FMS III WO Week 5 dr.

Margareta

1. Acute and chronic inflammation

a) To discuss general causes of cell and tissue injuries
 Exogenous causes:
a. Physical agents
i. Mechanic agents: fractures, foreign corps, sand, etc.
ii. Thermal agents: burns, freezing
b. Chemical agents: toxic gases, acids, bases
c. Biological agents: bacteria, viruses, parasites
 Endogenous causes:
d. Circulation disorders: thrombosis, infarction, hemorrhage
e. Enzymes activation – e.g. acute pancreatitis
f. Metabolic products deposals – uric acid, urea

b) To describe morphologic pattern in acute and chronic inflammation

 Acute Inflammation :
These changes are
1. Changes in the blood vessel walls
2. Blood flow within the vessels
3. Exudation –both fluid and cellular.
 Chronic inflammation

c) To know and describe the pathophysiologic and morphologic which occur in acute and chronic
inflammatory response
- Atrophy
- Hyperplasia
- Hypertrophy

d) To appreciate the role of the acute inflammatory response in the body’s defense mechanism

Actually, inflammation is our normal body way untuk mengatasi penyakit yg akan timbul dari suatu penyebab
penyakit. Our infections, wounds and any damage to tissue would never heal without inflammation - tissue
would become more and more damaged and the body, or any organism, would eventually perish.

e) To list the local and systemic clinical changes as the result of acute inflammation

 Local :
- Swelling  blockage of tubes, e.g bile ducts, intestine
- Exudate  compression e.g cardiac tamponade; loss of fluid e.g burns
- Pain and loss function, especially if prolonged
- Bystander effect exacerbates damage, may initiate autoimmunity
 Systemic :
- Acute phase response
- Spread of microorganisms and toxins
- Shock, SIRS
 f) Describe the differences between pathophysiology and pathology of acute and chronic
inflammation

g) To describe the correlation between clinical signs and morphologic changes (macroscopic and
microscopic)

LO

1. Inflammatory response :
 Acute :

Overview

 Acute Inflammation is a general pattern of immune response to Cell Injury characterized by rapid
accumulation of immune cells at the site of injury. The acute inflammatory response is initiated by both
immune and parenchymal cells at the site of injury and is coordinated by a wide variety of soluble
mediators.

Cellular Pathogenesis

 Overview
o The pathogenesis of acute inflammation occurs progressively through several stages of
prominent cellular changes. Initially, vasculature within and around the site of injury responds by
increasing blood flow and enhancing vascular permeability. Subsequently, immune cells are
recruitment to the vasculature and extravasate into the injured parenchyma. Extravasated
immune cells then migrate to the injured cells using gradients of inflammatory molecules as a
guide, termed chemotaxis. Once immune cells reach the site of injury they proceed to
phagocytose and degrade cellular debris and any microbes which may be present.
 Vascular Changes
o Immediately following the injurious stimulus there is a brief period of arteriolar vasoconstriction
for several seconds followed by a sustained vasodilation of local arterioles allowing for
substantially increased blood flow to the injured area. Additionally, endothelial cells in local
capillary beds contract, generating spaces between the cells which substantially increase
vascular permeability. In some injurious scenarios, such as burns, increased vascular
permeability may be a result of direct damage to endothelial cells. Increased local blood flow
accounts for the clinically visible heat and redness associated with acute inflammation while the
increased vascular permeability accounts for the localized edema.
 Immune Cell Extravasation
o Following the initiation of vascular changes, a variety of leukocytes bind to involved blood
vessels and exit into the parenchyma. However, the primary immune cell type to do so in
settings of acute inflammation is the neutrophil. Binding and extravasation of leukocytes follows
a series of well-described stages.
 oMargination: The vasodilation described above generally slows the flow of blood at the site of
injury and causes immune cells to move toward the periphery of the vessel, next to the vascular
wall.
o Rolling: Marginated immune cells initially display transient, low affinity interactions with
endothelial cells which result in their slowing down and literal rolling along the vascular wall.
These interactions are mediated by Selectins.
o Adhesion: Rolling sufficiently slows the immune cells to allow for much higher affinity
interactions between leukocyte Integrins and endothelial ICAMs to take place. These
interactions strongly adhere the cells to the vascular wall, stopping their further travel through
the blood stream.
o Extravasation: Once bound to the vascular wall immune cells extravasate into the parenchyma
by squeezing between endothelial cells. Interestingly, transmigrating leukocytes must dissolve
the underlying basement membrane using a variety of proteases
 Chemotaxis
o Newly extravasated leukocytes migrate to the site of injury along gradients of soluble chemical
mediators (Chemotactic factors). Some of these chemotactic factors are secreted by host cells
at or near the site of injury while others may be shed microbial components.
 Phagocytosis
o Upon arrival at the site of injury, immune cells begin to phagocytose and degrade cellular debris
along with any present microbes. Ultimately, clearance of injured host cells and removal of
microbes is the prime goal of the entire inflammatory process. However, some recruited immune
cells such as Macrophages and Dendritic Cells additionally travel to local lymph nodes with
degraded phagocytosed debris and act as Antigen Presenting Cells, thus initiating a potential
Adaptive Immune Response to a microbe, if present.

 Chronic :

Overview
Transition to a pattern of chronic inflammation develops following weeks of an unresolved inflammatory
process and can last months or even years. The molecular mechanisms by which this transition occurs is
poorly understood and only a few clues are beginning to be understood. What is clear is that the basic
demographic of immune cells changes at the site of injury as inflammation evolves into a chronic phase.
Following the initial injury, tissue repair processes are also activated; however, in settings of chronic
inflammation these repair processes become engaged chronically and thus can lead to significant architectural
distortion of the affected tissue.
Etiologies
A wide variety of etiologies can result in chronic inflammation with the key theme being that the initiating
source of cell injury remains unresolved. The source of injury may be a persistent microbial infection,
persistence of toxic particles, or the continuation of autoimmune pathogenic mechanisms. Whatever the case,
chronic inflammation evolves when the initial, acute inflammatory response cannot eliminate the source of
cellular injury.
Morphology
The prime feature of chronic inflammation is the prominent presence of macrophage and lymphocytes,
including \B-cells, Plasma Cells, and T-cells, at the site of injury. Consequently, chronic inflammation is
characterized primarily by a mononuclear cell infiltrate with a small contribution from or completely absent
presence of Neutrophils. When chronic inflammation is due to a parasitic infection, eosinophil and mast cell
may be a prominent feature of the infiltrate. Concomitant with the inflammatory process, histological features of
tissue repair are also observed. This may include features of angiogenesis as well as deposition of
extracellular matrix by fibroblasts which over time may lead to overt fibrosis.

2. Production of pus
During infection, macrophages release cytokines which trigger neutrophils to seek the site of infection
by chemotaxis. There, the neutrophils release granules which destroy the bacteria. The bacteria resist
 the immune response by releasing toxins called leukocidins.[3] As the neutrophils die off from toxins and
old age, they are destroyed by macrophages, forming the viscous pus.
Bacteria that cause pus are called pyogenic.
When the source of injury is concentrated and intense, large numbers of neutrophils may be recruited
to the site of injury. Neutrophils often release potent degradative enzymes into the surrounding tissue
which can severely damage host cells and result in significant destruction of tissue architecture. The
combination of recruited neutrophils which rapidly undergo apoptosis together with damaged cellular
debris and any present microbes manifests as an Abscess.
The whitish-yellow, yellow, yellow-brown, and even greenish color of pus is the result of an
accumulation of dead neutrophils.
Pus can sometimes be green because some white blood cells produce a green antibacterial protein
called myeloperoxidase. Pseudomonas aeruginosa, a bacterium, produces a green pigment called
pyocyanin. Pus from infections caused by P. aeruginosa is particularly foul-smelling. If blood gets into
the affected area the yellowish or greenish color may also have tinges of red.

3. Cell injury mechanism

There are 3 main hallmarks you can always expect to find in reversibly injured cells.

1. Depleted resources of ATP in the cell owing to decreased levels of Oxidative Phosphorylation.
2. Hydropic Cellular Swelling, a phenomenon caused by changes in ion concentrations and water influx.
3. Organelles within the cell show subtle alterations.

But how do you recognize a cell undergoing reversible cell damage under a light microscope?

1. Cellular Swelling
1. Organelle Changes
2. Fatty Changes

ATP Depletion :

The major causes are :

- Ischemia
- Mitochondrial damage
- Certain toxins as cyanide

Mitochondrial damage  Damage formation of mitochondrial permeability  Leads to loss of membrane

potential  Failure of oxidative phosphorylation  Progressive ATP depletion and necrosis

Ischemia and certain toxins cause an increase in cytosolic calcium concentration initially by releasing calcium
from intracellular and later from increased calcium influx across the cell membrane. Increased cytosolic
calcium causes cell injury.

Cellular Swelling:

Cellular swelling, also known as hydropic cellular swelling is an enlargement of an acutely injured cell, caused
by changes in ion concentration and water influx. It is the first change to occur during cell injury, and is the
result of a damaged ability of the cell to regulate ionic and fluid homeostasis due to a failure of the energy
dependent ion pumps in the plasma membrane. [Recall that a hallmark of reversibly injured cell is ATP
depletion – we can see why these energy dependent ion pumps fail.]

Now let us remember that the concentrations of ions in a particular area of

the body determines its osmotic pressure. Thus, the higher the concentration
of ions, the higher the osmotic pressure, and the more water will move to the
area.

The mechanism of cellular swelling can be understood by understanding the

components of ionic regulation, particularly that of Na+.

The components of Na+ regulation include:

1. Plasma Membrane
2. Plasma Membrane Na+ pump.
3. ATP concentration.

Usually, the plasma membrane forms a barrier against excessive amounts of Na+ within the extracellular fluid
from entering the cell. However, the plasma membrane is slightly “leaky” to Na+, allowing minimal amounts of
Na+ to gradually move into the cell. To compensate this, there is a perpetually active Na+/K+-/ATPase pump,
that pumps Na+ out of the cell constantly, in exchange for pumping K+ into the cell. This K+ is able to leave the
cell freely. This ensures that Na+ does not buildup within the cell. In cellular injury however, 3 things may
interrupt this process:

1. The plasma membrane may be damaged, increasing its leakiness to Na+, and thus overriding the
capacity of the Na+/K+-ATPase pump to keep Na+ at low levels.
2. The Na+K+-ATPase pump may be directly damaged, and thus Na+ is able to slowly build up within the
cell without being removed.
3. Interfering with the synthesis of ATP, the fuel source for the Na+/K+-ATPase pump.

The end result of all 3 processes is that osmotic pressure builds within the cell due to increased ions, and
water and fluids move into the cell, resulting in the cell becoming swelled and water-distended. If this occurs in
multiple cells in a tissue or organ, then the organ appears enlarged, with increased turgor, some pallor
(paleness) and increased weight.

As extra fluid builds up in the cell, the cell becomes distended and cellular organelles appear to become more
spaced out within the cell. More importantly, most of the extra fluid actually builds within the endoplasmic
reticulum, causing the ER to appear much more distended. As time goes on, regions of the ER burst and
become encapsulated in clear vacuoles containing chunks of the ER. This is known as vacuolar degeneration.

Other histological organelle changes that occur with cell swelling include:

1. Plasma Membrane Alterations, such as blebbing, blunting and loss of microvilli. Blebs are focal
protrusions of the plasma membrane, and may occasionally detach, without a loss of cell viability.
2. Mitochondrial Changes, namely swelling and the inclusion of small, amorphous (ill-formed, vague)
densities rich in phospholipid, which correlate with the onset of irreversible damage.
3. Dilation of the cisternae of ER, with detachment of polysomes, vacuolar degeneration and presence of
intracytoplasmic myelin figures (which will be explained later).
4. Nuclear Alterations, with disaggregations of granular and fibrillar elements of the nucleolus.
Alternatively, the granular core may completely disintegrate, leaving only a fibrillar element.
And here’s how hydropic cellular swelling looks under the microscope:

Fatty Change (Steatosis):

Yep, fatty change is called steatosis. This steatosis is caused in hypoxic, toxic and metabolic injuries and is
related to a dysfunction in the cell’s regulation of synthesis and elimination of triglycerides.

Excess lipids accumulate within the cells, usually parenchymal cells, that forms numerous vacuoles that
displaces the cytoplasm. If these vesicles are large enough to displace and distort the nucleus, it is referred to
as macrovesicular steatosis, as in the diagram below. If not, and the nucleus is undistorted, and there are
fewer and smaller vesicles, then microvesicular steatosis results, as shown below. Steatosis is actually a
scenario that occurs in several diseases, and thus there is no one clear mechanism, but rather a number of
different mechanisms. To simply categorize steatosis, we can divide diseases associated with microsteatosis
and macrosteatosis.

Inflammation process :

1. Pathogen atau kecelakaan fisik menyebabkan kerusakan cell dan disruption pada extracellular
matrix of the involved tissue.
2. Reaksi awal nya adalah vasoconstriction pada vessel di daerah injury (decreased vascular size)
3. Tubuh mengeluarkan macrophages and fibroblast to isolate and localized the tissue trauma.
4. Mast cells come and release histamine to increase dilation and vascular permeability.
5. Increased vascular permeability is caused by the contraction of endothelial cells in blood vessels,
causing plasma bisa keluar vessel (leakage)
6. Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space
as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure
intravascularly.
7. Lebih banyak plasma yg keluar dari intravascular causes increased viscosity of the blood and
menyebabkan slowing of the blood flow to allow chemical mediators and inflammatory cells to
collect and respond to the stimulus.
8. Edema causes increased in extravascular pressure  Menekan dan block vascular, lymphatic, and
nerve  Nyeri  cell dan saraf2 sekitar tertekan.
9. Jika ada blood vessel yg robek  Coagulation