Acute Inflammation: Causes, Mediators, and Morphology

Objectives of the Session

This session ...

• What is inflammation?
• Acute inflammation
• What stimulates acute inflammation?
• How do blood vessels react?
• How do leukocytes react?
• When does it stop?

Mediators of Acute Inflammation

• Cell derived mediators
• Plasma derived mediators

Morphology of Acute Inflammation

• Gross pathology
• Histopathology

Understanding Inflammation

Can you think what the benefits of inflammation are?

Inflammation aims to ...
Get rid of damaged or necrotic tissue
Remove microorganisms or other foreign material
Sets the scene for regeneration or repair of tissues

Harmful Aspects of Inflammation

Inflammation can also be harmful
Hypersensitivities
Autoimmune reactions
Prolonged inflammation (covered more in the lecture on chronic
inflammation)

Cardinal Signs of Inflammation

Rubor (redness)
MATTO
Tumor (swelling)
Celsus,
3000BC
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)
Rudolf Virchow,
19th Century
Anti-inflammatory lipid mediators and insights into the resolution of inflammation
Toby Lawrence, Derek A. Willoughby & Derek W. Gilroy
Nature Reviews Immunology 2, 787-795 (October 2002)

Acute Inflammation: Response to Stimuli

Rapid response to stimuli
3 components:

• Increased blood flow
• Increased vascular permeability
• Leukocyte emigration

NORMAL
Extracellular matrix
Occasional resident
lymphocyte or macrophage
Venule
Arteriole
INFLAMED
1 Increased blood flow
Arteriole dilation
Expansion of capillary bed
Venule dilation
3 Neutrophil emigration
2 Leakage of plasma
proteins -> edema
From: Robbins and Cotran
Pathologic Basis of Disease

Stimuli for Acute Inflammation

Microorganisms
Parasites, fungi, bacteria and viruses
Microbial toxins
Receptors e.g. Toll-like receptors (TLRs) and cytoplasmic receptors
Necrosis
Ischaemia, trauma, physical and chemical injury
Molecules released from necrotic cells
E.g. uric acid, ATP, HMGB-1 (DNA-binding protein), DNA
Hypoxia
Hypoxia-induced factor 1a (HIF-1a)
Induces vascular endothelial growth factor (VEGF) - increases vascular
permeability
Foreign bodies
Cause trauma or carry microbes
Hypersensitivity reactions / autoimmune disease
Self antigens
Excessive reactions to environmental or microbial antigens
Reactions whereby the immune system damages the animal's own tissues

Reactions of Blood Vessels in Acute Inflammation

vasodilation causes increased blood flow to area which contributes to redness and heat
Blood vessels change in order to allow plasma proteins and cells out of the
circulation into the site of the stimulus

• Release of excess fluid into tissue or body cavities is called oedema
• Release of fluid and cells from the circulation is called exudation
• An exudate is an extracellular fluid rich in protein and containing cells
• Has a high specific gravity
• Pus (purulent exudate) is rich in leukocytes (mainly neutrophils),
  debris of dead cells +/- microbes
• Ultrafiltrates of plasma (i.e. no increased vascular permeability) are caused
  by loss of osmotic pressure or high hydrostatic pressure
• Creates a transudate with low protein content and little or no cellular
  material
• Has a low specific gravity

Blood Vessel Dynamics: Transudate and Exudate

Hydrostatic
pressure
Colloid osmotic
pressure
A. NORMAL
Plasma proteins
Increased hydrostatic pressure
(venous outflow obstruction,
e.g., congestive heart failure)
Fluid leakage
Į
Decreased colloid osmotic
pressure (decreased protein
synthesis, e.g., liver disease;
increased protein loss, e.g.,
kidney disease)
B. TRANSUDATE
Fluid and protein leakage
C. EXUDATE
Vasodilation and stasis
Increased interendothelial spaces
Inflammation
From: Robbins and Cotran
Pathologic Basis of Disease

Vasodilation in Blood Vessels

When the insult to the tissue occurs there may be a few seconds of
vasoconstriction
This is followed by vasodilation
First the arterioles dilate opening new capillary beds in the region

• Allows increased blood flow to the tissue
• Causes erythema (heat and redness) at the site

Vasodilation is induced by histamine and nitric oxide (NO) acting on the smooth
muscle of the vessels

Increased Vascular Permeability Mechanisms

Increased vascular permeability allows escape of protein-rich exudate into the
tissue (oedema)
Three mechanisms promote the increase in vascular permeability:

1. Contraction of endothelial cells (increasing interendothelial spaces)
2. Endothelial injury (necrosis and detachment)
3. Increased transport through endothelial cells (transcytosis)

These mechanisms are not independent and may all be occurring at the same
time with some stimuli

Endothelial Cell Contraction and Permeability

Contraction of endothelial cells

• Increased spaces between the endothelial cells
• Most common mechanism of increasing vascular
  permeability
• Typically an immediate and transient response:

• Occurs immediately after exposure to the
  mediator and is short lived (15-30mins)
• Mediated by numerous chemical mediators
• E.g. histamine, bradykinin,
  leukotrienes, neuropeptide P

Sometimes it is a delayed with prolonged leakage:

• Some forms of mild injury (e.g. after burns,
  X- irradiation or ultraviolet radiation, and
  exposure
  to certain bacterial toxins)
• Vascular leakage begins after a delay of 2
  to 12
  hours, and lasts for several hours
  or even days
• Caused by contraction of endothelial cells
  or mild endothelial damage
  endothelial cells shrink
  From: Robbins and Cotran
  Pathologic Basis of Disease

Endothelial Injury and Permeability

Endothelial injury

• Direct damage to the endothelial cells leading to
  necrosis and detachment from the basement
  membrane
• Encountered in severe injuries (e.g. in
  burns) or by the actions of microbes that
  target endothelial cells
  (endotheliotropic)
• Typically starts immediately after injury and is
  sustained for several hours until the damaged
  vessels are thrombosed or repaired
• Neutrophils can also damage the endothelial
  cells whilst they are adhered during inflammation
  From: Robbins and Cotran
  Pathologic Basis of Disease

Transcytosis and Vascular Permeability

Transcytosis

• Fluids and proteins can be transported through the endothelial cells
  (transcytosis)
• Channels created by vesicles and vacuoles (vesiculovacuolar
  organelle) located near intercellular junctions allow this transport
• Mediators, e.g. VEGF, can promote this transport by increasing the
  number and size of the channels
  From: Robbins and Cotran
  Pathologic Basis of Disease

Fibrin and Plasma in Increased Vascular Permeability

Fibrin

• Plasma leaving the vessel acts to dilute the stimulus of acute inflammation
• Fibrinogen is one of the proteins which leaves vessels in exudates
• Fibrinogen polymerises to form fibrin
• Fibrin stops the stimulus spreading into nearby tissue
• Allows the leukocytes to target the inciting cause of inflammation
• Assists in blood clotting
• Acts as a scaffold for endothelial migration during wound healing
  A1
  LEFT: Lungs,
  ox; Fibrinous
  pleuritis
  RIGHT:
  Lungs, pig;
  Fibrin and
  cellular debris
  on the pleural
  surface
  (between
  arrows)
  From Pathologic Basis of Veterinary
  Disease 6th Edition
  From Joint Pathology Centre

Stasis in Blood Vessels

Stasis
Fluid loss + increased vessel diameter
slower blood flow
Increased concentration of red cells
increased viscosity of blood
Slower blood flow + increased viscosity
stasis
Stasis is observed as vascular congestion

• Allows leukocytes to accumulate on the vascular endothelium
• Endothelial cells are activated by mediators of inflammation, so express
  increased levels of adhesion molecules
• Leukocytes can then adhere to the endothelium and then migrate through the
  vessel wall

Reactions of Lymphatic Vessels

Don't forget lymphatic vessels!
Lymphatics normally drain the extravascular fluid (lymph) and take it to lymph
nodes
Lymph flow is increased in inflammation, draining the oedema fluid
Leukocytes and cell debris also enter the lymph
Both lymphatic vessels and blood vessels proliferate during inflammation
Secondary inflammation of the lymphatic vessels can occur = lymphangitis
The draining lymph nodes may also become inflamed = lymphadenitis
The lymph nodes will often increase in size too, due to hyperplasia of the
lymphoid follicles = reactive/inflammatory lymphadenitis

Recruitment of Leukocytes

Recruitment of leukocytes

1. Adhesion to the endothelium
2. Migration across the vessel wall
3. Migration to the stimulus

Adhesion to the Endothelium

Adhesion to the endothelium
When blood is flowing normally through vessels, the red blood cells travel
centrally and the leukocytes travel peripherally
When blood flow slows and stasis occurs, due to inflammation, the leukocytes
start to make contact with the endothelial surface = margination
These cells start rolling along the endothelium before coming to rest and
adhering with the endothelium
Adhesion between the leukocyte and endothelial cell is by complementary
adhesion molecules
Cytokines, secreted by cells as part of the inflammatory response, enhance the
expression of these adhesion molecules

Selectins and Leukocyte Adhesion

Recruitment of leukocytes
Adhesion to the endothelium
Selectins are proteins which mediate rolling
L-selectin is expressed on leukocytes
E-selectin is expressed on endothelial cells
P-selectin is expressed on platelets and endothelial cells
The selectins bind to ligands
They are sialylated oligosaccharides bound to mucin-like glycoprotein
backbones
Both the selectins and their ligands are expressed in response to cytokines
Within a couple of hours of endothelial cells begin to express E-selectin and the
ligands for L-selectin
P-selectin is redistributed from its intracellular stores (Weibel-Palade bodies) to
the cell surface
L-selectin is expressed on the tips of the microvilli of leukocytes, along with
ligands for E- and P-selectin
The interactions between selectins and their ligands is low-affinity, so that the
bound leukocytes and bind, detach and re-attach quickly, allowing rolling along the
endothelium