Acute Inflammation Flashcards
What is acute inflammation?
Inflammation is a defensive reaction (innate immune response) of a macro-organism against injury caused by trauma, toxic chemicals, or an invading pathogen
Protective response, but also a potentially harmful process: Components of inflammation that are capable of destroying microbes can also injury bystander normal tissue
Rapid response to tissue injury; minutes/hours to develop and of relative short duration (hours or days).
Triggers of acute inflammation
INFECTIONS
Bacteria, viruses, parasites, fungi, toxins
TISSUE DAMAGE DUE TO
Physical agents: Frost bites, burns, radiation (ionising, UV)
Chemical agents: chemical burns, irritants, bites
Mechanical injury and ischaemia: trauma, tissue crush, reduced blood flow
FOREIGN BODIES
splinters, sutures and dirt
What is the purpose of acute inflammation?
Alert the body and initiate appropriate immune response
Limit spread of infection/injury
Protect injured site from being infected
Eliminate dead cells/tissue
Create conditions needed for healing
5 Rs of acute inflammation
Recognition of injury Recruitment of leucocytes Removal of injurious agent Regulation (closure of inflammatory response) Resolution/Repair of affected tissue
The key signs of acute inflammation
- Heat (Latin: Calor)
Increased blood flow and metabolic
activity - Redness (Rubor)
Iincreased blood flow (hyperaemia) to injured area - Swelling (Tumor)
Fluid accumulation due to permeability of vessels - Pain (Dolor)
Release of pain mediators; pressure on nerve ends - Loss of function (Functio laesa)
Damage
Systemic changes due to acute inflammation
FEVER Endogenous pyrogens (IL-1, TNF-) Exogenous pyrogens (microbial components)
NEUTROPHILIA
GM-CSF (cytokine) stimulation of bone marrow to replenish dead neutrophils
ACUTE PHASE REACTANTS
- C-reactive protein (CRP), fibrinogen, complement, serum amyloid A protein (SAP)
- Produced in the liver
- Induced by the cytokines IL-6, IL-1, TNF-
- ↑ Fibrinogen => stacking of RBCs => faster sedimentation rate (↑ESR)
COMPLICATIONS
In rare cases causing a sever systemic inflammatory reaction called sepsis or a form of inflammatory response syndrome (SIRS)
The 4 components of an acute inflammatory response
Vascular:
acute changes in local vasculature. Vasodilatation, plasma exudation and oedema
Cellular:
infiltration of inflammatory cells. Cell recruitment, phagocytosis, NETosis
Humoral:
release of inflammatory mediators. Complement, plasma factors, clotting cascade, cytokines and chemokines
Resolution:
Inflammation is controlled and self-limiting. Healing, regeneration and repair of tissue
Vascular effects of acute inflammation
Vasodilation: an increase in vascular diameter
- Induce by histamine and serotonin released by injured cells, mast cells and macrophages
- This results in hyperaemia (increase in blood volume to the area) (Redness)
- The increased blood volume heats up the tissues (Heat)
Increased vascular permeability (micro vessels):
- Leading to leakage of fluids into the tissues (Swelling)
- As exudate accumulates, pressure increases. Nerve endings are stimulated by the excess fluid and inflammatory mediators (Pain).
- Endothelial cell activation increasing their expression of adhesion molecules
Overall effect: leucocytes and plasma proteins exit vessels and enter the inflammation site to deal with infection
How does oedema occur as a result of inflammation?
Endothelial cell constriction:
Gaps occur due to contraction of e.g myosin and shortening of individual endothelial cells.
→
Loss of proteins (esp. albumin and fibrinogen) from plasma into the tissue increase the osmotic pressure/gradient, leading to fluid leakage to the area, causing oedema.
Cell transmigration
What is inflammatory exudate consist of?
Water, salts, small plasma proteins (fibrinogen),
inflammatory cells and RBCs
-> get out of vessels and enter tissues or serous cavities
Transudate
fluid leaks due to altered osmotic/hydrostatic pressure; vessel permeability normal
Serous inflammatory exudate
A few cells, no/few microbes
Fluid derived from plasma / secreted by mesothelial cells
Serous cavities (pleura, peritoneum, pericardium)
Skin blisters (burns, viral infections)
Purulent (fibrino-purulent) inflammatory exudate
Pus: many leucocytes (neutrophils), dead cells, microbes
Pus-producing bacteria (pyogenic) e.g. Staphylococci
e.g. acute appendicitis
e.g. abscess (localised collection of purulent inflammation)
Fibrinous inflammatory exudate
fibrin deposition (derived from fibrinogen in plasma)
large vascular leaks (fibrinogen exits blood & enters tissue)
serous cavities (meninges, pleura, pericardium)
can lead to scarring if not cleared (fibroblasts => collagen)
Types of inflammatory exudate
Serous
Purulent (fibrino-purulent)
Fibrinous
Haemorrhagic
Haemorrhagic inflammatory exudate
Red blood cells predominate
Blood vessel rupture, truama
What are the mediators of inflammation?
Cells: Macrophages Neutrophils Mast cells Platelets
Humoral factors: Complement Plasma factors Clotting cascade Cytokines Chemokines
What are the first cells to recognise pathogens?
Tissue resident macrophages are generally the first tissue resident cell to recognise an invading pathogen through pattern recognition receptors (PRRs) on their cell surface.
The macrophage becomes activated to engulf the bacterium and:
- Immediately produces mediators of inflammation for example,, prostaglandins, leukotrienes and platelet activating factor (PAF)
- Next the macrophage secretes inflammatory cytokines and chemokines
Activated tissue resident macrophages secrete what inflammatory cytokines
IL-1, IL-6, CXCL-8 (IL-8), IL-12 and TNF-α
What secretes histamine and why?
Mast cells in the tissue secrete Histamine
These chemical signals released by activated macrophages and mast cells at the injury site cause endothelial activation, vasodilation and increased vascular permeability
Describe the process of cell recruitment to site of injury
Mast cells in the tissue secrete Histamine
These chemical signals released by activated macrophages and mast cells at the injury site cause endothelial activation, vasodilation and increased vascular permeability
Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins.
The complement system is also activated very soon after initial infection producing the various complement fragments
Chemokines released by inflammatory cells attract more phagocytic cells from the blood to the injury site.
Neutrophils are recruited to kill pathogens and remove cell debris at the site
Monocytes are recruited and differentiate into macrophages which enhances clearance by phagocytosis
Regulation and tissue repair is promoted by the release of immunoregulatory factors (TGF-)
Neutrophil recruitment in acute inflammation
- Margination & rolling
- Integrin activation by chemokines
- Firm adhesion to endothelium
- Transmigration through endothelium into tissue
- Chemotaxis (attraction and movement) to inflamed site
4 steps of neutrophil recruitment
This process may be divided into four steps
- Rolling mediated by selectins
- Activation by chemoattractant stimulus
- Arrest and adhesion mediated by integrins and cell adhesion molecules
- Transendothelial migration
What molecules are involved in neutrophil recruitment?
Adhesion molecules:
- Selectins
- Integrins
- Immunoglobulin superfamily cell adhesion molecules (CAMs)
What do selectins do and what types are there?
Mediate rolling of neutrophils, expressed by activated endothelium
P-selectin – pre-formed granules
E-selectin – induced by IL-1 and TNF- (cytokines produced by macrophages, mast cells, endothelial cells at site of inflammation)
L-selectin - Leucocytes (neutrophils, monocytes, lymphocytes) express L-selectin; ligands on endothelium
What binds to ligands on neutrophils?
Endothelial selectins bind to ligands on neutrophils
Ligands – carbohydrates (PSGL-1, sialyl-Lewisx)
Low affinity interaction requiring repetitive contacts
How do selectins mediate rolling
As cells are flowing low affinity interaction IS disrupted by flowing blood => repetitive binding and detaching => rolling; slow down
How are integrins activated by chemokines?
Neutrophils rolling slows them down increasing contact to endothelium
Neutrophils express integrins (LFA-1)
Integrins in low affinity configuration; no binding to ligands
Activated endothelial cells produce chemokines
Chemokines bind to receptors on neutrophils
Integrins are activated to change to high affinity configuration
Integrins bind to ligands on endothelium
Integrin ligands: ICAM-1, VCAM-1
What induces integrin ligands?
Integrin ligands are induced by IL-1 and TNF- (cytokines produced by macrophages, mast cells, endothelial cells at site of inflammation)
Results in firm adhesion of neutrophils to endothelium
What is the result of integrin activation by chemokines?
Induces firm adhesion of neutrophils to endothelium
Name 2 integrin ligands
ICAM-1= intercellular adhesion molecule-1; VCAM-1 = vascular cell adhesion molecule-1
Neutrophil transmigration
Neutrophils migrate through interendothelial spaces
Neutrophils pass through vessel wall and enter tissue
Migrate (chemotaxis) through tissue towards inflamed site
Gradient of chemoattractants guides migration in tissues
Describe the process of neutrophil chemotaxis
Movement of cells through tissue towards inflamed sites
Guided by chemoattractants:
- produced at site of infection/damage
- diffuse into adjacent tissue and form a gradient
- >
- Bacterial components (peptides containing N-formyl-methionine-leucine-phenylalanine; lipids)
- > chemokines (IL-8)
- > complement components (C5a)
- > leukotriene B4 (LTB4)
- >
Mechanisms involved in neutrophil pathogen destruction?
Release of granule content
Phagocytosis
Generation of reactive oxygen/nitrogen species
Formation of Neutrophil Extracellular Traps
(NETs) (netosis)
What are NETs?
Neutrophil Extracellular Traps
Mesh of nuclear content (chromatin)
Mesh traps microbes
Contains anti-microbial molecules
Small vs large granules
SPECIFIC (SMALL)
Lysozyme, collagenase, gelatinase, lactoferrin, alkaline phosphatase
AZURUPHIL (LARGE)
Myeloperoxidase, lysozyme, defensins, acid hydrolases, proteases (elastase, cathepsin G, collagenases, proteinase 3)
Granule content can cause tissue damage
Why are monocytes recruited?
To fight infection and differentiate into macrophages that promote dead cell clearance and
tissue repair
Which leucocytes survive longer?
Monocytes (24-48h) survive longer, proliferate, Monocytes differentiate into macrophages in tissues
Neutrophils (6-24h) short lived, die in tissues
What WBCs act in allergies and parasite infections?
Eosinophils
WBCs in viral infections
Lymphocytes
Resolution of inflammation
Inflammatory naturally damages the tissue
Termination of acute inflammatory reaction is IMPORTANT to avoid extensive bystander damage
Inflammatory mediators degrade as they are short lived or are used up.
Apoptosis of neutrophils and their subsequent clearance drive potent anti-inflammatory and tissue-restoring mechanisms.
Critical role of macrophages, which secrete anti-inflammatory and reparative mediators, and orchestrate these reparative process.
Lost tissue replaced: cell regeneration / connective tissue
If the inflammatory response does not reach a critical threshold of activation the mechanisms of regulation are not promoted effectively
Outcomes of acute inflammation
