Acute Inflammation

Dr.Djumadi Achmad, SpPA(K)

“human body is continually exposed to
conditions that result in damage”
• Sunlight, pollutants, trauma
• Infectious agents – viruses, bacteria, fungi,
parasites
• Cancer – damage from within
Human Defence
“multilevel system of interactive defense”
• First line of defense – innate resistance – barriers
• Second line of defense – inflammation (innate)
• Third line of defense – adaptive (acquired)
immunity - memory
 Levels of Defence

1st Barriers-physical
-biochemical

2nd Inflammatory Response

-rapid (biochemical & cellular)
-nonspecific
3rd Adaptive
-specific
-memory
First Line of Defense
• Physical and mechanical barriers
– Skin
– Linings of GI, GU & Respiratory tracts
• Sloughing of cells
• Coughing and sneezing
• Flushing
• Vomiting
• Mucus and cilia
First Line of Defense
• Biochemical barriers
– Synthesized and secreted – saliva, tears, ear wax,
sweat and mucus
– Antimicrobial peptides (skin,urethra)
– Normal bacterial flora
Second Line of Defense
• Inflammatory response
“any injury to vascularized tissue”
 Inflammation
• “In-flame” – to set fire. (red, hot, pain)
• Inflammation is “dynamic response of
vascularised tissue to injury.”
• It is physiologic, protective response.
• Serves to bring defense & healing
mechanisms to the site of injury.
 Causes of Inflammation :
 Physical agents – Trauma, radiation
 Infection – microbial agents
 Chemicals – acid, alkali, toxins
 Ischemia / Infarction – necrotic tissue
 Foreign bodies - exogen/endogen
 Immune reaction - hypersensitivity
 Inflammation ...
• The protective vascular and connective tissue response to
tissue injury
• Dilute
• Destroy
• Isolate
• Start repair process
• Without inflammation, infections would go unchecked,
wounds would never heal, and injured tissues might remain
permanent festering sores
 The Sequential Steps of the Typical
Inflammatory Reaction
1) Recognition of the injurious agent
2) Recruitment of leukocytes,
3) Removal of the agent,
4) Regulation (control) of the response
5) Resolution (repair)
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 Recognition of Microbes and Damaged Cells

 Recognition of offending agents is the first step in all

inflammatory reactions

 Several cellular receptors and circulating proteins are

capable of recognizing microbes and products of cell
damage and triggering inflammation
 Cellular Receptors for Microbes
 Cells express 3 receptors site:
 Plasma membrane (for extracellular microbes)
 Endosomes (for ingested microbes)
 Cytosol (for intracellular microbes)
 The receptors act as cell sensor to the
foreign invaders in any cellular compartment
 Sensors of cell damage
 Cytosolic receptors that recognize a diverse set of
molecules that are liberated or altered as a
consequence of cell damage

These molecules include:

 Uric acid (a product of DNA breakdown),
 ATP (released from damaged mitochondria)
 Reduced intracellular K+ concentrations (because of
plasma membrane injury)
 DNA when it is released into the cytoplasm
 Cont..
• These receptors activate inflammasome
(a multiprotein complex)  cytokine IL-1
recruits leukocytes  inflammation
• Gain of function mutation in the sensor 
autoinflamatory syndrom
• The inflammasome also involved in: Gout
(inflamation to urate crysal), Lipid (metabolic
syndrom), atherosclerosis, and amyloid
deposit in the brain (Alzheimer Diseases)
 Acute Inflammation
• Short duration: minutes, hours, few days
• Vasodilation  redness and warmth (rubor, calor)
• Exudation of fluid and plasma proteins  edema
(tumor)
• Emigration of white blood cells, mostly neutrophils
to site of injury
• Tumor, rubor, calor, dolor
 Cardinal Signs of Acute
Inflammation
• Calor : Warm – Hyperaemia.
• Rubor : Redness – Hyperaemia.
• Dolor : Pain – Nerve, Chemical med.
• Tumor : Swelling – Exudation
• Functio laesa: Loss of function
 Surgical wound inflammation

Calor, Rubor, Dolor, Tumor, Loss of function.

 Acute Inflammation
• Immediate and early response to tissue injury
(physical, chemical, microbiologic, etc.)
– Vasodilation
– Vascular leakage and edema
– Leukocyte emigration (mostly PMNs)
 Acute Inflammation - Vasodilation
• Brief arteriolar vasoconstriction followed by
vasodilation in the area of injury
– Accounts for warmth and redness (rubor, calor)
– Opens microvascular beds
– Increased intravascular pressure causes an early
transudate (protein-poor filtrate of plasma) into
interstitium (edem – tumor)
 Figure 2-1 The major local manifestations of acute inflammation, compared to
normal. (1) Vascular dilation and increased blood flow (causing erythema and
warmth); (2) extravasation and extravascular deposition of plasma fluid and proteins
(edema); (3) leukocyte emigration and accumulation in the site of injury.
 Vascular Leakage
• Vascular permeability (leakiness) commences
– transudate gives way to exudate (protein-rich)
– increases interstitial osmotic pressure contributing
to edema (water and ions)
Principal mechanisms of increased vascular permeability in
inflammation, and their underlying causes.
Principal mechanisms of increased vascular permeability in
inflammation, and their underlying causes.
Recruitment of leukocytes to Inflammation Site

 The changes in blood flow and vascular permeability

are quickly followed by an influx of leukocytes into
the tissue

 The journey of leukocytes from the vessel lumen to

the tissue is a multistep process that is mediated and
controlled by adhesion molecules and cytokines
(chemokines)
 The Journey of Leukocytes

• In the lumen: margination, rolling, and adhesion to

endothelium
• Migration across the endothelium & vessel wall
• Migration in the tissues toward site of injury
(chemotaxis)
 Margination and Rolling

• With increased vascular permeability, fluid leaves the

vessel causing leukocytes to settle-out of the central
flow column and “marginate” along the endothelial
surface
• Early rolling adhesion mediated by selectin family of
adhesion molecules
• Endothelial cells and leukocytes have complementary
surface adhesion molecules which briefly stick and
release causing the leukocyte to roll along the
endothelium until it eventually comes to a stop as
mutual adhesion reaches a peak
Margination of neutrophils
 Adhesion

• Rolling comes to a stop and adhesion results

• Other sets of adhesion molecules participate, such as
the integrins
• Ordinarily down-regulated or in an inactive
conformation
 Migration (Diapedesis)

• Its occur mainly in postcapillary venules

• Stimulated by chemokines, and facilitated by
adhesion molecules (CD31 or PECAM)
• Migrate through interendothelial space 
pierce the BM  extravascular tissue
• Early in inflammatory response mostly PMNs
• Cytokine and chemotactic signals + adhesion
molecules  other leukocytes (monocytes,
lymphocytes, etc)
 Migration in the tissues toward site of injury
(chemotaxis)

• Chemotaxis: locomotion along a chemical gradient

• Exogenous: bacterial products (peptides and some
lipids)
• Endogenous chemoattractants:
• Cytokines : chemokine family (IL-8)
• Components of the complement system (C5a)
• Arachidonic acid metabolites: mainly LTB4
Cellular Event (margination, rolling, adhesion,
migration, phagocytosis & killing)
Migration of Neutrophils
 Phagocytosis

Phagocytosis involves three sequential steps:

 Recognition and attachment of the particle
to be ingested by the leukocyte.
 Engulfment, with subsequent formation of
a phagocytic vacuole.
 Killing or degradation of the ingested
material.
Lysosomal Enzymes & Other Lysosomal Proteins

 Neutrophils & monocytes contain lysosomal granules

 Neutrophils have 2 main types of granules
• The smaller (specific granules): lysozyme, collagenase,
gelatinase, lactoferrin, plasminogen activator, histaminase
• The larger azurophil granules: myeloperoxidase, lysozyme,
defensins and acid hydrolases
 Both types of granules can fuse with phagocytic
vacuoles containing engulfed material
 Neutrophil Extracellular Traps (NETs)
• NETs are extracellular fibrillar networks that
provide a high concentration of antimicrobial
substances at sites of infection
• NETS prevent the spread of the microbes by
trapping them in the fibrils
 Leukocyte-Mediated Tissue Injury
• Leukocytes are important causes of injury to
normal tissues under several circumstances :
– When the inflammatory response is
inappropriately directed against host tissues
autoimmune diseases
– When the host reacts excessively against usually
harmless environmental substances, as in allergic
diseases (asthma)
 Leukocyte Activation and Removal of Offending
Agents

• Leukocytes can eliminate microbes and dead cells by

phagocytosis, followed by their destruction in
phagolysosomes.
• Destruction is caused by free radicals (ROS, NO)
generated in activated leukocytes and lysosomal
enzymes.
• Neutrophils can extrude their nuclear contents to
form extracellular nets that trap and destroy
microbes.
 Leukocyte Activation and Removal of Offending
Agents

• Enzymes and ROS may be released into the

extracellular environment.
• The mechanisms that function to eliminate microbes
and dead cells are also capable of damaging normal
tissues (the pathologic consequences of
inflammation).
• Antiinflammatory mediators terminate the acute
inflammatory reaction when it is no longer needed.
 Termination of the Acute Inflammatory
Response
• Inflammation after the offending agents are removed.
Mediators of inflammation have short half-lives, and are
degraded after their release
• Neutrophils will die by apoptosis within a few hours after
leaving the blood
• Switch in the type of AA metabolite produced, from
proinflammatory leukotrienes to antiinflammatory lipoxins
• Liberation of antiinflammatory cytokines, including TGFbeta
and IL-10, from macrophages and other cells
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