Download 11 Acut inflammation BA

THE ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
Innate immune mechanisms establish a state of
inflammation at sites of infection
Acute inflammation
A rapid response to an injurious agent that
serves to deliver leukocytes, plasma
proteins and fluids to the site of injury
Triggers of acute inflammation
• Infections (bacterial, viral, fungal, parasitic) & microbial toxins
• Tissue necrosis: ischemia, trauma, physical or chemical injury
(e.g., thermal injury; irradiation; some environmental chemicals)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (hypersensitivity or autoimmune reactions)
Major components of inflammation
– Vascular changes
• Vasodilation
• Vascular permeability
• Increased adhesion of white
blood cells
– Cellular events
• Recruitment and activation of
neutrophils (polymorphonuclear
leukocytes) and monocytes
Classical signs of acute inflammation
•
•
•
•
•
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Maturation of mononuclear phagocytes and dendritic cells
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Macrophages respond to pathogens by using
different receptors to stimulate phagocytosis
and cytokine secretion
Effector functions of macrophages
Macrophages respond to infection by secreting
inflammatory cytokines
Systemic actions of cytokines in inflammation
Neutrophils are directed to sites of infection through
interactions between adhesion molecules
Neutrophil chemotaxis
acPGP: N-acetyl Proline-Glycine-Proline – neutrophil chemoattractant
MMP: matrix metalloproteinase
Neutrophil granulocytes
• 68% of circulating leukocytes, 99% of circulating
granulocytes
• Phagocytic cells
• Are not present in healthy tissues
• Migration  elimination of pathogens (enzymes,
reactive oxygen intermediates)
• Main participants of acute inflammatory
processes
Killing of bacteria by neutrophils involves the fusion of
two types of granule and lysosomes with the phagosome
Killing of bacteria by neutrophils is dependent
on a respiratory burst
Neutrophils are stored in the bone marrow and
move in large numbers to sites of infection,
where they act and then die.
PUS
Pus is a whitish-yellow, yellow, or yellow-brown exudate produced
by vertebrates during inflammatory pyogenic bacterial infections.
Pus consists of creamy, protein-rich fluid, known as liquor puris,
and dead cells.
Acute injury of myocardium
Fever production in response to TNF, IL-1, and IL-6
proinflammatory cytokines
hypothalamic control of
body temperature
increased ‚set-point’ value
fever
ACUTE-PHASE REACTION
IL-6
Liver
ACUTE-PHASE REACTION
Pentraxin family:
CRP – opsonization, complement activation
SAP – opsonization, complement activation,
binding of mannose/galactose
Collectin family:
MBL – part of the complement system
(SP-A/D – collectins of lungs)
Complement proteins (C1-C9)
Fibrinogen  blood clotting
The kinetics of acute-phase proteins in the blood
Chemical mediators
 Vasodilation
– Prostaglandins (PG), nitric oxide (NO)
 Increased vascular permeability
– vasoactive amines (histamine, serotonin), C3a and C5a
(complement system), bradykinin, leukotrienes (LT), PAF
 Chemotactic leukocyte activation
– C3a, C5a, LTB4, chemokines (e.g. IL-8)
 Fever
• IL-1, IL-6, TNFα, PGE2
 Pain
• Prostaglandins, bradykinin
 Tissue damage
• Neutrophil and Macrophage products
– lysosomal enzymes
– Reactive oxygen species (ROS)
– NO
NSAIDs and Paracetamol:
inhibiting COX-1 and COX-2
 preventing the synthesis
of prostaglandins
Resolution of acute inflammation
Septic shock
Triggering factors :
• systemic infection (bacteraemia)
• microbial cell wall products and/or
toxins released from the pathogens into
blood circulation.
Result:
Systemic activation of
neutrophils and macrophages

High level of cytokine (TNF-alpha) production:
„cytokine storm”

Excessive inflammatory response
Septic shock
The key molecule of the process: TNF-alpha
TNF-alpha and other inflammatory cytokines
capillar permeability
blood pressure
high fever
multiorgan failure
DIC
disseminated
intravascular
coagulation
Therapy: anti-TNF-alpha antibody
DIC
Disseminated Intravascular Coagulation
• pathologic activation of
thrombotic process
• distress of thrombotic
process, bleeding
• other causes:
snake bite, septic
abortion, acute obstetric
complications, malignant
tumors, leukemias
DIC: Disseminated Intravascular Coagulation