What are the 3 purposes of inflammation?
1) Remove the cause of injury
2) Remove necrosis (dead tissue)
3) Initiate repair
Although inflammation has a purpose, give 2 ways in which it can be damaging?
1) Can damage nearby tissues and be destructive
2) Can be inappropriate - chronic inflammatory disease
What are the 3 kind of cells that predominate in chronic inflammation?
1) Plasma cells
2) Lymphocytes
3) Macrophages
What is the difference between chronic and granulomatous inflammation?
Granulomatous inflammation is a specific type of chronic inflammation
Granulation tissue and scar tissue are formed in chronic inflammation, can they also be formed in acute inflammation?
Yes, but they are more abundant in chronic inflammation
What are the 4 main differences between chronic and acute inflammation?
1) Chronic has a slow onset - days - months
Acute has a quick onset - mins - hours
2) Chronic often has more subtle clinical signs
Acute has very prominent clinical signs
3) In chronic, plasma cells, lymphocytes and macrophages predominate
In acute neutrophils are the main cell involved
4) Chronic is severe and progressive
Acute is often mild and self limiting
What is meant by primary chronic inflammation?
Primary chronic inflammation has all the histological features of acute inflammation but there is no initial of acute inflammation
Does acute inflammation always lead to chronic inflammation?
No in most cases acute inflammation doesnt lead to chronic inflammation as the acute inflammation resolves the problem
In what 2 ways can acute inflammation lead to chronic inflammation?
1) Acute inflammation can progress to chronic inflammation
2) Recurrent episodes of acute inflammation can lead to chronic inflammation
What is the most common type of acute inflammation to lead to chronic inflammation?
Suppurative (pus-forming) type
Give 5 causes of primary chronic inflammation?
1) Some infections
2) Primary granulomatous disease
3) Endogenous material
4) Exogenous material
5) Some autoimmune
Describe how suppurative acute inflammation can progress to chronic inflammation?
1) Pus forms an abscess which is deep-seated
2) Drainage is delayed and the abscess forms thick walls made from granulation and fibrous tissue
3) Rigid walls of the abscess fail to come together after drainage and the stagnating pus becomes organised by the in growth of granulation tissue to be replaced by a fibrous scar
Give an example of a condition in which recurrent episodes of acute inflammation lead to chronic inflammation?
Cholecystitis
Multiple recurrent episodes of acute inflammation lead to replacement of gall bladder wall muscle with fibrous tissues
Predominant cell type becomes lymphocyte rather than neutrophil polymorph
Presence of indigestible material also favours progression to chronic inflammation, what particular kind?
Indigestible material is resistant to the action of lyzosomal enzymes - foreign bodies tend to provoke a specific type of chronic inflammation called granulomatous inflammation - this causes macrophages to from multinucleate giant cells called foreign body giant cells
What are the main types of lymphocytes involved in chronic inflammation?
1) Plasma cells which produce Ab
2) T cells which produce cytokine which have an important role
What is the macroscopic appearance of chronic inflammation?
Depends on the type and the type of tissue
What are the 5 most common macroscopic appearances of chronic inflammation?
1) Chronic ulcer - eg. chronic peptic ulcer, base is lined by granulation tissue and fibrous tissue extends through the muscle layer
2) Chronic abscess cavity
3) Thickening of wall of hollow viscus
4) Granulomatous inflammation presence of granulomas - with or without caseous necrosis
5) Fibrosis - may become most prominent feature when most of the chronic inflammatory cell infiltrate has subsided
What are the predominant features in repair of tissue from chronic inflammation?
Angiogenesis followed by fibroblast proliferation and collagen synthesis resulting in granulation tissue
What are the microscopic features of chronic inflammation? 5
1) Lymphocytes, plasma cells and macrophages
2) Few eiosinophils may be present, very few neutrophils
3) Some macrophages form multinucleate cells
4) Exudation fluid is not prominent
5) May be production of new fibrous tissue from granulation tissue
What is granulation tissue?
Important component of healing, comprises small blood vessels in a connective tissue matrix with myofibroblasts
What is a granuloma?
An aggregate of epithelioid histocytes and other cells - lymphocytes and histiocytic giant cells
Appearance may be augmented by the presence of caseous necrosis
What is a common feature of the many of the stimuli that induce granulomatous inflammation?
Indigestibility of particulate matter by macrophages
What does the association of eiosinophils with granulomas indicate?
Often indicates parasitic infection
What is the role of macrophages in chronic inflammation, what do they respond to and where are they derived from?
1) Respond to chemotactic stimuli
2) Macrophages in inflamed tissue are derived from monocytes that have migrated out of the blood vessels and become macrophages in the tissues
3) They phagocytose material and produce a range of important cytokines
What are the 3 morphological features of chronic inflammation?
1) Infiltration with mononuclear cells (macrophages, plasma cells and lymphocytes)
2) Tissue destruction
3) Healing by fibrosis
What is meant by recruitment, proliferation and immobilisation of macrophages in chronic inflammation?
1) Recruitment - Monocytes enter damaged tissue and from endothelium of blood vessel
2) Proliferation - macrophages proliferate locally in damaged tissue
3) Immobilisation - of macrophages within tissues
What is a fibroma?
Fibrous tissue which arises from 1 cell line
What kind of cell induces the laying down of connective tissue in fibrosis?
Macrophages
What are histiocytic giant cells including function?
Form where material is indigestible to macrophages
Multinucleate giant cells with >100 nuclei
Develop when 2+ macrophages try to engulph the same particle
No known function, not phagocytic
Name 2 bacterial granulomatous diseases?
1) TB
2) Leprosy
Name a parasitic granulomatous disease?
Schistosomiasis
Name a fungal granulomatous disease?
Cryptococcus
Name 1 granulomatous disease caused by synthetic materials?
1) Silicosis
Name 2 granulomatous diseases with unknown causes?
1) Sarcoidosis
2) Crohn’s disease
What are the 2 concentric layers of cells found in an early granuloma?
Middle - macrophages
Edge - lymphocytes
What are the 3 concentric layers of cells found in a noncaseating epitheloid granuloma?
Middle - epithelioid macrophages and langerhan’s type giant cells
2nd layer - Lymphocytes and plasma cells
Outer layer - Fibroblasts producing collagen
What are the 4 concentric layers of cells found in a caseating epitheloid granuloma?
Middle - caseous necrosis
2nd layer - Epitheloid macrophages and langerhan’s type giant cells
3rd layer - lymphocytes, plasma cells
Outer layer - Fibroblasts producing collagen
What is the role of inflammation in MS?
plasma cells and T lymphocytes are seen in white matter where macrophages break down myelin
What is the role of inflammation post MI and in atherosclerosis?
1) Myocardial fibrosis pots MI
2) Inflammation makes an important contribution to development of atheroma
Macrophages adhere to the endothelium, migrate in intima and with T lymphocytes express cell adhesion molecules which recruit other cells, macrophages are also involved in processing the lipids that accumulate in plaques
Give the 4 broad causes of chronic inflammation?
1) Acute inflammation
2) Persistent infection
3) Autoimmunity
4) Prolonged exposure to toxins
What type of granulomas are typical of TB?
Caseous granulomas
What 2 events lead to the formation of granulomas in primary pulmonary tuberculosis?
1) 0-3 weeks - Alveolar macrophages in the lungs engulph TB, they also release cytokines to recruit more macrophages, the engulphed bacterium proliferate inside the macrophage
2) > 3 weeks - Dendritic cells present antigens to T cells in lymph nodes to mount a T cell response
These 2 events lead to a granuloma forming for the purpose of containing infection and eliminating bacteria
Describe the granuloma formed in TB?
Contains macrophages, epitheloid cells and langerhans giant cells all surrounded by T lymphocytes, they are caseous, epitheloid macrophages surround necrotic region that has a T cell rim
What is meant by an epitheloid cell?
Activated macrophages resembling epithelial cells. elongated, pale eiosinophillic cytoplasm, single ovoid nucleus which is less dense than that of a lymphocyte.
Which 2 cytokines are important in the formation and function of a granuloma?
TNF - alpha
INF gamma
What are the 2 mechanisms of healing that can occur following acute inflammation?
1) Healing by regeneration
2) Healing by repair
Roughly why does regeneration occur as opposed to repair and visa versa?
If cells of the tissue can regrow - healing by regeneration
If cells of the tissue cannot regrow - healing by repair
What sort of tissue occurs in repair compared to regeneration?
Repair - scar tissue forms
Regeneration. - tissue returns to normal
What is the difference in resulting function from regeneration compared to repair?
In repair you get fibrosis and scarring and therefore loss of function
In regeneration you get restitution of specialised function
What are the 3 kinds of cell populations considered in terms of repair and regeneration?
1) Labile cell populations
2) Stable cell populations
3) Permanent cell populations
What are the 2 main properties of labile cell populations, do they have regenerative capacity and why and given an example?
1) High normal turnover
2) Active stem cell population
Have an excellent regenerative capacity as can just increase proliferation rate
An example is epithelia
What are stable cell populations sometimes known as?
Quiescent populations
What are the 2 main properties of stable cell populations, do they have regenerative capacity and give 2 examples?
1) Low physiological turnover
2) Turnover can massively increase if needed
So have good regenerative capacity
Examples are liver and renal tubules (70% partial hepatectomy in rat - restores in 10-14 days)
What are the 2 main properties of permanent cell populations, do they have regenerative capacity and give 2 examples?
1) No physiological turnover
2) Long life cells
No regenerative capacity
Neurons and muscle cells
What has stem cell research around permanent cell populations shown?
They can be forced to regenerate but for all intents and purposes they cant
At which stages in the cell cycle are the 3 types of cell populations?
1) Labile - constantly cycling
2) Stable - In quiescent G0 phase - can go in if need to
3) Permanent - Completely out of cell cycle
The architecture of a tissue is important, why may tissues made up of labile or stable cell populations not be able to regenerate normal tissue and function?
Tissues are made up of many cell types, eg. not just a section of epithelia
To regenerate tissues need a complex connective tissue framework on which the cell populations can regenerate, if that connective tissue framework is collapsed even if cells can regenerate normal tissue cannot
Rebuilding of complex architectural stuctures such as glomeruli or lungs is limited
Why does liver cirrhosis occur even though liver cells have capacity to regenerate?
1) Collapse of the reticulin (connective tissue) framework of the liver
2) Liver cells cannot repopulate the normal architecture
3) Leads to formation of regenerative nodules divided by fibrous septa
4) Dont get regeneration of hepatic lobules so the liver cannot carry out its function
Give the 3 properties of stem cells?
1) Prolonged self renewal
2) Asymmetric replication (every cell that replicates one remains as a stem cell and the other goes on to become specialised)
3) Reservoirs are present in many adult tissues known as stem cell niches
What are stem cell niches?
Reservoirs of stem cells in adult tissues
What is the significance of stem cell niches in regeneration?
Survival of stem cell niches is crucial to regeneration
Even if a tissue is made up of cells with regenerative capacity if the stem cell niche is destroyed then those tissues will not regenerate
Give 2 examples of insults to tissues which can result in the destruction of stem cell niches?
1) Full thickness burns
2) Radiation
Why is it important to control regeneration?
Regeneration requires proliferation and if this goes unchecked it could result in neoplasia
How is regeneration controlled?
1) Complex control by growth factors
2) Cell to cell interactions (eg. contact inhibition)
3) Cell to matrix interactions
What 3 main things does whether regeneration occurs depend on?
1) Tissue cell kinetics (type of cell populations)
2) Architecture
3) Stem cell survival
What is a scar?
Non specialised fibrous tissue
Why does repair occur?
When normal tissue structure cannot be replaced as tissue damaged is not now capable of regeneration
Does repair have functional consequences?
Depends on the amount of scar tissue formed and where it forms
Eg. scarring of the myocardium post MI may have no functional consequence if its a small area, but may have large consequences if there is a larger area of scarring or it effects a part of the myocardium involved in conduction leading to heart block
What are the 3 main components of granulation tissue?
1) New capillary loops
2) Phagocytic cells (macrophages and neutrophils - leads on from acute inflammation)
3) Fibroblasts/myofibroblasts
What are myofibroblasts?
Fibroblasts which have aquired myofibrils so become contractile
Why implications may the presence of myofibrils in wound healing have?
1) May be good as reduced the area of epithelia that needs to be formed to cover the wound
2) Can have functional consequences as it leads to contraction of the wound (eg. circumferential burns)
Give 2 examples of problems relating to wound contraction?
1) Contractures after burns
2) Oesophageal peptic strictures - damage to the oesophagus due to gastric reflux can lead to formation of scars which contract and narrow the lumen impeding swallowing
What is meant by organisation?
Basic stereotyped pathological process
Repair of specialised tissue by formation of fibrous scar
Starts by formation of granulation tissue which matures into fibrous tissue ie. a scar
What is granulating?
Formation of granulation tissue
Maturation of granulation tissue into fibrous tissue tends to happen over what time period?
~3 months
What 4 things happen to granulation tissue as it matures into fibrous tissue?
1) Cellularity decreases - fibrous tissue is relatively acellular with little metabollic demand
2) Vascularity decreases
3) Amount of collagen and ECM increases
4) Strength increases
What are the 2 types of factors that may inhibit healing?
1) Local
2) Systemic
What is a haematoma?
Collection of clotted blood
What are the 5 local factors which can inhibit healing and why?
1) Infection - persistent infection = persistent inflammation = persistent tissue damage = inhibits healing
2) Haematoma - Holds tissue apart, cant heal as edges not together
3) Blood supply - need nutrients for healing process to occur
4) Foreign bodies - Can lead to infection
5) Mechanical stress
What is meant by a catabolic state?
Start to break down proteins as not enough caloric input
Give 8 systemic factors which may inhibit healing and why?
1) Age - younger = heal faster
2) Drugs - steroids generate catabolic state
3) Anaemia - healing process requires O2
4) Diabetes - catabolic state or vascular disease which limits nutrient, causes a metabollic deficit in fibroblasts
5) Malnutrition - need proteins to heal
6) Catabolic states - need proteins to heal
7) Vitamin C deficiency - needed for synthesis of collagen
8) Trace metal deficiency - co-enzymes for various reactions
What are the 3 main (and 4th extra) stages in organisation of tissue?
1) Endothelial cell proliferation, buds, canalisation, new vessels
2) Phagocytes - remove dead/damaged tissue
3) Proliferation and migration of myofibroblasts, synthesis collagen and ECM, acquire myofibrils and contractile ability
(4) Wound contraction)
What are the 2 types of wound healing?
1) Healing by first intention
2) Healing by second intention
What is healing by first intention?
Occurs in a clean, uninfected surgical wounds
Get good haemostasis, edges are opposed eg. with surgical sutures
What are the 3 stages in healing by first intention (with times)?
1) Inevitably you will get an area of clot forming between the edges - dont want a haematoma, just get a small fibrinous clot - 24 hours
2) 3-7 days, phagocytic cells remove fibrinous clot and organisation begins
3) Weeks - epithelia forms and get a small scar
healing by second intention occurs when the wound edges are not opposed, give 5 reasons why this may be the case?
1) Extensive loss of tissue
2) Apposition not possible
3) Large haematoma
4) Infection
5) Foreign body
How is healing by second intention different from healing by first intention?
Not a fundamentally different process
More florid granulation tissue reaction
More extensive scarring
How do ulcers heal?
Healing by second intention
Wound strength increases over time, what is its general strength after, 7 days, 4 weeks and 12 weeks and at what point are sutures taken out, why then?
7 days - 10%
4 weeks - 70%
12 weeks - 80%
Sutures taken out on day 7, this is a compromise, wound must be able to maintain integrity but also want to remove a foreign body as soon as possible to reduce infection risk
How does fracture healing occur?
- When a bone is broken you get a large haematoma at fracture site
- Removal of necrotic fragments by phagocytic cells
- Osteoblasts lay down woven bone leading to the formation of a callus at the fracture site
- Get remodelling according to mechanical stress
- Get replacement by lamellar bone
Give 5 reasons that non union of fractures can occur?
1) Misalignment of the 2 fragments
2) Movement of the 2 fragments
3) Infection
4) Interposed soft tissue (soft tissue between the 2 fragments)
5) Pre-existing bone pathology eg. pathological fracture caused by cancer in the bone, wont heal as normal tissue has been destroyed by pathological process so no surrounding osteoblasts to lay down new bone at the fracture sight and heal the fracture
How do supporting cells in the CNS differ from those of the rest of the body?
Body - collagen and fibroblasts
Brain - no collagen or fibroblasts, instead have glial cells
How is damage to brain tissue resolved?
Damaged tissue is removed often leaving a cyst which is surrounded by reactive gliosis (proliferation of astrocytes (brains version of fibrous tissue)
What is meant by reactive gliosis?
Proliferation of astrocytes, a type of glial cell
Does scarring occur in the brain?
No you get gliosis rather than scarring
Healing is tightly controlled by a complex network of cytokines, why are these clinically significant?
Control needed to avoid neoplasia - the cytokines involved are those that are often perverted in neoplasia and thus are of interest in cancer therapies
Name 7 growth factors which are involved in the control of healing?
1) Epidermal growth factor alpha
2) Transforming growth factor beta
3) Platelet-derived growth factor
4) Keratinocyte growth factor
5) Tumour necrosis factor
6) Vascular endothelial cell growth factors
7) Transforming growth factor alpha
Do you get granulation tissue or a scar in healing by primary intention?
Get much less granulation tissue, often dont get a scar and often you get a return to normal tissue function
Do you get tissue loss and granulation tissue in healing by secondary intention?
Yes, get tissue loss and get granulation tissue replaced by a scar.
