Pathology Flashcards
what is inflammation
- local physiological response to tissue injury
- complex reaction in vascularised connective tissue
role of inflammatory response
serves to destroy,dilute or wall of injurious agent (primarily a protective response)
when is inflammation harmful (3)
- life-threatening hypersensitivity reactions
- chronic inflammatory diseases e.g. rheumatoid arthritis and crohn’s
- repair by fibrosis may lead to disfiguring scars
types of inflammation (2)
- acute
- chronic
what is acute inflammation
the initial and often transient series of tissue reactions to injury (involving several processes)
what is chronic inflammation
subsequent and often prolonged tissue reactions following the initial response
principle causes of acute inflammation (5)
- microbial infections (viruses,bacteria such as E.coli, actinomycetemcomitans)
- hypersensitivity reactions (inappropriate or excessive immune reaction which damages tissues, including reactions to parasites)
- physical agents (trauma, uv light, thermal agents inc. burns or frostbite)
- irritant and corrosive chemicals (acids, alkalis, infecting agents releasing chemical irritants)
- foreign bodies (e.g. splinters,dirt,sutures,restorative material)
physical characteristics of inflammation (5)
- redness (dilation of blood vessels)
- heat (increase in blood flow, hyperaemia)
- swelling (due to accum. of fluid exudate in extravasc. space)
- pain (stretching/distortion of tissues by inc. fluid, also chemical mediators inc. bradykinin produce pain)
- loss of function (due to swelling and pain,conscious and reflex)
processes of acute inflammation (2)
- vascular phase
- exudative and cellular phase
what occurs in vascular phase of acute inflammation (2)
- dilation (pre capillary bed sphincter opens,most capillaries are full)
- increased permeability of blood vessels (oxygen carbon dioxide and some nutrients transfer via diffusion, main transfer of fluid and solute is by ultrafiltration as described by starling)
what occurs in exudative/cellular phase of acute inflammation
fluid and cells escape from permeable venules
what is oedema
the net increase in extravascular fluid
what is within the fluid exudate that builds up in extravascular space (and role of these components) (2)
- proteins including immunoglobins and fibrinogen:
- > immunoglobins important in destruction of invading organisms
- > fibrinogen (fibrin on contact with ECM, hence acutely inflamed organ surfaces commonly covered in fibrin)
role of lymphatics in acute inflammation
continually remove exudate (it is replaced by new exudate)
how does vascular permeability increase
- via formation of endothelial gaps in venules (lined with single layer of endothelial cells)
- > endothelial cells contain contractile proteins, which when stimulated by chemical mediators (histamine, bradykinin) they pull open transient pores
- > endothelial cells are not damaged in this process
which chemical mediators bring about an increase in vascular permeability (2)
- histamine
- bradykinin
location of leaked fluid when vascular permeability increases during acute inflammation
confined to POST CAPILLARY VENULES
causes of immediate and transient increased vascular permeability
- chemical mediators:
- > histamine
- > bradykinin
causes of immediate and sustained increased vascular permeability
severe direct vascular injury e.g. trauma
cause of delayed and prolonged increased vascular permeability
endothelial cell injury e.g. X-rays, bacterial toxins
cellular component of acute inflammation
neutrophil (diagnostic feature of acute inflammation, accumulates in extracellular space)
->aka polymorphonuclear leucocytes
what type of cell is a neutrophil
leukocyte
function of neutrophils (6)
- kill organisms
- ingest offending agents
- degrade necrotic tissue
- produce chemical mediators
- produce toxic oxygen radicals
- produce tissue damaging cells
steps involved in neutrophils reaching site of inflammatory stimulus (3)
- margination (flow in plasmatic zone of blood vessels, occurs ONLY in venules)
- adhesion (interaction between adhesion molecules on its surface and the endothelial surface)
- transendothelial migration/transmigration (following firm adhesion, neutrophils insert pseudopodia into junctions between endothelial cells, then cross through basement membrane into extravascular space)
predominant molecules involved in migration of neutrophil across basement membrane into extravascular space (4)
- increased expression of selectins on endothelium
- loose, rolling adhesion between selectins and their receptors on the leucocyte
- firm adhesion between activated integrins on leucocyte and ICAM-1 (intercellular adhesion molecule 1) on endothelial cell
- transmigration is mediated by ICAM-1, integrins and PECAM-1 (CD31)
what increases leucocyte surface adhesion molecule expression (3)
- complement component C5a
- leukotriene B4
- tumour necrosis factor (TNF)
what increases endothelial cell expression of adhesion molecules to which neutrophils and other leucocytes bond (3)
- IL-1
- endotoxins
- tumour necrosis factor (TNF)
how do neutrophils find the site of inflammatory stimulus
-process called chemotaxis (‘locomotion orientated along a chemical gradient’)
compounds chemotactic/trigger chemotaxis for neutrophils (4)
- bacterial products
- complement components
- cytokines
- products produced by the neutrophils themselves
what is the result of the series of chemical reactions caused by the binding of chemotactic agents to cell receptors (4)
- release of intracellular calcium
- influx of extracellular calcium
- > increased cytosolic calcium triggers assembly of contractile proteins responsible for cell movement
- > locomotion involves rapid assembly and disassembly of contractile filaments)
role of endogenous chemical mediators (5)
- > drive the process of acute inflammation
- cause:
- > vasodilation
- > emigration of neutrophils
- > chemotaxis
- > increased vascular permeability
- > itching and pain
chemical mediators of inflammation released from cells (6)
- histamine
- lysosomal compounds
- serotonin
- chemokines
- leukotrienes
- prostagladins
result of release of chemical mediator histamine from cells
- vacular dilatation
- transient increase in vascular permeability
which cells release histamine (4)
- mast cells
- eosinophils
- basophils
- platelets
where are lysosomal compounds released
from neutrophils
result of release of lysosomal compounds
may increase vascular permeability and activate complement
type of serotonin present in high conc. in platelets
5 hydroxytryptamine
effect of serotonin release from cell
causes increased vascular permeability
what are chemokines and role
- proteins which attract various types of leucocyte to the site of inflammation
- > various chemokine bind to ECM components setting up a gradient of chemotactic molecules fixed to the extracellular matrix
what are leukotrienes synthesised by
arachidonic acid, especially in neutrophils
role of leukotrienes
- posses vasoactive properties
- involved in type I hypersensitivity
what are prostaglandins
fatty acids synthesised by many cell types
effect of prostaglandins release
- increased vacslar permeability
- stimulate platelet aggregation
plasma factors in inflammation (4 enzymatic cascade systems which mediate various aspects of inflammation in addition to other functions)
- complement system
- kinin system
- coagulation system
- fibrinolytic system
function of the complement system
innate and adaptive immunity for defence against microbes
what makes up the compliment system
compliment proteins C1-C9 and their cleavage products
what does complement activation cause (3)
- increased vascular permeability (C3a, C5a, C4a)
- chemotaxis (C5a)
- opsonization (C3b)
what causes complement activation (4)
- bacterial endotoxins
- products of kinin, coagulation and fibrinolytic systems
- antigen-antibody complexes
- enzymes released from dying cells
what occurs as a result of complement activation (5)
- oponisation of pathogens (facilitates phagocytosis)
- increased vascular permeability
- recruitment of inflammatory cells (neutrophils, monocytes, eosinophils and basophils)
- killing of pathogens
- histamin release from mast cells (vasodilation)
role of the kinin system
- generates vasoactive peptides from plasma proteins called kininogens by the action of specific kallikreins
- activation of coagulation factor XII leads to formation of kinin e.g. bradykinin
what activates the kinin system
coagulation factor XII (hageman factor)
what does bradykinin cause (4)
- increased vascular permeability
- arteriolar dilatation
- smooth muscle contraction (e.g. bronchial)
- pain
what occurs during the coagulation system
- conversion of soluble fibrinogen into fibrin
- > hageman factor/coagularion factor XII is activated by contact with extracellular materials and enzymes of bacterial origin
fibrin
major component of the acute inflammatory infiltrate
role of activated XII
-can activate the COMPLEMENT, KININ, COAGULATION AND FIBRINOLYTIC systems
the fibrinolytic system
- counterbalances coagulation
- plasminogen factors (from endothelium, leucocytes and other tissues) cleave plasminogen -> plasmin
- plasmin responsible for fibrin -> fibrin degradation products (may have local effects on vascular permeability)
- plasmin also cleaves C3
role of lymphatic system in acute inflammation
- the lymphatic channels become dilated as they drain away the oedema fluid of the inflammatory exudate (limits extend of oedema in tissues)
- antigens are carried to regional lymph nodes for recognition by lymphocytes
role of the neutrophil polymorph (variation)
- movement (chemotaxis)
- recognition and adhesion to micro-organisms
- phagocytosis and intracellular killing of micro-organisms (oxygen dependent and oxygen independent mechanisms)
what is opsonisation
the process of coating a particle to target it for phagocytosis
what do most organisms have to be coated in to be recognised for phagocytosis
opsonins
eg’s of major opsonins (3)
-Fc fragment of IgG (presumably naturally occurring antibody against the ingested particle)
C3b (fragment of C3 generated by complement activation)
-collectins (plasma proteins which bind to microbial cell walls)
what do opsonins do
bind to specific receptors on leucocytes and greatly enhance phagocytosis
what is phagocytosis
complex process by which phagocytes such as neutrophils and macrophages engulf and ingest microorganism or other cells and foreign particles
3 steps involved in phagocytosis
- recognition (by particles on leucocyte surface receptors) and attachment
- engulfment
- killing and degradation
what happens to neutrophils following phagocytosis
they undergo apoptosis
what enhances efficiency of phagocytosis
opsonisation of particles
what initiates the process of active phagocytosis
attachment of a particle to a phagocyte receptor
what occurs during engulfment phase of phagocytosis
- cytoplasmic extensions flow around the particle resulting in complete engulfment of the particle within a phagosome made by the cell membrane
- the phagosome then fuses with the lysosomal membrane, resulting in discharge of the lysosome content into the phagolysosomes
2 mechanisms of killing and degradation during phagocytosis
- oxygen dependent (phagocytosis results in products of oxygen reduction which causes intracellular killing of microorganisms)
- oxygen dependent (via the action of substances in leucocyte granules, e.g. lysosome which attacks bacterial coat)
what occurs after killing during phagocytosis
acid hydrolase from lysosomes degrade the microorganisms within the phagolysosome
where are leucocyte products released during activation and phagocytosis
into extracellular space as well as into the phagolysosome
key products in neutrophils and macrophages (3)
- lysosomal enzymes
- oxygen derived active metabolites
- products of arachidonic acid metabolism including prostaglandins and leukotrienes
effect of lysosomal produce release (5)
- these products may cause endothelial and tissue damage
- > activates coagulation factor XII
- > attracts other leucocytes into the area
- > damages local tissues
- > increases vascular permeability
- > pyrogens producing systemic fever
macroscopic appearances of acute inflammation (6)
- necrotising (septic necrosis, bacterial putrefaction)
- serous (thin protein rich fluid exudate)
- catarrhal (mucus hyper secretion)
- fibrinous (exudate contains plentiful fibrin)
- suppurative (production of pus)
- membranous (epithelium coated by fibrin)
what is suppuration and cause
=formation of pus
->stimulus almost always infective agent (e.g. pyogenic bacteria such as staphylococci)
components of pus (3)
- dead neutrophils
- bacteria
- cellular debris
drainage of abscess
- has central collection of pus with an adjacent zone of preserved neutrophils surrounded by membrane of sprouting capillaries and vascular dilation and occasional fibroblasts
- > on draining abscess cavity collapses and is obliterated by organisation and fibrosis
- > deep seated abscesses may drain along a sinus tract or fistula
formation of ulcer (ulceration)
-local defect or excavation of the surface of an organ/tissue that is produced by the sloughing of inflammatory necrotic tissue
frequent locations of ulcers
- mucosa of mouth, GI tract, GU tract
- low limbs (chronic ulcers) in those with circulatory disturbance
beneficial effects of acute inflammation (6)
- dilution of toxins (can be carried away by lymphatics)
- entry of antibodies (due to increased vascular permeability)
- stimulation of the immune response (fluid exudate containing antigens reaches local lymph nodes)
- fibrin formation (impedes movement of micro-organisms)
- delivery of nutrients and oxygen (aided by blood flow)
- transport of drugs (e.g. antibiotics)
harmful effects of inflammation (3)
- digestion of normal tissues
- swelling (eg. laryngeal oedema, brain swelling)
- inappropriate inflammatory response (e.g.. type I hypersensitivity)
systematic effects of acute inflammation (5)
- fever
- constitutional symptoms
- weight loss
- reactive hyperplasia of the reticuloendothelial system
- haematological changes
coordination of fever
- coordinated by the hypothalamus
- it is a coordinated endocrine, autonomic and behavioural response
endocrine response of fever (3)
- secretion of acute phase proteins by the liver including C-reactive protein (CPR) and serum amyloid protein (SAA)
- > these proteins act as opsonins and bind complement
- increased production of glucocorticoids activating a stress response
autonomic response of fever (3)
- blood is redirected from the skin to deep vascular beds to minimise heat loss through skin
- increased pulse and blood pressure
- decreased sweating
behavioural response of fever (4)
- rigors (shivering)
- anorexia (loss of appetite)
- somnolence (drowsiness)
- malaise
why is fever beneficial during inflammation
-elevation in temp. of even a few degrees may improve the efficiency of leukocyte killing and probably impairs replication of many offending micro-organisms
constitutional systems of acute inflammation
- malaise
- anorexia
- nausea
how does acute inflammation cause weight loss
due to negative nitrogen balance, particularly when there is extensive chronic inflammation
reactive hyperplasia of the reticuloendothelial system (systematic effect of acute inflammation)
-nodal enlargement caused by hyperplasia of lymphoid follicles and hyperplasia of the phagocytic cells lining the sinuses
haematological changes as a systematic effect of acute inflammation
- increased erythrocyte sedimentation rate (ESR)
- anaemia (eg. blood loss, haemolysis, chronic disorders)
- leucocytosis (eg. lymphocytosis, neutrophilia, eosinophilia)
what is leucocytosis and what causes it
- increased total number of WBC’s
- > usually due to accelerated release of cells from the bone marrow reserve pool (IL-1 and TNF)
- > prolonged infection will induce proliferation of precursors in the bone marrow also mediated by IL-1 and TNF
which type of WBC do most bacterial infections produce (leucocytosis)
neutrophilia
which type of WBC can viral infections produce (leucocytosis)
lymphocytosis
which type of WBC is usually produced during allergic disorders/parastitic infections (leucocytosis)
eosinophilia
sequelae of acute inflammation (5)
- resolution
- suppuration (->discharge of pus)
- repair and organisation
- fibrosis
- chronic inflammation
what is resolution following inflammation
resolution means the complete restoration of the tissues to normal after an episode of acute inflammation
factors favouring resolution (4)
- minimal cell death/tissue damage
- occureence in an organ/tissue with regenerative capacity (e.g.. liver)
- rapid destruction of the causal agent
- rapid removal of fluid and debris by good local vascular drainage
what is organisation following inflammation
organisation of tissues is their replacement by granulation tissue
factors favouring organisation (3)
- large amounts of fibrin formed
- substanital necrosis
- exudate and debris cannot be removed or discharged
formation of granulation tissue during organisation
- capillaries grow into the inflammatory exudate accompanied by macrophages and fibroblasts
- > predominate features of repair are angiogenesis (formation of new blood cells), followed by fibroblast proliferation and collagen synthesis
what regulates the processes involves in organisation/formation of granulation tissue
growth factors
role of growth factors
stimulate cell proliferation regeneration and angiogenesis (e.g. TNF,EGF, FGF)
when does acute inflammation progress to chronic inflammation
if the agent causing acute inflammation is not removed
what occurs in progression of acute inflammation to chronic inflammation (2)
- organisation of the tissue
- change of cellular exudate character
how may chronic inflammation arise (2)
- develop from acute inflammation
- primary chronic inflammation (more common)
factors favouring the progression from acute to chronic inflammation (3)
- indigestible substances such as glass and suture material may result in chronic suppuration (foreign body reaction)
- deep seated suppurative inflammation in which drainage is delayed or inadequate will result in a thick abscess wall composed of fibrous/granulation tissue (the rigid walls fail to come together after drainage, pus within the cavity becomes organised and eventually results in a fibrous scar)
- recurrent episodes of acute inflammation and healing may eventually result in clinicopathological entity of chronic inflammation
osteomyelitis
mandible
chronic cholecystitis
replacement of wall by fibrous tissue and lymphocytes rather than neutrophils predominate
predominant cells of chronic inflammation (3)
- lymphocytes
- plasma cells
- macrophages
examples of primary chronic inflammation (6)
- resistance of infective agent to phagocytosis and intracellular killing (e.g. tuberculosis, leprosy brucellosis, viral infections)
- foreign body reactions ito endogenous materials (e.g. gout, may be acute or chronic)
- foreign body reactions to exogenous materials (e.g.. asbestos fibres)
- some autoimmune diseases (e.g. rheumatoid arthritis)
- specific diseases of unknown aetiology (e.g. ulcerative colitis)
- primary granulomatous diseases (e.g. sarcoidosis)
macroscopic appearances of chronic inflammation (4)
- chronic ulcer (mucosa is breached, base is lined by granulation tissue, fibrous tissue extends through muscle layers)
- chronic abscess cavity (eg. osteomyelitis)
- thickening of the wall of a hollow viscus by fibrous tissue (e.g.. intestine)
- granulomatous inflammation (eg. tuberculosis, caseous necrosis)
most prominent feature of chronic inflammatory reaction
- may be fibrosis (formation of granulation tissue results in fibrosis)
- > when most of the chronic inflammatory cell infiltrate has subsided, fibrosis may lead to distortion and stricture formation (narrowing) eg. crown’s disease
ulcerative colitis
chronic inflammatory bowel disease
formation of macrophage in chronic inflammation
blood monocyte -> tissue macrophage
