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THE ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
Acute inflammation
Acute inflammation is a protective response that is intended to
eliminate the initial cause of cell injury, as well as the necrotic
cells and damaged tissues resulting from the original insult, and
to initiate the process of repair.
The cells and molecules of host defense, including leukocytes
and plasma proteins, normally circulate in the blood, and the
goal of the inflammatory reaction is to bring them to the site of
infection or tissue damage
Triggers of acute inflammation
• Infections (viral, bacterial, fungal, parasitic) & microbial toxins
• Trauma, physical or chemical injury (e.g., thermal injury;
irradiation; some environmental chemicals)
• Tissue necrosis (e.g. ischemia)
• Foreign bodies (splinters, dirt, sutures, crystal deposits)
• Immune reactions (hypersensitivity and autoimmune reactions,
which tend to persist, with features of chronic inflammation)
Major components of inflammation
– Vascular changes
• Vasodilation
• Increased vascular permeability
• Increased adhesion of white
blood cells
– Cellular events
• Recruitment and activation of
neutrophils (polymorphonuclear
leukocytes) and monocytes
Classical signs of acute inflammation
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•
•
•
•
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Recognition of microbes and necrotic or
damaged cells
Macrophages and dendritic cells express different classes
of pattern-recognition receptors that sense the presence
of microbes and molecules from damaged or dead cells
Robbins Basic Pathology (9th Edition)
Activated macrophages secrete inflammatory cytokines
Mast cells are also able to sense „danger”- and
„stress”-signals
!
!
http://dx.doi.org/10.3389/fimmu.2015.00238
Physical or thermal injury also activates mast cells
Vascular changes
Formation of oedema
Robbins Basic Pathology (9th Edition)
Vasodilation:
histamine, prostaglandins, NO
Increased vascular permeability: histamine, leukotrienes, bradykinin (15-30 min)
TNF, IL-1 (hours)
Activation of the complement pathways
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Mediator systems triggered by activation of factor XII
Leukocyte recruitment and activation
Mechanisms of neutrophil migration through blood vessels
Margination and rolling
E-selektin and P-selektin
on endothelial cells
/histamine, trombin, TNF, IL-1/
Adhesion
• chemokines trigger conformational
changes of integrins on the surface
of neutrophils
• Ligands for integrins on
endothelial cells
/TNF, IL-1/
Transmigration
driven by chemokines /e.g. IL-8/
Chemotaxis
Move toward sites of infection along
a chemical gradient
Chemotaxis of neutrophils
• chemokines (e.g. IL-8)
• leukotriene B4
• C3a, C5a
• Bacterial products
/N-formyl-metionin polipeptides/
• Products of collagen
cleveage
MMP: matrix metalloproteinase
acPGP: N-acetyl Proline-Glycine-Proline – neutrophil chemoattractant
Activation of neutrophils
Robbins Basic Pathology (9th Edition)
Neutrophils have the most efficient killing mechanisms
among phagocytes
Killing mechanisms of neutrophils
(neutrophil extracellular traps)
cathepsins, defensins, lactoferrin,
lysozyme, NADPH oxidase, iNOS
myeloperoxidase, elastase
DNA, chatepsins, lactoferrin,
myeloperoxidase, elastase
Leukocytes are secreting harmful
substances such as enzymes and ROS; therefore,
they are important causes of injury to normal cells
and tissues during inflammation!
Large reserves of neutrophils are stored
in the bone marrow and move in large numbers
to sites of infection, where they act and then die
Morphologic pattern of acute inflammation
• serous
• fibrinous
• haemorrhagic
• gangrenous
• ulcerative
• suppurative (purulent)
The purulent exudate (pus) consists of creamy protein-rich fluid (liquor
puris), neutrophils, debris of dead pathogens and necrotic cells. Certain
organisms (e.g., staphylococci) are more likely to induce such localized
suppuration and are therefore referred to as pyogenic (pus-forming).
Abscesses are focal collections of pus.
Kinetics of vascular and cellular events during
acute inflammation
Role of macrophages in acute inflammation
Classical and alternative macrophage activation
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Role of matrix metalloproteinases (MMP) in inflammation
They have role in:
• chemotaxis
• migration
• antimicrobial activity
(neutrophil elastase)
• TNF release
doi:10.1038/nri1418
Chemical mediators of acute inflammation
Local and systemic actions of cytokines in inflammation
Robbins Basic Pathology (9th Edition)
IL-6 (IL-1)
Acute-phase reaction
Máj
α1 antitrypsin, α1 antichymotrypsin
protease inhibitors
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 protein production in the blood
The principal cell-derived and plasma protein mediators
in acute inflammation
Robbins Basic Pathology (9th Edition)
EC: endothelsejtek
Role of mediators in different reactions of inflammation
 Vasodilation
– Histamine, prostaglandins, nitric oxide (NO)
 Increased vascular permeability
– Vasoactive amines (histamine, serotonin), C3a and C5a
(complement system), bradykinin, leukotrienes (LT), PAF
 Chemotactic leukocyte activation
– Chemokines (e.g. IL-8), C3a, C5a, LTB4, TNF α, IL-1
 Fever
• IL-1, IL-6, TNFα, prostaglandins
 Pain
• Prostaglandins, bradykinin
 Tissue damage
• Neutrophil and Macrophage products
– lysosomal enzymes
– Reactive oxygen species (ROS)
– NO
Production of arachidonic acid metabolites and
their roles in inflammation
!
!
Robbins Basic Pathology (9th Edition)
Outcomes of acute inflammation
Outcomes of acute inflammation
Features of chronic inflammation
• Prolonged host response to persistent stimulus
• Caused by microbes that resist elimination, immune
responses against self and environmental antigens, and
some toxic substances (e.g., silica)
• Characterized by persistent inflammation, tissue injury,
attempted repair by scarring
• Cellular infiltrate consisting of activated macrophages,
lymphocytes, and plasma cells, often with prominent
fibrosis
• Mediated by cytokines produced by macrophages and
lymphocytes (notably T lymphocytes), with a tendency to
an amplified and prolonged inflammatory response owing
to bidirectional interactions between these cells