the acute inflammation and acute-phase response. innate immune mechanisms establish a state of...

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