pathology of healing

Question 1

Angiogenesis
What Is angiogenesis and when does it occur?

Answer 1

● Branching and extension of existing vessels
● Recruitment of endothelial progenitor cells
● Occurs during wound healing, chronic inflammation, physiological processes
such as endometrial proliferation and in tumour formation/growth

Question 2

Wound Healing
What are the sequence of events involved in wound healing?

Answer 2

● Blood clot
● Granulation tissue (angiogenesis, migration and proliferation of fibroblasts)
● Cell proliferation and collagen deposition (of extracellular matrix)
● Scar formation (blanching, type 3 collagen initially which is replaced by type 1)
● Wound contraction via myofibroblasts
● Connective tissue remodelling (ECM synthesis and degradation)
● Recovery of tensile strength

Question 3

What is wound contraction?

Answer 3

● A process that usually occurs in large surface wounds and helps to close the
wound by decreasing the gap between its dermal edges.
● This reduces the wound surface area and is an important feature of healing by
secondary intention.
● It is mediated by a network of myofibroblasts that form at the edge of the wound.

Question 4

How do skin wounds recover tensile strength?

Answer 4

● Increase in collagen synthesis (type 1 collagen)
● Reduction in collagen degradation for the first 2 months
● Then structural modification of collagen with cross linking and increased fibre
size

Question 5

What is the approximate timeframe for the recovery of tensile strength in skin
wounds?

Answer 5

● Skin wounds have 10% tensile strength at 1 week (usually when sutures are
removed)
● Improves for the first 3 weeks and plateaus at 3 months when tensile strength is
70-80% of the original
● May never recover to 100%

Question 6

Scar formation and fibrosis
What are the phases involved in scar formation?

Answer 6

● Inflammation
● Fibroblast migration and proliferation
● Angiogenesis
● Extracellular matrix deposition (usually collagen)
● Tissue remodelling
● Wound contraction

Question 7

What factors influence scar formation?

Answer 7

● Tissue environment and extent of tissue damage
● Intensity and duration of stimulus
● Conditions that inhibit repair i.e. foreign body, infection or inadequate blood
supply
● Systemic disease states i.e. diabetes, steroid use
● Nutritional status
● Genetic predisposition to scar formation i.e. keloid

Question 8

Fibrosis
Describe the pathogenesis of fibrosis

Answer 8

● Fibrosis involves the excess deposition of collagen and extracellular matrix in
chronic disease
● Usually a combination of healing and chronic inflammation
● Characterised by a persistent stimulus (infection, autoimmune, trauma)
● Macrophages are the key cells involved and the process is governed by growth
factors which stimulate the proliferation and activity of fibroblasts

Question 9

Please give some examples of fibrosis

Answer 9

● Cirrhosis
● Chronic pancreatitis
● Pulmonary fibrosis
● Constrictive pericarditis
● Glomerulonephritis

Question 10

Immunity - Immunoglobulins
What are the types of immunoglobulins and their clinical significance?

Answer 10

● IgA - secretory
● IgD - antigen recognition by B cells
● IgE - important in anaphylaxis
● IgG - complement activation, infection fighting and immunity to past infections
● IgM - complement activation and is the first produced in acute infection

Question 11

Draw and label a typical immunoglobulin

Answer 11

● Y shape
● Base of the Y has two parallel lines (the effector portion)
● The angled top parts of the Y each have two lines representing the heavy and
light chains. This is the antigen binding portion
● The tips of the antigen binding portion (i.e. the most superior part of the arms of
the ‘Y’) are known as the variable region, because they are different on different
antibodies

Question 12

Type 1 Hypersensitivity
Outline the immunological mechanisms leading to anaphylaxis

Answer 12

● Exposure to antigen
● Presentation of antigen to T helper cells by dendritic cells
● T helper cells differentiate into TH2 cells
● These release cytokines that act on B cells to produce IgE
● IgE binds to mast cells
● Repeat exposure to an antigen causes cross linking of IgE on mast cells leading
to degranulation and release of vasoactive amines, lipid mediators and cytokines
● The action of these mediators on end organs results in clinical manifestations of
anaphylaxis – vasodilation, vascular leakage and smooth muscle spasm

Question 13

What are the features of innate and acquired immunity?

Answer 13

Innate
● Early response
● Mediated by toll like receptors
● Bind common microbe sequence
● Defence mechanisms that are not specific i.e. interferons, phagocytosis

Acquired
● T cell mediators - antigen presenting cells, MHC markers, antigen presentation. T
cells release cytokines and are responsible for orchestration of the immune
response.
● B cells differentiate into plasma cells
● Memory cell formation, meaning secondary exposure leads to a magnified
response.

Question 14

What are the clinical manifestations of anaphylaxis?

Answer 14

● Skin – rash, swelling
● Respiratory – wheeze, breathlessness, stridor
● GIT – diarrhoea and vomiting
● Cardiovascular – tachycardia, hypotension, shock and cardiovascular collapse

Question 15

What is type 2 hypersensitivity?

Answer 15

Hypersensitivity caused by antibodies that react with antigens present on cell surfaces or
in the extracellular matrix
Antigens can be intrinsic to the tissue or extrinsic i.e. drug metabolite

Question 16

Describe the mechanisms involved in hypersensitivity type 2 and give examples of each mechanism

Answer 16

*Opsonisation and phagocytosis
IgG antibodies opsonise cells, complement activation generates C3b and C4b which are
recognised by phagocyte receptors resulting in phagocytosis and destruction of
opsonised cells.
Examples: transfusion reactions, autoimmune haemolytic anaemia

*Complement and Fc receptor mediated inflammation: antibodies bind to fixed tissue
such as basement membranes and/or extracellular matrix which activates complement.
The generation of C5a and C3a cause increased vascular permeability and activate
inflammatory cells causing local tissue destruction.
Examples: glomerulonephritis, vasculitis, goodpastures syndrome

*Antibody mediated cellular dysfunction: antibodies directed against cell surface receptors
impair or dysregulate function without causing cell injury or inflammation
Examples: myasthenia gravis, graves disease, pernicious anaemia

Question 17

Type 3 Hypersensitivity
Explain the pathogenesis of Type 3 Hypersensitivity

Answer 17

Antibodies bind antigen to form complexes, which are then deposited in tissues where
they cause inflammation and tissue damage either directly or by activating complement.
3 phases involved in systemic diseases
● Formation of antigen/antibody complexes in the circulation
● Deposition of those immune complexes in various tissues
● Inflammatory reaction at the site of the deposition, causing tissue injury. This can
take around 1o days to evolve.

Question 18

What are some diseases caused by type 3 hypersensitivity?

Answer 18

Serum sickness, SLE. Post strep GN, reactive arthritis

Question 19

What are some clinical features of type 3 HS?

Answer 19

Fever, urticarial, arthralgia, lymph node enlargement, proteinuria

Question 20

Describe the sequence of events that lead to a type 4 hypersensitivity reaction.

Answer 20

● Initial injury
● Reaction is initiated by antigen-sensitised CD4+ or CD8+ T cells
● Antigen may be transported in the lymphatics of the damaged tissue
● Damage may occur via cytokines or via direct cell-mediated tissue injury

Question 21

What are some examples of type 4 hypersensitivity reactions?

Answer 21

● Type 1 diabetes
● Multiple sclerosis
● Rheumatoid arthritis
● Inflammatory bowel disease
● Guillian Barre
● Contact dermatitis
● Tuberculin reaction
● Granulomatous disease
● Viral hepatitis

Question 22

What is a neoplasm?

Answer 22

● Abnormal growth of tissue that exceeds and is uncoordinated with that of the
original tissue

Question 23

How do cancer cells invade the extracellular matrix and then metastasise?

Answer 23

● Loosening of intercellular junctions
● Attachment to the basement membrane and interstitial connective tissue
components
● Degradation of extracellular matrix via proteases, collagenases and other
enzymes
● Migration of tumour cells via circulatory spread and/or embolization.
● Form metastatic deposits at other sites in the body

Question 24

Why do some tumours metastasise to sites other than their natural blood and
lymphatic drainage areas?

Answer 24

● Some organs/tissues have adhesion molecules to which tumour cells bind
preferentially
● Some organs express chemokine receptors that attract cancer cells
● Downstream tissue may also be an environment that is not conducice to cancer
cell growth i.e. skeletal muscle

Question 25

Genetics of cancer
What is an oncogene?

Answer 25

A changed form of a gene that is usually involved in normal cell growth, resulting in a
transformed phenotype when expressed in the cell.
The most common are H-Ras or K-Ras mutations which make up 30% of all human
tumours.

Question 26

How are oncogenes activated?

Answer 26

3 mechanisms - mutation, gene duplication or regulatory gene translocation
Before it becomes an oncogene through transformation, these genes are called
proto-oncogenes.

Question 27

Paraneoplastic syndromes
What is a paraneoplastic syndrome?

Answer 27

● A complex of symptoms that cannot be readily explained by the local or distant
spread of a tumour or by elaboration of hormones from the tissue in which the
tumour arose
● Occurs in around 10% of people with malignant disease

Question 28

What are the main types of paraneoplastic syndromes?

Answer 28

Endocrinopathies
● Cushing’s syndrome – release of ACTH by small cell lung Ca
● SIADH – release of ADH by small cell lung Ca or intracranial disease
● Hypercalcaemia – from parathyroid like hormones, seen in squamous cell lung
Ca and breast cancer
● Carcinoid syndrome – from release of serotonin/bradykinin, seen in bronchial
cancers, stomach and pancreatic Ca
● Polycythaemia – from EPO release, seen in renal tumours

Nerve and muscle syndromes
● Myasthenia – via immune mechanisms, seen in some bronchogenic carcinomas
● Other neurological syndromes can be seen with breast Ca

Dermatological
● Acanthosis nigricans, seen in gastric, lung and uterine Ca
● Dermatomyositis, seen in bronchogenic and breast Ca

Question 29

What is the cause of cachexia in cancer?

Answer 29

● Poorly understood phenomenon
● Thought to be multifactorial – anorexia, elevated basal metabolic rate and
humoral factors such as TNF/cytokines. Some possible influence of tumour
produced factors.