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THE ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
Innate immune mechanisms establish a state of inflammation at sites of infection
A rapid response to an injurious agent that serves to deliver leukocytes, plasma proteins and fluids to the site of injury
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)
Triggers of acute inflammation
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
• Redness (rubor) • Swelling (tumor) • Heat (calor) • Pain (dolor)• Loss of function (functio laesa)
Classical signs of acute inflammation
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 chemoattractantMMP: 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 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.
PUS
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
Liver
IL-6ACUTE-PHASE REACTION
Pentraxin family:CRP – opsonization, complement activationSAP – 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
ACUTE-PHASE REACTION
The kinetics of acute-phase proteins in the blood
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
Chemical mediators
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
DIChigh fever multiorgan failure
Therapy: anti-TNF-alpha antibody
disseminated intravascular
coagulation
DICDisseminated 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
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