VIVA: Pathology - Inflammation Flashcards
Describe the major components of acute inflammation
2/3 to pass:
- Small vessel dilatation: leading to increased blood flow
- Increased vascular permeability: enabling plasma proteins and leukocytes to leave the circulation
- Leukocyte emigration: emigration of leukocytes from microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
What are the mechanisms responsible for increased vascular permeability in inflammation?
2/4 to pass:
1. Endothelial cell contraction/retraction:
- Most common
- Gaps in venules (increased inter-endothelial spaces) due to histamine, bradykinin and leukotrienes, causes an immediate transient response (lasting 15-30 mins)
- Other stimuli (e.g. UV radiation, burns, some bacterial toxins) result in delayed (2-12hrs) prolonged (hrs to days) leakage
2. Direct endothelial injury:
- Results in endothelial cell necrosis and detachment
- Rapid onset but may last days
- E.g. from severe burns, microbial toxins, neutrophils themselves
3. Transcytosis:
- Increased transport of fluids and proteins through the endothelial cell
- VEGF may increase the number +/- size of transport channels
- Contribution to acute inflammation is uncertain
4. Leukocyte-mediated leakage:
- In venules and pulmonary capillaries
5. New vessel formation:
- New blood vessels leaky
- Mediators include VEGF
- Long-lasting (hrs)
What is chemotaxis of leucocytes?
Locomotion/movement of white cells* along a chemical gradient
After exiting circulation, leucocytes move in the tissues by chemotaxis towards the site of injury
*needed to pass
What are the mediators that aid chemotaxis?
Chemo-attractants include:
- Exogenous: most commonly bacterial products */proteins/peptides
- Endogenous: cytokines * (e.g. IL-8), complement * (e.g. C5a), arachnidonic acid * metabolites (e.g. LTB4)
All bind to specific receptors and promote polymerisation of actin in the leucocyte
*2 mediators needed to pass
What cell types are present in chronic inflammation?
Macrophages*
Multinucleate giant cells
Lymphocytes
Eosinophils
Plasma cells
Mast cells
Neutrophil polymorphs (scarce)
*needed to pass + two others
What processes mediate the persistent accumulation of macrophages seen in chronic inflammation?
- Continued recruitment of monocytes* (continued expression of adherence and chemotactic factors - macrophage activation factor)
- Local proliferation of macrophages
- Immobilisation of macrophages (migration inhibition factor)
*needed to pass
What clinical conditions can cause chronic inflammation?
Persistent infection:
- Tuberculosis
- Syphilis
- Abscess
- Empyema
- Osteomyelitis
Prolonged exposure to an agent:
- Exogenous: foreign body, persistent trauma, silica (causing silicosis)
- Endogenous: lipid (causing atherosclerosis)
Autoimmune:
- Rheumatoid arthritis
- Multiple sclerosis
- Inflammatory bowel disease
- Systemic lupus erythematosus
Describe the vascular changes in acute inflammation
All 3 needed to pass:
1. Vasodilation: opening of arterioles and capillary beds, mediated by histamine and NO, leading to increased blood flow
2. Increased vascular permeability
3. Stasis: due to plasma protein permeability and increased viscosity
Describe the role of complement in inflammation
Family of >20 proteins (including C1-9) which once activated, trigger cascade culminating in:
- Recruitment and activation of lymphocytes (C3a, C5a)* -> triggers inflammation
- Formation of Membrane Attack Complex (MAC)* -> causes cell lysis
- Phagocytosis (C3b)* -> phagocyte recognises C3b bound to microbe (opsonisation)
*2/3 needed to pass
What is croup?
Acute laryngotracheobronchitis* in children
An inflammatory/spasmodic narrowing of the airway* produces a barking cough and inspiratory stridor
Causes are predominantly viral, especially parainfluenza virus* (others include RSV, adenovirus and influenza)
*needed to pass
Describe the main characteristics of acute inflammation
Relatively rapid onset
Alterations in vascular calibre that increase blood flow*
Leaky microvasculature* (structural changes in microvasculature that permit plasma proteins and leucocytes to leave circulation, causing oedema)
Emigration of leucocytes (especially neutrophils)* and their accumulation and activation at site of infection to eliminate offending agent
Duration of hours to days
*needed to pass
What stimuli cause production of inflammatory mediators?
2 to pass:
- Substances released from necrotic cells
- Microbial products
- Cell injury
- Mechanical irritation
What are the chemical mediators of acute inflammation and what are their actions?
4 needed to pass (including actions):
- Histamine: vasodilation, increased vascular permeability, endothelial activation
- Serotonin: vasodilation, increased vascular permeability
- Prostaglandins: vasodilation, increased vascular permeability, pain, fever
- Leukotrienes: increased vascular permeability, chemotaxis, leucocyte adhesion and activation
- Platelet-activating factor: vasodilation, increased vascular permeability, chemotaxis, leucocyte adhesion, chemotaxis, platelet degranulation, oxidative burst
- Complement (e.g. C5a, C3a, C4a): vasodilation, chemotaxis, leucocyte activation
- Cytokines (e.g. TNF, IL-1): local endothelial activation and adhesion, fever, pain, anorexia, hypotension, decreased vascular resistance (shock)
- Chemokines: chemotaxis, leucocyte activation
- Kinins: increased vascular permeability, vasodilation, pain, smooth muscle contraction
- Reactive oxygen species: killing of microbes, tissue damage
- Nitric oxide: vascular smooth muscle relaxation, killing of microbes
- Proteases (activated during coagulation): endothelial activation, leucocyte recruitment
How are leucocytes delivered to the site of injury?
This is a multistep process mediated and controlled by adhesion molecules and chemokines:
- Margination*:
- Occurs when leucocytes adopt a peripheral position along the epithelium
- Followed by rolling (transient adherence mediated by selectins), activation and firm attachment (mediated by integrins) to the endothelium
- Polymerisation of actin at the leading edge of the cell establishes a “front wheel” drive in the direction of injury - Transmigration (diapedesis)*:
- Across the endothelium
- Migration through inter-endothelial spaces typically in post-capillary vanules
- Via PECAM1, CD31, integrins - Chemotaxis*:
- Leucocytes moves toward the site of injury along a chemical gradient of chemoattractants, which can be exogenous (e.g. bacterial products) or endogenous (e.g. cytokines, IL-8, C5a)
What chemical mediators are responsible for pain, fever and tissue damage?
IL-1*, TNF, prostaglandins, bradykinin, neutrophil and macrophage lysosomal enzymes, oxygen metabolites, NO
*needed to pass + one other
What are the different types of acute inflammation?
2 to pass (with examples):
1. Serous inflammation:
- Thin fluid from plasma or mesothelial lining cells
- E.g. burns, effusions (pericardial, pleural)
2. Fibrinous inflammation:
- More severe injuries and greater vascular permeability allows larger molecules such as fibrin
- Characteristic of inflammation in body cavities (pericardial sac, meninges, pleura)
3. Suppurative / purulent inflammation:
- Large amounts of pus / purulent exudates (made up neutrophils, necrotic cells, oedema fluid)
- Causes can be classified by organism type (e.g. staphylococcal) or by site (e.g. appendicitis)
4. Ulcers:
- Local defect in surface of an organ/tissue
What are the outcomes of acute inflammation?
2/4 needed to pass:
- Complete resolution +/- scarring
- Abscess formation (suppurative inflammation)
- Fibrosis (fibrinous inflammation)
- Chronic inflammation
Describe the sequence of cellular events in acute inflammation
Leucocytes are the major cell type involved *:
- In first 6-24hrs neutrophils predominate, and monocytes/macrophages in 24-48hrs *
- Margination:
- Stasis of blood flow leads to increased leucocytes lining endothelial cell (margination) * - Extravasation:
- Leucocyte adhesion to endothelial wall and diapedesis (transmigration) across into interstitium *
- Recruitment, adhesion and transmigration are mediated by various mediators such as histamine, platelet-activating factor, cytokines and various attraction molecules (variously called immunoglobulins, integrins, selectins, mucin-like glycoproteins) - Chemotaxis:
- Leucocyte migration to site of injury *
- Chemotaxis and activation is mediated thru various bacterial products, cytokines, chemical factors, Ag-Ab complexes, products of necrosis - Leucocyte activation:
- To enable phagocytosis and enzyme release * - Phagocytosis and release of various enzymes from leucocytes
*needed to pass
What leucocyte types are characteristic of acute inflammation?
Neutrophils (first 6-24hrs)*
Monocytes 24-48hrs
Neutrophils may last longer (4 days) in Pseudomonas infection
Lymphocytes in viral
Eosinophils in hypersensitivity
*needed to pass + one other
Why do neutrophils predominate in the inflammatory response in the first 6-24hrs?
1/4 needed to pass:
- More numerous in the blood
- Respond more rapidly to chemokines
- May attach more firmly to adhesion molecules
- Neutrophils are short-lived: disappear after 24-48hrs (monocytes live longer)
What is the role of leucocytes in acute inflammation?
2/5 needed to pass:
- Recognition and attachment to materials (opsonins) mediated by receptors
- Killing of microbes via phagocytosis, engulfment, or killing and degradation (hydrogen peroxide, myeloperoxidase, halide)
- Release of products which amplify the inflammatory reaction (lysosomal enzymes, reactive oxygen/nitrogen species)
What are the characteristics of chronic inflammation?
Inflammation for a prolonged period * (week or more)
Infiltration with mononuclear cells, including macrophages *, lymphocytes and plasma cells
With simultaneous:
- Active inflammation
- Tissue destruction *
- Attempts at repair * by connective tissue replacement (angiogenesis, fibrosis)
*3/4 needed to pass
What products are released by activated macrophages in chronic inflammation?
Products associated with tissue injury*:
- Toxic oxygen metabolites
- Proteases (elastases, collagenases)
- Neutrophil chemotactic factors
- Coagulation factors
- Arachidonic acid metabolites
- Nitric oxide
Products associated with fibrosis*:
- Growth factors (e.g. PDGF, FGF, TGF)
- Fibrogenic cytokines
- Angiogenesis factors (FGF)
- “Remodelling” collagenases
*needed to pass + 5 examples
What is the complement system?
Plasma protein system involved in immunity against microbes
Complement proteins numbers C1-9 are present in plasma in inactive forms
Describe the main pathways by which complement activation occurs
- Classical pathway*: involves Ag-Ab complex
- Alternative pathway*: triggered by microbial surface molecules (e.g. endotoxin), with no Ab involvement
- Lectin pathway: plasma mannose-binding lectin binds to carbohydrate on microbe
All pathways result in cleavage and activation of C3 (the most important and abundant complement component)
*needed to pass + explanation of how it is activated
How do activated complement products mediate acute inflammation?
- Vascular effects*:
- Increased vascular permeability and vasodilation via C3a and C5a mediated histamine release from mast cells - Leucocyte adhesion, chemotaxis and activation:
- Via C5a - Phagocytosis:
- C3b acts as opsonin on microbe and leads to phagocytosis - Cell lysis by the membrane attack complex (MAC):
- Composed of multiple C9 molecules
*needed to pass + one other
Of the complement components, which are the most important inflammatory mediators?
C3 and C5
What is an Arthus reaction?
Acute, localised inflammatory response
Type III hypersensitivity reaction: excess of antibody precipitates as immune complexes which cause a localised vasculitis
Typically in response to vaccination
Which cells release histamine?
Widely distributed in tissues, richest sources include (need 2/3 to pass):
- Mast cells
- Basophils
- Platelets
Which mediators of inflammation are derived from cells?
Pre-formed:
- Vasoactive amines (histamines, serotonin)*
Newly synthesised:
- Arachidonic metabolites (prostaglandins, leukotrienes, lipoxins)*
- Reactive oxygen and nitrogen species
- Nitric oxide
- Platelet-activating factor
- Cytokines (TNF, IL-1)
- Chemokines
*needed to pass + one other
What are the effects of histamines in an inflammatory response?
Dilation of arterioles*
Increased vascular permeability of the venules*
Can cause vasoconstriction of large arteries
*needed to pass
