Wk3 Inflammation Flashcards
Compare features of acute and chronic inflammation
- onset
- cellular
- tissue injury
- local and systemic signs
What is inflammation?
- Reaction of a vascularized living tissue to local injury → not dead tissue
the body reacting to something that is harmful - can be chemical factors or physiological factors etc.
What causes inflammation?
Basically everything:
- infectious agents
- endogenous causes (autoimmune reactions, new antigens released)
- exogenous causes (infectious, traumatic, physical, chemical)
Why do we need inflammation?
- Dilution/inactivation of biological and chemical toxins
- killing microbes, necrotic tissue, neoplastic cells
- degradation (foreign material)
- providing healing factors → stimulating fibroblasts and scar/tissue repair**
- Goal is to bring all of these cells to the site of damage/inflammation
What are some sentinel cells in tissues
- macrophage
- dendritic cells
- mast cells
- recruit monocytes/leukocytes etc. to cite
Why does excessive inflammation cause cancer?
inflammatory cells releasing growth factors and cytokines → cell proliferation which is a main factor of cancer cells
also by producing free radicals → destroy DNA
Signs of inflammation are: (5 clinical signs)
- swelling
- redness
- feel warm/heat
-
pain
- loss of function (Added bit later)
What causes redness in inflammation?
blood vessels dilation → e.g. scratching skin causes redness as blood vessel dilation occurs
What causes heat in inflammation
increased blood flow → increased temperature
what causes swelling in inflammation
extravascular accumulation of fluid → oedema → mediates swelling
why do we experience pain in inflammation
swelling and release of inflammatory mediators -→ stimulating pain
why do we have loss of function in inflammation
cell degeneration and necrosis
- until tissue repair occurs, you will have some tissue that is lost
Features of acute inflammation**
- Rapid onset
- Short duration
- exudation of fluid and plasma proteins
- leukocytic emigration (neutrophils** → first cell on site (replaced after 3-7 days in chronic inflammation))
Features of chronic inflammation*** (duration, cell types, end result etc.)
Longer duration
lymphocytes and macrophages
proliferation of blood vessels
fibrosis
tissue necrosis
sequela to acute inflammation or can be directly chronic
Why are neutrophils first on site?
- there are more in the blood and they respond quickly to chemokines → attach more firmly to the endothelium which is the first thing that occurs during inflammation
- Remember: type of leukocyte depends on age of inflammatory response and type of stimulus…
What are the first cells to arrive in:
- viral infections
- allergies
- parasitic infections
- lymphocytes → viral
- mast cells* → allergies
- eosinophils → parasitic
2 triggers of inflammatory process are:
- microbial or parasitic products within host tissue (PAMPs - pathogen associated molecular patterns)
- cellular and tissue injury (DAMPS = damage associated molecular patterns)
what does activation of PAMPS and DAMPS do
activate macrophage, release cytokines, lipid mediators, chemokines → activation of inflammatory process*
Major components of acute inflammation
increased blood flow
neutrophil emigration
leakage of plasma proteins → oedema (fluid)
Why do we have vascular changes in acute inflammation?
have to have increase vascular change (larger vessels) so that inflammatory cells can get to the site of injury (leukocytes, neutrophils etc.)
- increased movement of plasma proteins and leukocytes out of circulation
- leaking membrane as well → so cells can move from intravascular to extravascular space to site of injury**
Reactions of blood vessels in acute inflammation***
- injury
- activation of inflammatory cells
- proinflammatory chemical mediators → 2 pathways:
- → vasodilation (by cytokines)
- slowing of blood flow
- leukocyte margination
- OR to increased vascular permeability
- fluid leakage to extracellular space*
***Events during inflammation: different mechanisms depending on biological/physical features of infectious agent are… (3 mechanisms)
- retraction of endothelial cells (histamine, other mediators)
- endothelial injury (caused by burns, microbial toxins, rapid)
- increased trancytosis → within endothelial cells, transport across cell layer and increased number of channels → more things going from blood into extravascular tissue
- these can act together or alone
4 movements of the leukocyte recruitment to site of inflammation
- margination
- rolling
- diapedesis
- migration to agent
What is each stage of leukocyte recruitment mediated by?
mediated by adhesion molecules: cell surface proteins:
- integrins is an example of one, glycoprotein
- on leukocytes and endothelium
Explain rolling process of leukocyte immigration
- temporarily bind to endothelium and then are released
- weak interactions between selectins
- selectins: E endothelium, P platelets, L leukocytes → these are mediating the rolling process
Explain stable adhesion process of leukocyte immigration
- Stronger process
- Binding of B2 integrin on leukocytes to ICAM1
What is leukocyte adhesion deficiency?
Cause: lack of B2 integrin expression
- so leukocytes can undergo rolling but they never get into the tissue as they cannot form stable adhesion to endothelium
- Causes ulcers, abscesses without puss, penumonia etc as not even neutrophils can get to the site of inflammation
Explain diapedesis in leukocyte immigration process
Adhesion molecules:
- PECAM1
- Junctional adhesion molecules (JAMs)
- transport across the membrane into extracellular space and migrate to site of inflammation
What is chemotaxis?
movement along a chemical gradient → movement of leukocytes towards the site of injury
- change shape etc due to changing intracellular proteins
What can chemoattractants be (exo and endo…)
- exogenous: bacterial products
- Endogenous: cytokines (IL8 attracting neutrophils, eotaxin attracting eosinophils, MCP macrophage protein)
Functions of chemoattractants?
- activation of inflammatory cells
- antiviral activity
- regulation of immune system
- haematopoiesis, angiogenesis, cell growth
- can also mediate cancer/tumour cells reproducing in other tissues → migrate to other tissue cites…
What are the defensive functions of leukocytes once they are activated?
- phagocytosis
- liberation of substances that destroy extracellular microbes and dead tissues → substances within leukocytes granules** → released into extracellular space
- production of chemical mediators (cytokines) → amplify inflammatory response to fight infection quicker
Chemical mediators: Histamine*
- what are the producers of histamine?
mast cells** main ones
basophils
platelets
What are the functions of histamine? (6 main ones)
- vasodilation*
- increased vascular permeability
- pain and itchy
- nerve reflexes
- bronchial constriction → e.g. suffering from asthma, narrowing of respiratory tree as lots of histamine are being produced (contracts SM cells to narrow lumen)
- eosinophilic chemotaxis → recruit eosinophils important in allergic reactions
What is the main role of the complement system?
- cascade of events with activation of plasma proteins after inflammation, injury, clotting etc.
to amplify the reaction from inflammatory cells → recruit and activate more leukocytes during infection etc.
- and make macrophages kill microbes in more efficient way
Arachidonic acid* metabolites: what happens during injury to cell membrane?*
- slide 51
Fatty acid inside of the membrane, injury to membrane by inflammation causes release of arachidonic acid
- two enzymes: lipoxygenase pathway and cycloxygenase pathway
- why does this matter? because important when taking steroids or aspirin etc.
- they act on this cascade
Relationship between steroids and NSAIDs and arachidonic acid (AA)
steroids and NSAIDs inhibit the arachidonic acid pathway
- steroids are stronger as they inhibit higher up the pathway (the phospholipases stage before the arachidonic acid pathway is even started*
- whereas NSAIDs inhibits COX-1 and 2 stage further down*
Serous inflammation
- acute inflammation
- fluid with low plasma and no/low leukocytes
- slight increased vascular permeability
catarrhal inflammation: what occurs in this
- uterus, trachea, stomach etc have goblet cells and mucous producing cells
- inflammatory process is stimulating excessive amount of mucous.. occurs only in some organs, only with mucous producing or goblet cells
- e.g. snotty nose is excessive mucous production
Fibrinous inflammation (slide 55)
What is this?
- Fibrin produced → means leakage of endothelial wall is quite massive → big increase in vascular change causes fibrinous inflammation (fibrin on the outside**)
Systemic effects of acute inflammation:
Function: conserve energy and mobilise resources
- loss of appetite
- lethargy
- muscular wasting
- haemodynamic changing
Acute inflammation effects:
- fever
- leukocytosis
- alterations to acute phase proteins
3 systematic effects of acute inflammation?
- fever
* increase production of neurotransmitters - leukocytosis
* increased release of cells (young and not mature) → if infection is really bad you will have release of less mature neutrophils (as had to be released very quickly) - acute phase proteins
- increase during inflammation (serum amyloid, fibrinogen)
- involved in fighting agent and tissue repair
Outcomes of acute inflammation?
- resolution (best outcome)
- scarring (after substaintial tissue destruction)
- progression into chronic inflammation (Worst)
- no resolution, infection is persisting..
Key features of chronic inflammation
- fibroplasia and angiogenesis (granulation tissue)
- initiation of wound healing
- lymphocytes, plasma cells, macrophages, MGCs
- Necrosis: more than acute inflammation
- no vascular changes like acute inflammation
Why does inflammatory response become chronic or arise as chronic?
- failed elimination of the inciting stimulus by the acute inflammation
- unique features of the inciting stimulus
Biological mechanisms resulting in chronic inflammation (slide 70)
- persistence/resistance
- isolation in encapsulated material: antibiotics not working
- unresponsiveness (indestructible material)
- autoimmunity and leukocyte defects
Main cells of chronic inflammation: Difference between monocyte and macrophages
monocyte is in the blood
macrophages are in the tissue levels
- can recognise macrophage as activates when you can see many vacuoles*
**what are the 2 different activation pathways of macrophages in chronic inflammation?
-
classical activation (M1 macrophages)
* most important when have microbes causing chronic inflammation* -
alternative activation (M2 macrophages)
* less microbicidal (M1 are already doing this*); involved in tissue repair (fibroblast activation, increased collagen, increased angiogenesis (formation of new blood cells)
Other cells involved in chronic inflammation
lymphocytes
neutrophils: occur in persistent inflammation (chronic active inflammation) where reaction with features of both acute (necrosis, neutrophils) and chronic (macrophages and fibrosis)
Difference between different distributions of lesions
focal
multifocal
diffuse
focal = 1 area being affected
multifocal = different focal spots e.g. 3
diffuse = cant see lesion as such because entire tissue is effect (many inflammatory cells)
What is definition of repair after chronic inflammation
restoration of tissue architecture and function after an injury
2 types of reactions after tissue damage/injury and what are the differneces between the two?
regeneration → going back to normal
scar formation → patching up the injury and some changes in the structure/function of the original organ
What is involved in regeneration in tissue repair process?
Limited process in mammals* only a few exceptions:
- can only happen in organs with stem cell compartment or high cellular turnover**
- SKIN → stem cells and high cell turnover in the epidermis
- HAEMATOPOIETIC SYSTEM
- GI TRACT
When does scar formation occur in tissue repair?
- damages tissue incapable of complete reformation
- e.g burn on skin
- high damage in skin (Wide and deep tissue damage)
What is involved in cell and tissue regeneration?
- cell proliferation
- integrity of extracellular matrix
- development of mature cells from tissue stem cells (skin, intestine, cornea)
Tissues of the body are divided into three categories…
- labile/ continuously dividing tissues
- stable tissues
- permanent tissues
continuously dividing tissues: how do these tissues effect regeneration?
easy regeneration after damage
- e.g. enterocytes: epidermis, GIT, transitional epithelium are continuously dividing
- continuously lost and replaced: can regenerate
stable tissues in regeneration:
- Cells have proliferative activity
-
capable of dividing after injury**
- e.g. the liver are stable tissues
- Remarkable capacity to regenerate (after tumour etc. in liver after operation)
permanent tissues in tissue repairation (slide 104)
any injury is irreversible and repair can occur ONLY by SCAR FORMATION
- examples: BRAIN and HEART**
When does repair by scar formation occur
- tissue injury is severe or chronic with extensive damage
- nondividing cells are injured
- NO restitution of the original structure, but ‘patching’
What factors influence the repair process:
- intensity and duration of the infection/stimulus
- conditions inhibiting repair (e.g. not cleaned properly, blood supply.)
- various diseases inhibiting repair (vitamin C deficiency effects collagen formation)
Angiogenesis:
formation of new blood vessels from pre-existing vessels
Why is angiogenesis important during wound healing?
Needs nutrients and oxygen supply for wounds to heal (just like normal tissues). Thus this comes from blood vessels, therefore we have more blood vessels during these stages.
- oxygen supply
- removal of waste products
- drainage of excess fluid
- vascular pathway for cells
Also seen in cancer…
Second step of wound healing in scar formation: formation of granulation tissue
granulation tissue: pretty rough/granular
- at this stage is not mature scar
- many fibroblasts but not many collagen fibres → more dominated by blood vessels
last stage of scar formation: maturation of the connective tissue
- less cellular: but LOTS of connective tissue in this stage
- patching: not original tissue anymore in scar formation
Remodelling of the connective tissue (slide 111)
- only the connective tissue necessary to repair the defect should be produced (balance in productive of connective tissue)
First intention healing in skin wounds:
- first intention: not much damage, mild scaring and regeneration on top is very effective
- where scar is we have normal tensile strength of the skin but no hair follicles etc.
second intention healing* in wound repair
- intense inflammation
- massive tissue loss
- substantial scar formation
- takes more time to heal
- reduced tensile strength with increased risk of ulceration..
- lots of tissue loss so lesion will be repaired but will be more prone to ulceration
