by different kind of cells, the component of inflammation: Endothelial cells or Lymphocyte or the Monocyte …… etc to organize such process)

This is example of Acute Inflammation process of the blood and you see the predominance of neutrophils, so

this is example of pneumonia .

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So what are the Local Manifestations of Acute Inflammation?

Normally the hydrostatic pressure and the plasma colloid pressure will control the blood flow in and out of the vessel, the plasma colloid pressure is produced by the content of blood of proteins

The hydrostatic pressure is produced by the pressure of the fluid through the lumen to outside. So we have like counter acting each other keeping the balance between the fluid extra migration and fluid coming inside the cells

in a control pulse (we call this Homeostasis) .

In the figure above :

We normally have a net pressure to outside at the arteriolar side (the net forces are to outside). We need the blood to get out for nutrition and to eliminate the other

substances or to get oxygen etc……

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The pressure in the region in between the arteriole and the venule ( in the capillaries) is less different,it is equivalent.

The pressure in the venule side is usually (the net pressure) to inside and this is mainly to remove the fluid and the cells from outside back to the venule.

In the figure below:

You can see here, increase in the blood flow due to vasodilatation, endothelial contraction, escape of the fluid and the molecules to the outside which we call it exudation (if it contains high protein content) and of course lead to the inflame process.

There are five classic signs of acute inflammation

1 -Heat: It occurs because of the increase in the blood flow and this will increase the temperature at the site of the increase blood flow.

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2 -Redness: It occurs because of the Vasodilatation .

3 -Swelling:It occurs if there is more escape of fluid and proteins to the connective tissue you will have edema and this will lead to swelling.

4 -Pain:Of course such swelling, hotness and redness will compress the local areas and will lead to pains.

5 -Loss of Function:Serious pains will lead to loss function .

Now what are the specific forms of vascular changes that we have?

1 -Arteriolar dilatation follows transient vasoconstriction (the first initial step of the vascular changes)

2 -Increased vascular permeability and stasis: Arteriolar vasodilatation will lead to increase in the Hydrostatic pressure and lead to more fluid outside to the connective tissue and it will lead to what we call it transudate.

Later stages: the blood vessels become leakier and this will result in → loss (leakage) of proteins and more cells and this will lead to what call it exudate.

3 -Margination of leukocytes: the WBC is the larger than the RBC components so the RBC will flow through the centre of stream of the blood and the WBC will go around it near the periphery of the vessel.

Fluid Movement in Microcirculation in Normal Tissue:

In the Figure below:

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In the normal state the net flow is out (in arteriole side) & the net flow is in (in venule side) & there is no net flow of at the capillaries region .

Fluid Movement in Microcirculation in Inflamed Tissue

In this Figure below:

You can see here 1)that the net flow in the arteriole regoin is out and is longer than usual because of the vasodilatation and increasing blood flow .

2)The capillary also has more Hydrostatic pressure because the vasodilatation so there will be an out net flow in the capillary region unlike the normal state which doesn’t have.

3)the venule will become dilated also. So the net flow will be out of the venule unlike the normal net flow which is in.

Al that is due to-:

1-increase hydrostatic pressure due to vasodilation

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2-decrease plasma colloid pressure due to leakega of plasma protein . so the net flow will be out in all the micro vessels .

How does inflammation lead to leakiness of endothelial cells ?

1 - Endothelial cell contraction :

This will limiting the intracellular spaces between the endothelium, and this will allow the fluid to escape outside.

- It is Reversible.

-Immediate transient response with short life usually last for (15-30 minutes).

-Induced by: histamine, bradykinin, leukotrienes, neuropeptide substance P.

- Mostly in postcapillary venules.

2 - Endothelial cell retraction :

- It is also Reversible.

-It is more prolong Starts 4-6 hours after injury and stays for 24 hours.

- Induced by: IL-1, TNF, and IFN-g.

3 - Direct endothelial injury :

- Severe injury. Detachment of endothelial cells in order to increase exudation

- We call it Immediate Sustained Response.

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- All microvessels can be affected {which means arterioles, venules and capillaries can be affected}

4 - Delayed Prolonged Response :

-Begins after delay (2-12 hours), lasts for hours or days.

- Caused by thermal injury, UV radiation, and bacterial toxins. And affect only the venules and capillaries.

5 - Leukocyte-Dependent Endothelial Injury :

- Which is mediated by one of the activated Leukocyte which produce many toxin that will damage endothelium (cytokines)

6 - Increased Intracytosis (Transcytosis) of proteins through Vesiculovacuolar Pathway :

- This is mainly stimulated by VEGF (Vascular Epithelial Growth Factor); this means we will have more transport of protein and plasma through the vesicular pathways which are present within the cells (endothelial

cells) .

7 - Leakage from newly formed blood vessels :

- In any inflammatory process usually in later stages, we can get what we call angiogenesis; and this is probably one of the earlier stages of regeneration; creating more new blood vessels to bring more blood for such generation and repairing. These newly formed blood vessels still leaky until they mature enough to form intracellular junctions.

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Doctor: Your husband needs a silent environment so that he can rest. Here are some sleeping pills.

Wife: When will I give it to him?

Doctor: Those are for you! : Wink

. اللي مني مو هاي النغاشة. حطها اللي هو التفريغ كتب

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This is an example of Edema:

You can see the vesicle and this is because of accumulation of fluid outside the microvessles.

Edema in Inflammation has two types:

1 - TRANSUDATE : -Mechanism: hydrostatic pressure imbalance across

vascular endothelium (escape of more fluids) -Fluid of low protein content (ultra filtrate of blood

plasma) - Specific gravity <1.012.

2 - Exudate : -Mechanism: alteration in normal permeability of

small blood vessels in area of injury. - Fluid of high protein content (>.3g/dl) & increased

cellular debris. - Specific gravity >1.020 .

*someone ask the dr about the specific gravity and he answered that it just a number of measurement for a

test .

Cellular Events:

1 -Margination, rolling and adhesion. (we will go in details)

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2 -Transmigration between endothelial cells.

3 -Migration in the interstitium toward the site of stimulus.

4 -Phagocytosis and degranulation. Killing the infectious agent

5 -Release of leukocyte products.

This an example of Neutrophil Margination:

As you see thee rbc's in the center of the vessel and the leukocytes are around it .

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Done by: Waleed Al-NasserCorrected by : correction team

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Thanks to my all friends: Al-qaisi & Anagreh & Younes & Khtaeeb and to heroes team : Shlool & Quaz'a & Tamimi &

Qudsi …………

Special thanks for "Al-Hasan………… ".

W.W.M

WW

Forgive me for any mistake & sorry for the late…

When the Mirror of Life Gets Misty with the Fog of Reality, Just try wiping it with your Faith and You Will See the Clear Reflection of

your Dreams Once Again....

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