7. Chronic Inflammation Flashcards
What is the purpose of inflammation?
- remove the cause of injury
- remove necrosis that has occurred due to injury
- initiate repair of the tissues
How can inflammation be a bad thing?
- can damage nearby tissues and be destructive
- can be inappropriate (chronic inflammatory diseases and autoimmune diseases)
What are 4 main features of ACUTE inflammation?
- fast onset (mins-hours)
- neutrophil polymorphs
- prominent signs
- mild, self-limiting tissue injury
What are the 4 main features of CHRONIC inflammation?
- slow onset (days)
- macrophages, lymphocytes
- subtle signs
- severe, progressive
Neutrophil polymorph is the main cell in which type of inflammation?
Acute
These neutrophils cause phagocytosis of invading organisms
Which type of inflammation creates prominent signs?
Acute
redness, heat etc
Which type of inflammation has a slow onset?
Chronic
Can take days or even weeks or months in the case of autoimmune diseases
In which type of inflammation are the signs most likely to be missed?
Chronic
Can get progressive and severe disease before the signs are picked up on (the signs are subtle)
Why might autoimmune diseases go unnoticed?
Signs of chronic inflammation are often subtle and progressive and autoimmune diseases often mimic other diseases
Summarise ACUTE inflammation
initial reaction to cell injury
vessels dilates and leak, protein-rich exudate
possible outcomes = resolution, suppuration, organisation into scars, chronic inflammation
What are the dominant cells in CHRONIC inflammation?
lymphocytes, plasma cells, macrophages
What is particularly abundant in chronic inflammation?
Granulation and scar tissue
Is chronic inflammation primary or secondary?
Usually primary but can be sequential from acute
But chronic is not the normal response to acute - normally acute resolves and forms pus etc.
What causes chronic inflammation?
- some infections
- endogenous material
- some autoimmune
- exogenous material
- primary granulomatous disease
Give examples of infections which can cause chronic inflammation?
TB, leprosy, some viruses
Give examples of endogenous material that can cause chronic inflammation
- necrotic adipose tissue
- uric acid crystals
Give examples of exogenous material that can cause chronic inflammation
- asbestos fibres
- sutures
- implanted prostheses
Define exogenous
External origin (outside of the body)
Give examples of autoimmune diseases
rheumatoid arthritis, SLE, pernicious anaemia
What is pernicious anaemia?
An autoimmune disease
Autoantibodies to intrinsic factor and gastric parietal cells lead to no B12 absorption and anaemia results
Give two examples of granulomatous disease
Crohn’s disease
Sarcoidosis
What is a granuloma?
A collection of inflammatory cells
A collection of immune cells called histiocytes
Describe sarcoidosis
granulomas collect in many organs, mainly the lungs and lymph nodes within the chest cavity
Viewed as an immune reaction to usually an infection
In which type of acute inflammation, is progression to chronic most common?
suppurative (pus forming) acute inflammation
Describe the progression from acute to chronic inflammation?
Pus can form an abscess, if the abscess becomes deep enough the walls thicken and become filled with granulation and fibrous tissue - this make a permanent cavity for pus to sit in - this makes it more difficult for the immune system to reach - if this happens recurrently it can lead to chronic inflammation
What is an abscess?
A painful collection of pus
What is granulation tissue?
Repair/healing tissue
New connective tissue and tiny blood vessels that form on the surfaces of a wound during the healing process
What is chronic cholecystitis?
Gall bladder inflammation usually doe to stones
Stones persist - thickened gall bladder wall - fibrous tissue - chronic cholecystitis - chronic pain - may need gall bladder removal
What are the main morphological features of chronic inflammation?
- infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells)
- tissue destruction
- healing by fibrosis
Give examples of mononuclear cells
- macrophages
- lymphocytes
- plasma cells
They are involved in chronic inflammation
What are the macroscopic features of chronic inflammation?
Dependent on the actual disease
Define ‘caseating’
Necrosis with conversion of damaged tissue into a soft substance (cheesy necrosis, soft damaged tissue)
What are the macroscopic features of chronic peptic ulcer? (a type of chronic inflammation)
- mucosal breach
- granulation tissue at the base
- fibrous tissue extends through the wall
What are the macroscopic features of chronic abscess cavity? (a type of chronic inflammation)
Pus becomes encapsulated into fibrous tissue that immune system has difficulty reaching
What is Crohn’s disease?
A chronic inflammatory disease of the intestines, characterise why non-caseating granulomas
Are the granulomas in Crohn’s caseating or non-caseating?
Non-caseating
Are the granulomas in TB caseating or non-caseating?
Caseating
Is fibrosis characteristic of chronic inflammation?
Yes, fibrosis is prominent once the inflammatory infiltrate has stopped
What are the main microscopic features of chronic inflammation?
- cellular infiltrate of lymphocytes, plasma cells and macrophages
- production of new fibrous tissue from granulation tissue
- exudation of fluid is NOT prominent (like it is with ACUTE inflammation)
Is exudate prominent in acute or chronic inflammation?
ACUTE inflammation only
What is characteristic of macrophages microscopically?
Irregular border
What is characteristic of lymphocytes microscopically?
Tiny dark cells
How do plasma cells look different from lymphocytes microscopically?
Plasma cells are bigger than lymphocytes
What are the two types of lymphocytes involved in chronic inflammation?
- B lymphocytes
- T lymphocytes
B cells and T cells are lymphocytes involved in chronic inflammation? What do T cells do?
Produce cytokines
B cells and T cells are lymphocytes involved in chronic inflammation? What do B cells do?
Become plasma cells which produce antibodies
What are the functions of cytokines which are produced by T cells?
- attract macrophages
- attract neutrophils (chemotaxis) and factors such as histamine
- cause perforins to kill invading cells
- produce interferons
Cytokines help to attract factors such as histamine. What does this do?
Histamine increases vascular permeability to WBCSs and proteins, we see this in the acute inflammatory reaction
What do macrophage inhibition and macrophage activation factors do?
Macrophage inhibition factor traps macrophages in the tissue
Macrophage activation factors cause phagocytosis
Cytokines produce interferons. What do they do?
Interferons activate natural killer cells and macrophages - useful for attacking viruses!
What do macrophages do?
Engulf and digest cellular debris and microbes
Name 4 cell types that are found in the connective tissue. (rather than the blood stream)
- macrophages
- mast cells
- plasma cells
- fibroblasts
What is the function of mast cells?
The source of mediators such as histamine (increases vascular permeability to WBCs and proteins)
What is the function of fibroblasts?
Secrete structural proteins eg. collagen. The increase in collagen during inflammation leads to scar tissue
Polymorphonuclear leukocytes are found in the blood stream. What is an alternative name?
Granulocytes
Name some types of polymorphonuclear leukocytes/granulocytes
- neutrophils
- basophils
- eosinophils
- mast cells
Where are polymorphonuclear leukocytes produced?
In the bone marrow
What is the general function of polymorphonuclear leukocytes?
Elimination of microbes and dead tissue
What is the most abundant phagocyte?
Neutrophils.
Found in the blood stream
What is the function of eosinophils?
Good antigen presenting cells
Do not phagocytose so much
What is the function of basophils?
Produce histamine (increase vascular permeability)
What do injured basophils release?
Prostaglandins which help increase blood flow to the infection site
Basophils release prostaglandins as well as histamine why is this important?
It is important that increased blood flow comes along with increased vascular permeability
What do macrophages which are already at the site of damage do?
They release cytokines which signal to monocytes
What do monocytes do?
They enter damages tissue from the endothelium of blood vessels
= leukocyte extravasion
= recruitment
A lot of macrophages are needed to deal with a invading organism, how is this achieved?
Macrophages proliferate locally in damaged tissue
What happens to macrophages within the tissue?
They are immobilised
Where do the macrophages in inflamed tissues come from?
They come from monocytes that have migrated out of blood vessels
What is recruitment?
When monocytes travel to damaged tissue from the endothelium of blood vessels
As well as phagocytosing bacteria, macrophages can also cause damage to the surrounding tissue. How do they do this?
They release proteases which can cause damage.
Damage to surrounding tissue also caused during phagocytosis
As well as phagocytosis, what else do macrophages do?
- stimulated by low o2 to produce factors that induce angiogenesis for blood vessel formation in granulation tissue
- induce cells to re-epithelialise the wound and create granulation tissue
Are macrophages long- or short-lived
Macrophages are long-lived
If a macrophage cannot kill an organism, what may it be able to do?
They can hold and contain viable organisms e.g. M.tuberculosis and M. leprae
Granulation tissue is new connective tissue and blood vessels. List some features of granulation tissue
- grows up from wound base
- angiogenesis
- fibroblasts deposit collagen
- inflammatory cells
- macrophages important
How does granulation tissue appear?
Light red or dark pink due to capillaries
Painless if healthy, soft and moist
What is the key cell type in granulation tissue formation?
Macrophages
Important in re-epithelialisation and angiogenesis
What is the aim of the formation of granulation tissue?
To repair by replacement of injured tissue by fibrous tissues (this leads to scar tissue)
What does granulation tissue look like microscopically?
Can see many new vessels (can tell because of RBCSs) and can see lots of inflammatory cells in the stroma (lots of small dark cells)
What is fibrosis?
Formation of excess fibrous connective tissue during repair of damaged tissue
What is a fibroma?
A mass of fibrous/connective tissue
Arises from 1 cell line
What induces the laying down of connective tissue such as collagen?
Macrophages
What is a granuloma?
An aggregate (nodule) of epithelioid histiocytes and other cells such as lymphocytes and histolytic giant cells
What do epithelioid histiocytes look like histologically?
Large vesicular nuclei
Eosinophilic cytoplasm (=stains pink)
Give examples of granulomatous diseases
- TB
- leprosy
- Crohn’s disease
- sarcoidosis
When can histiocytic giant cells form?
Where material is indigestible to macrophages eg. tubercle bacilli which have cell walls resistant to macrophages
Another indigestible material is sutures
What are the main features of histolytic giant cells?
- multinucleate (may have >100 nuclei)
- develop when 2+ macrophages try to engulf the same particle
- no known function, not phagocytic
- given different names according to appearance
What does eosinophils look like histologically?
Binuclear and pink/red
Look like tomatoes with sunglasses on
What are macrophages also known as when in tissues?
Histiocytes
Therefore granulomas can be considered to be collections of macrophages
What do epithelioid histiocytes secrete?
Angiotensin converting enzyme
ACE
What are 2 types of histiocytic giant cell?
- langerhans giant cells
- foreign body giant cells
Langerans giant cells and foreign body giant cells are 2 types of histiocytic giant cells. What is the difference between them?
Langerhans giant cells = horseshoe arrangement of peripheral nuclei, seen in TB often
Foreign body giant cells = large cells with randomly scattered nuclei, seen in relation to foreign body material
Do giant cells define a granuloma?
No. Giant cells are often seen in granulomas but solitary giant cells in the absence of epithelioid histiocytes is NOT a granuloma
Name a BACTERIAL gramulomatous disease
- TB
- leprosy
Name a PARASITIC granulomatous disease
schistosomiasis
Name a FUNGAL granulomatous disease
cryptococcus (mainly seen in immunocompromised people)
Name a granulomatous disease which is of unknown cause
- sarcoidosis
- Crohn’s disease
What is leprosy?
Chronic infection by mycobacterium leprae. Granulomas of nerve, respiratory tract, skin and eyes. Results in loss of pain sensation and subsequent injuries which goes on to cause inflammation and scarring
What is the 1st of the 4 stages of TB? (1 week)
- inhale M. tuberculosis into lung
- invades alveolar macrophage
- enters via macrophage mannose receptor (phagocytosis)
- multiplies inside macrophage
What is the 2nd stage of the 4 stages of TB? (weeks 2-3)
- exponential proliferation of M/ tuberculosis
- cannot be contained in a single macrophage
What is the 3rd stage of the 4 stages of TB?
- proliferation and phagocytosis balanced
- 90% of patients stop here and do not develop symptoms and signs
- round complex formed with TB and infected macrophages in centre and normal macrophages surrounding
- TB can survive years here
- not contagious
- immune system may destroy TB and just leave a scar
What is the 4th stage of the 4 stages of TB?
- 5% of cases
- reactivation 12-24 months after stage 1
- proliferation and cavity formed away from immune cells
- active, symptomatic infection
- contagious
- more likely in immune compromised
What do the layers of an early granuloma consist of?
inside = macrophages outside = lymphocytes
What do the caseous epithelioid granuloma consist of?
inside = caseous necrosis
- epithelioid macrophages and langerhans giant cells
- lymphocytes and plasma cells
outside = fibroblasts producing collagen
What does caseous necrosis look like histologically?
a pink, granular mass
What do langerhans giant cells look like histologically?
huge and have a large number of nuclei
How does the cardiovascular system response to MI?
Cut off of blood supply to heart muscle causes chronic inflammation of heart muscle = myocardial fibrosis - can lead to heart failure/arrhythmias
How is inflammation involved in atheroma formation?
Macrophages adhere to epithelium and recruit other cells, process lipids that accumulate in plaques
What is seen in MS inflammation?
Plasma cells and T lymphocytes are seen in white matter where macrophages break down myelin
What are the possible clinical outcomes of chronic inflammation?
- persistence of infection
- prolonged exposure to toxic agents
- autoimmune disease
What enzyme does H. pylori produce and what does it do?
Proteases - damage intestinal lining - gastritis - loss of protective barrier - enzymes access stomach - ulcer - perforation
Which enzyme metabolises ETOH (alcohol)?
Cytochrome P450 E1
How does ETOH lead to apoptosis, necrosis and fibrosis and therefore cirrhotic liver disease?
- reactive oxygen species (ETOH activates macrophages, produces TNF alpha, mitochondria produce reactive oxygen species)
- free radicals (produced by oxidation of NADPH)
What happens in rheumatoid arthritis (an autoimmune disease)?
Inappropriate immune response
Recruitment of inflammatory cells which then accumulate in target areas (in this case, the joints)
What happens in SLE? (an autoimmune disease)
You get accumulation of inflammatory cells (inflammatory attack) anywhere (can get myocarditis, nephritis etc)
In summary, what are the 4 general causes of chronic inflammation?
- acute inflammation
- persistent infection
- autoimmunity
- prolonged exposure to toxins
