Pathoma

Chapter 2

1. Acute inflammation

Part 1
 Inflammation
o Allows inflammatory cells, plasma proteins, and fluid to exit blood
vessels and enter the interstitial space
o Divided into acute and chronic inflammation
 Acute inflammation
o Characterized by presence of oedema and neutrophils in tissue
o Arises in response to infection or tissue necrosis
 Goal is to eliminate pathogen or clear the necrotic debris
 24h after MI you see presence of neutrophils (WCC will
rise)
 Immediate response with limited specificity
o Innate immunity
 Epithelium over body surfaces to protect, mucous layer,
compliment system (can be activated in blood), mast cells,
macrophages (consumes and presents pathogens), neutrophils,
eosinophils, basophils, etc.
 Remember that adaptive immunity is not a part of acute
inflammation (specific) and includes lymphocytes which produce
antibodies and T cells which have receptors (more in chronic
inflammation)
 Mediated by several factors
o Toll like receptors
 Present on cells of the innate immune system (macrophages
and dendritic cells)
 Recognize pathogen associated molecular patterns (PAMPs)
which are commonly shared by microbes, and when they see the
patterns they know there is an invader and they turn on the
inflammatory response
 Example: CD14 (toll like receptor) on macrophages recognize
LPS (example of a PAMP) on the outer membrane of GN bacteria
 TLR activation results in upregulation of NF-kB (transcription
factor)
 Turns on the acute inflammatory response
 Activates immune response genes
 Leads to production of multiple immune mediators
 TLR are also present on cells of adaptive immunity
(lymphocytes) so also mediate chronic inflammation
o Arachidonic acid
 Released from the phospholipid cell membrane by
phospholipase A2
  Acted on by cyclooxygenase or 5-lipooxygenase
 Cyclooxygenase produces PG
 PGI2, PGD2, and PGE2 mediate vasodilation (arteriole)
and increased vascular permeability (post capillary venule)
 PGE2 also mediates fever and pain
 5-lipooxygenase produces LT
 LTB4 attracts and activates neutrophils
 The following attracts and activates neutrophils:
LTB4, C5a, IL-8, and bacterial products
 LTC4, LTD4, and LTE4 mediate vasoconstriction,
bronchospasm, and increased vascular permeability (contract
pericytes to increase space in between endothelial cells)
 Overall contract smooth muscle
o Mast cells
 Widely distributed throughout connective tissue
 Activated by 3 mechanisms:
 Tissue trauma
 Complement proteins C3a and C5a
 By products of activation of complement
system
 Cross linking of cell surface IgE and antigen
 Immediate response
 Release of preformed histamine granules
 Mediates vasodilation of arterioles and
increased vascular permeability of post capillary venule
 Delayed response
 Production of arachidonic acid metabolites, particularly
leukotrienes
 Leukotrienes maintain acute inflammatory
response
o Complement
 Proinflammatory serum proteins
 "Complement"/assist with inflammation
 Circulate as inactive precursors
 Activation of complement
 Classical pathway
 C1 binds to IgG or IgM that is bound to antigen
 "GM makes classic cars"
 Alternative pathway
 Microbial products directly activate compliment
 Mannose-binding lectin (MBL) pathway
 MBL binds mannose on microorganisms and
activates complement
 Result
 C3 convertase gets generated
 Convert C3 to C3a and C3b
 C3b helps to generate C5 convertase
  Convert C5 to C5a and C5b
 C5b complexes with C6-C9 to make MAC
 Lysis of microorganism
 Key products
 C3a and C5a: trigger mast cell degranulation
 C5a: chemotactic for neutrophils
 C3b: opsonin for phagocytosis
 MAC: lyses microbes by creating holes in cell
membrane
o Hageman factor
 Inactive proinflammatory protein produced in liver
 Activated upon exposure to subendothelial or tissue collagen
 In severe GN sepsis, Hageman factor plays an important role in
disseminated intravascular coagulation (DIC)
 Hageman factor in turn activates
 Coagulation and fibrinolytic systems
 Complement
 Kinin system: cleaves high molecular weigh kininogen
(HMWK) to bradykinin, which mediates vasodilation, increased
vascular permeability, and pain
 Cardinal signs of acute inflammation
o Redness (rubor) and warmth (calor)
 Due to vasodilation, which results in increased blood flow
 Occurs via relaxation of arteriolar smooth muscle
 Key mediators are histamine*, PGs, and bradykinin
o Swelling (tumor)
 Due to leakage of fluid from post capillary venules into the
interstitial space
 Key mediators are histamine (separates endothelial cells) and
tissue damage (disruption of wall of blood vessel)
o Pain (dolor)
 Bradykinin and PGE2 sensitize sensory nerve endings
o Fever
 Pryogens cause macrophages to release IL-1 and TNF
 These cause increased COX activity in perivascular cells of
hypothalamus
 Increased PGE2 raises temperature set point
Part 2
 3 general phases of inflammation
o Fluid phase, neutrophil phase (peak is at 24 hours), and macrophage
phase (peak is at day 2-3)
 Neutrophil arrival and function
 Step 1: Margination
o Vasodilation slows blood flow in post capillary venules
o Cells marginate from centre of flow to periphery
 Heavy particles can move to the periphery (margination)
 Step 2: Rolling
 o Marginated cells (neutrophils) need to be slowed down by hitting
"speed bumps" called selectins which are upregulated on the endothelial
cells
o P selectin is released from Weibel-Palade bodies; mediated by
histamine
 Weibel Palade bodies contain P selectins and Von Willebrand's
factor
o E selectin is induced by TNF and IL-1
o Selectins:
 Bind sialyl Lewis X on leukocytes
 Interaction results in rolling of leukocytes (neutrophils and
macrophages do this) along vessel wall
 Step 3: Adhesion
o Need to stop the leukocyte so it can exit the blood vessel
o Cellular adhesion molecules (CAMs - there are ICAMs and VCAMS) are
upregulated on endothelium by TNF and IL-1
o Integrins upregulated on leukocytes by C5a and LTB4
o Interaction results in firm adhesion to vessel wall
o Leukocyte adhesion deficiency
 Autosomal recessive defect of integrins (CD18 subunit)
 Clinical findings:
 Delayed separation of the umbilical cord
 Umbilical cord dies at birth so it undergoes
necrosis, therefore inflammation
 Umbilical cord normally falls off with the help of
neutrophils which eats away at the tissue
 Increased circulating neutrophils
 50% of neutrophils are circulating hrough the
blood but 50% are stuck hanging out in the blood vessels
of the lung (marginated pool)
 They are waiting in the blood vessels in the lung
just waiting to be called into the lung
 If there is lack of adhesion, then there will not
be a marginated pool at the lung, so they will be
circulating in the blood
 Recurrent bacterial infections that lack pus formation
 Pus is dead neutrophils sitting in fluid
 So since they cannot get neutrophils into the
tissue, they cannot make pus
 Step 4: Transmigration and chemotaxis
o Leukocytes transmigrate across the endothelium of post capillary
venules
o Move toward chemical attractants
o Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4
 Step 5: Phagocytosis
o Consumption of pathogens or necrotic tissue
o Enhanced by opsonins (IgG and C3b)
  Helps neutrophils to recognize what they are suppose to eat
o Pseudopods
 Arm extensions off of the leukocyte that wrap around
pathogen
 These pseudopods extend and wrap around the pathogen to
form phagosomes (a circular space with the internalized pathogen
in it that is within the neutrophil)
 Internalized and merged with lysosomes to form
phagolysosomes
 Chediak-Higashi Syndrome
 Autosomal recessive protein trafficking defect
 Characterized by impaired phagolysosome formation
 Phagosome has to be guided to the lysosome by a
microtubule "railroad" system
 This microtubule "railroad" system is defective in this
syndrome
 Clinical features:
 Increased risk of pyogenic infections
 Cannot destroy the organism that the
neutrophils consume
 Neutropenia
 Need to be able to move cellular
components, etc. during cell division so you have
defect in generation of neutrophils
 Giant granules in leukocytes
 Package in the golgi apparatus cause
they are made here and suppose to be distributed
via the railroad system so they pile up right by the
golgi so you can see it on histology
 Defective primary haemostasis
 Dependant on platelets and they
contain dense core granules and if they cannot be
distributed properly there is going to be a problem
with the platelets and therefore haemostasis
 Albinism
 1 melanocyte produces melanin
(pigment of skin) for 25 keratinocytes so they have
to make the pigment then hand it off to the
keratinocytes via the railroad system so do not get
proper pigmentation of the skin
 Peripheral neuropathy
 Proteins made in the cell body of neuron
but need to be transported along the axon to the
peripheries
Part 3
 Step 6: Destruction of phagocytosed material
o Oxygen dependant killing
  Most effective mechanism
 HOCl generated by oxidative burst in phagolysosomes destroys
phagocytosed microbe
 Remember O2 to O2- by NADPH oxidase (this step is
the oxidative burst)
 O2- to H2O2 by SOD
 H2O2 to HOCl (bleach) by myeloperoxidase
 Chronic granulomatous disease
 Poor O2 dependant killing
 Due to NADPH oxidase defect (X linked or AR)
 Regular infections and gets granulomas
 Infection and granuloma formation with catalase
positive organisms
 S aureus*
 P cepacia* - important one to know
 S marcescens
 Nocardia
 Aspergillus
 This is because H2O2 can be converted to bleach
dependant on NADPH oxidase (O2 to O2- to H2O2 to HOCl),
but also most bacteria make a bit of H2O2 so some of that can
be converted to HOCl so that can make up for lack of NADPH
oxidase
 Problem is there are bacteria that are catalase
positive so they destroy H2O2 before HOCl can be made
so in these people we have NO HOCl being made
 Why there are only infections with catalase
positive bacteria since there is no way to make bleach
 Nitroblue tetrazolium test
 Used to screen for CGD
 Turns blue if NADPH oxidase can convert O2 to
O2-
 Remains colourless if NADPH oxidase is
defective
 Myeloperoxidase deficiency
 Results in defective conversion of H2O2 to HOCl
 Tend to be asymptomatic
 But higher risk of candida infections
 NBT test will be normal
o O2 independent killing
 Less effective
 Occurs via enzymes present in leukocyte secondary granules
(example: lysozyme and major basic protein)
 Major basic protein is in eosinophils
 Step 7: Resolution
o Neutrophils undergo apoptosis
 Pus is dead neutrophils within fluid
 o Disappear within 24 hours after resolution of inflammatory stimulus
 Macrophages predominate after neutrophils
o Peak 2-3 days after inflammation begins
o Derived from monocytes in blood
o Arrive via the margination, rolling, adhesion, and transmigration
sequence
o Ingest via phagocytosis
 Destroy phagocytosed material using enzymes in secondary
granules
 O2 independent killing mostly via lysozyme enzyme
o Manage the next step of the acute inflammatory process
 Basically decide the next step depending on how good things
are looking
 Resolution and healing (via IL-10 and TGF-B are anti
inflammatory)
 Continued acute inflammation (via IL-8 produced by
macrophages to call in more neutrophils)
 Remember that acute inflammation is not really
based on time it is based on the response
 Acute inflammation could still be going on for 8
weeks cause you still have a neutrophilic response
 Abscess
 Area of fibrosis around the area of infection so
inflammation gets trapped in that space
 Walled off area of acute inflammation managed
by neutrophils
 Chronic inflammation
 If they think that the neutrophils cannot handle
it anymore (viral infection, etc.)
 Could present viral infection via MHC class 2
(since macrophages are antigen presenting cells) to T
helper cells

2. Chronic inflammation

 Characterized by lymphocytes and plasma cells in tissues (mononuclear cells)

 Delayed response (usually a couple days) but more specific (adaptive
immunity)
 Stimuli
o Persistent infection (most common)
o Infection with viruses, mycobacteria, parasites, and fungi
o Autoimmune disease
o Foreign material
o Some cancers
 T lymphocytes
o Produced in bone marrow as progenitor T cells
o Further develop in the thymus
  T cell receptor (TCR) undergoes rearrangement
 Progenitor cells become CD4+ helper T cells or CD8+ cytotoxic
T cells
o T cells use TCR complex for antigen surveillance
 TCR complex (remember CD3+ also a part of the complex)
recognizes antigens presented on MHC
 CD4+ T cells: MHC class 2
 CD8+ Tcells: MHC class 1
o Activation of T cells requires
 Binding of antigen/MHC complex
 Additional 2nd signal
o CD4+ T cell activation
 Extracellular antigen is phagocytosed, processed, and
presented via MHC class 2 (APCs)
 B7 on APC binds CD28 on CD4+ T cells providing 2nd activation
signal
o Activated CD4+ helper T cells
 Secrete cytokines that "help" inflammation
 Divided into 2 subsets (CD8+ T cells and B cells)
 TH1 subset: helps CD8+ T cells
 IL-2 (T cell growth factor and CD8+ T cell
activator)
 IFN-gamma (macrophage activator)
 TH2 subset: helps B cells
 IL-4 (class switching IgG to IgE)
 IL-5 (eosinophils chemotaxis and activation,
maturation of B cells to plasma cells, and class switching
to IgA)
 IL-10 (inhibit TH1 phenotype)
o CD8+ cytotoxic T cell activation
 Intracellular antigen is processed and presented on MHC 1
(can see if foreign protein is being produced in a cell)
 IL-2 from CD4+ TH1 cell provides 2nd activation signal
 Cytotoxic T cells are activated for killing
o Activated CD8+ cytotoxic T cells
 Cytotoxic killing
 Secretion of perforins and granzyme; induce apoptosis
(activate caspases) of target cell
 Or expression of FasL, binds Fas on target cell activating
apoptosis (activate caspases)
 B lymphocytes
o Immature B cells are produced in the bone marrow
o Undergo Ig rearrangement to become naïve B cells that express
surface IgM and IgD
o B cell activation (2 ways)
 First way is antigen binding by surface IgM or IgD
  Other way is B cell antigen presentation to CD4+ helper T cells
via MHC 2
 CD40 receptor on B cell binds CD40L on helper T cell
providing 2nd activation signal
 Helper T cell then secretes IL-4 and IL-5 (mediate B cell
isotype switching, hypermutation, and maturation to plasma
cells)
 Now can secrete more types of Ig than just
IgM/IgD
 Chronic inflammation can be subdivided into non-granulomatous and
granulomatous
 Granulomatous inflammation
o Subtype of chronic inflammation
o Characterized by granulomas
 Epitheloid histiocytes (macrophages with abundant pink
cytoplasm)
 Normally macrophages have foamy clear cytoplasm but
when activated can become more pink and now called an
epitheloid histiocytes which aggregate/accumulate to form
granulomas
 Other features do not have to be present but often are
 Surrounded by giant cells (multinucleated cell with
large cytoplasm) and rim of lymphocytes
 Divided into noncaseating and caseating subtypes
 Non caseating granulomas lack central necrosis
 The histiocytes all have their nuclei
 Reaction to foreign material
 Breast implant that leaks that release foreign
material that enters lymphatics and causes enlarged
axillary lymph nodes
 Sarcoidosis
 Beryllium exposure
 Crohn's disease
 Histological feature of Crohn's is granulomas
 Ulcerative colitis have crypt abscesses:
neutrophils in the base of the colon crypts
 Cat scratch disease
 Usually stellate shaped granulomas in the neck
 Caseating granulomas exhibit central necrosis
 In the centre will see pink and blue debris and cannot
make out the cells
 Characteristic of TB and fungal infections
 AFB to look for TB
 Silver stain (GMS stain) to look for fungus
o Steps involved in granuloma formation
 Same steps for non caseating and caseating
 Macrophages present antigen via MHC 2 to CD4+ helper T cells
  Macrophages secrete IL-12, inducing CD4+ helper cells to
differentiate into TH1 subtype
 TH1 cells secrete IFN-gamma, which converts macrophages to
epitheloid histiocytes and giant cells

3. Primary immunodeficiency

 DiGeorge Sydrome
o Developmental failure of the 3rd and 4th pharyngeal pouches
o Due to 22q11 microdeletion
o Presentation
 T cell deficiency (lack of thymus)
 T cells are created in bone marrow but get educated in
thymus to become CD4+ or CD8+ T cells
 Patients will have problems fighting viruses and fungal
infections
 Hypocalcaemia (lack of parathyroids)
 Abnormalities of the heart (superior), great vessels, and face
(lower)
 Severe combined immunodeficiency (SCID)
o Defective cell-mediated (T cell) and humoral (B cell) immunity
o Aetiologies
 Cytokine receptor defects
 CD4+ T cells (helper) use cytokines to help B cells to
become mature and helps CD8+ T cells to become
activated to fight infection
 So cytokines drive the maturation of the entire chronic
inflammatory state
 Adenosine deaminase deficiency (highest yield)
 Enzyme that is necessary for deamination of adenosine
and deoxyadenosine
 Build of adenosine and deoxyadenosine in lymphocytes
is toxic to lymphocytes
 MHC class II deficiency
 MHC class II is recognized by the CD4+ T cells
 So with deficiency cannot activate CD4+ T cells
 CD4+ T cells are so important since they help B cells
and CD8+ T cells
o Characteristics
 Susceptibility to fungal, viral, bacterial, and protozal infections
 Including opportunistic infections and live vaccines
o Treatment
 Sterile isolation
 Stem cell transplant
 Haematopoietic stems cells will differentiate into T
cells and B cells
 X-linked agammaglobulinemia
o Complete lack of immunoglobulin
o Due to disordered B cell maturation
o Naïve B cells cannot mature to plasma cells (what actually secretes
the immunoglobulin into the blood)
o Due to mutated Bruton tyrosine kinase (BTK)
 BTK is a signalling molecule that is necessary for a B cell to turn
into a plasma cell
 X linked
o Presentation
 After 6 months of life
 Since baby has mom’s antibodies up to this point
 Recurrent bacterial (cannot opsonize), enterovirus (since IgA
protects GI mucosa against infection), and Giardia (since IgA
protects GI mucosa against infection) infections
 Live vaccines (example: polio) must be avoided
 Common variable immunodeficiency (CVID)
o Low immunoglobulin due to B cell or helper T cell (since they produce
IL4 or 5 to help B cells) defects
o Increased risk for bacterial, enterovirus, and Giardia infections, usually
late in childhood
o Increased risk for autoimmune disease and lymphoma
 IgA deficiency
o Low serum and mucosal IgA; most common Ig deficiency
o Increased risk for mucosal infections, especially viral
o Note: patients with celiac disease often have IgA deficiency
 Hyper-IgM syndrome
o Characterized by elevated IgM
o Due to mutated CD40-ligand or CD40 receptor
 Second signal cannot be delivered to helper T cells during B
cell activation
 Remember B cells can be activated in two ways
o IgM is on the surface of naïve B cell and an
antigen can bind to this IgM – then the plasma
cell will secrete IgM
 This activation is still intact in this
disorder
o Second way is that B cell can internalize antigen
and present it using MHC class II to CD4+ T cells
 But there also needs to be a second
stimulus with CD40 (ligand) on the B cell
binding to the CD 40 receptor on the T
cell
 Now the CD4+ T cell will produce IL 4
and IL 4 which causes stimulus for the B
 cell to mature and undergo class
switching to produce IgA, IgG, and IgE
 Cytokines necessary for Ig class switching not produced
 Low IgA, IgG, and IgE result in recurrent pyogenic infections
(IgG), especially at mucosal sites (IgA)
 IgM will be high
 Wiskott-Aldrich syndrome
o Triad
 Thrombocytopenia
 May see petechiae and mucosal bleeding
 Eczema
 Recurrent infections (defective humoural and cellular
immunity
o Due to mutation in Wiskott-Aldrich syndrome protein (WASP) gene
 X-linked
 Complement deficiencies
o C5-C9 deficiency – increased risk for Neisseria infection
o C1 inhibitor deficiency – hereditary angioedema characterized by
oedema of the skin (especially periorbital) and mucosal surfaces
 C1 inhibitor normally acts to inhibit C1 so it does not over
activate the complement cascade
 So in this disorder we have over activation of C1 and therefore
over activation of complement – vasodilation, vascular
permeability, etc. leading to oedema

4. Autoimmune disorders

 Characterized by immune-mediated damage of tissues

 1% prevalence in the US
 Involves loss of self-tolerance
o Self-reactive lymphocytes are regularly generated by undergo
apoptosis (negative selection) or become anergic (would not receive
second activation signal – go to sleep)
 More common in women
o Classically affects women of childbearing age
 Aetiology
o Environmental trigger in genetically susceptible individuals
o Increased incidence in twins and association with certain HLA
subtypes
 Systemic lupus erythematosus
o Systemic autoimmune disease
o Antibodies versus host damage multiple tissues
o Type II (cytotoxic – antibodies bind target and destroy target) and
type III (antigen-antibody complex – deposits in tissues)
hypersensitivity reactions
o Clinical features
  Fever and weight loss
 Since chronic inflammatory state
 Malar “butterfly” rash, especially upon exposure to sunlight
 Arthritis
 Pleuritis and pericarditis
 CNS psychosis
 Due to inflammation in brain
 Renal damage
 Common cause of death in lupus patients
 Can cause different types of damage
o Nephritic syndrome
 Diffuse proliferative glomerulonephritis
is most common injury and is a type of
nephritic damage
o Nephrotic syndrome
o Mesangial deposition
 Endocarditis, myocarditis, or pericarditis
 Libman-Sacks endocarditis
o Vegetations on both sides of the valve
o These are non-infectious vegetations – immune
deposition and reaction to this deposition
 Anemia, thrombocytopenia, or leukopenia
 Antibodies against RBCs, platelets, and WBCs
o Renal failure (diffuse glomerulonephritis) and infection
 Common causes of death
o Characterized by ANA and anti-dsDNA antibodies
 ANA is sensitive
 Anti-dsDNA is specific
o Antihistone antibody is characteristic of drug-induced SLE
 Hydralazine, procainamide, and isoniazid are common causes
 Removal of drug usually results in remission
o Antiphospholipid syndrome is associated with SLE
 Autoantibody against proteins bound to phospholipids
 Anticardiolipin and lupus anticoagulant are the most common
antibodies
 Lead to false-positive syphilis test (anticardiolipin)
 Also causes falsely elevated PTT lab studies (lupus
anticoagulant)
 However the problem with the lupus anticoagulant is
that the patient is actually hypercoaguable
o Arterial and venous thrombosis
o Deep venous thrombosis, hepatic vein
thrombosis (Budd Chiari syndrome – seem in
polycythaemia vara, but also in lupus), placental
thrombosis (recurrent pregnancy loss), and
stroke
 o Requires lifelong anticoagulation
 Sjogren syndrome
o Autoimmune destruction of lacrimal and salivary glands
o Lymphocyte-mediated damage (type IV hypersensitivity reaction) with
fibrosis
o Presentation
 Dry eyes, dry mouth, and recurrent dental carries in an older
woman
 Dental carries since saliva constantly washes surface of
teeth
 “Can’t chew a cracker, dirt in my eyes”
o Characterized by ANA and anti-ribonucleoprotein antibodies
 Anti-Sjogren’s Syndrome (SS)-A and anti-SS-B (types of anti-
ribonucleoprotein antibodies)
o Often associated with other autoimmune diseases
 Especially rheumatoid arthritis
o Increased risk for B-cell lymphoma
 Presents as unilateral enlargement of parotid gland late in
disease course
 Scleroderma
o Autoimmune tissue damage with activation of fibroblasts and
deposition of collagen (fibrosis)
o Divided into diffuse and localized types
o Diffuse type exhibits diffuse skin and early visceral involvement
 Almost any organ can be involved
 Oesophagus is commonly affected, resulting in disordered
motility (dysphagia for solids and liquids)
 Affects peristalsis
 Characterized by ANA and anti-DNA topoisomerase I (Scl-70)
antibody
o Localized type exhibits local skin and late visceral involvement
 Calcinosis (calcification of tissues)/anti-centromere antibodies
 Raynaud phenomenon
 Esophageal dysmotility
 Sclerodactyly (usually involves fingers)
 Telangiectasias (dilated blood vessels on surface of skin) of
skin
 Mixed connective tissue disease
o Autoimmune mediated tissue damage with mixed features of SLE,
systemic sclerosis (scleroderma), and polymyositis (involves proximal
muscles – difficulty combing hair and walking up stairs)
o Characterized by serum antibodies against U1 ribonucleoprotein

5. Wound healing and repair

 Healing is initiated when inflammation begins

 o Occurs via a combination of regeneration and repair
 Regeneration
o Replaces damaged tissue with the native tissue
o Dependent on regenerative capacity of the tissue
o Tissues are divided into 3 types based on regenerative capacity
 Labile tissues continuously cycle to regenerate tissue
 Small and large bowel (stem cells in mucosal crypts)
 Skin (stem cells in basal layer)
 Bone marrow (haematopoietic stem cells: cannot see
in histology but the marker is CD34+)
 Stable tissues are quiescent, but can reenter cell cycle
 Regeneration of liver by compensatory hyperplasia
after partial resection
 Each hepatocyte produces additional cells and then
reenters quiescence
 Another example is proximal renal tubular cells of the
kidney
 May need to put patient with acute tubular
necrosis (ATN) on dialysis while kidney repairs
 Permanent tissues lack significant regenerative potential
 Myocardium
 Skeletal muscle
 Neurons
 Repair
o Replaces damaged tissue with fibrous scar
 Occurs when regenerative stem cells are lost or when tissue
lacks regenerative capacity
 If you cut your skin too deep that you cut through and
remove the basal layer
 MI will always repair with a fibrous scar (will see white
scar in myocardium) since myocardium lacks regenerative
capacity
o Granulation tissue (not a granuloma) is initial phase of repair
 Fibroblasts (deposit type 3 collagen)
 Capillaries (provide nutrients)
 Myofibroblasts (contract wound down)
o Eventually results in scar formation
 Type 3 collagen is replaced by type 1 collagen
 Remember type 1 collagen: bone (high tensile
strength)
 Type 2 collage: cartilage
 Type 3 collagen: blood vessels, granulation tissue,
embryonic tissue including skin (pliable)
 Type 4: basement membrane
 Collagenase removes type 3 collagen and requires zinc as a
cofactor
o Mechanism of regeneration and repair
  Mediated by paracrine signalling via growth factors
 TGF-alpha: epithelial and fibroblast growth factor
 TGF-beta: important fibroblast growth factor; inhibits
inflammation
 Secreted by macrophages
 PDGF: endothelium, smooth muscle, fibroblast growth
factor
 FGF: angiogenesis, skeletal development
 VEGF: angiogenesis
 Interaction of factors with receptors results in gene expression
and cellular growth
o Cutaneous healing occurs via primary or secondary intention
 Primary
 Wound edges are brought together
 Minimal scar formation
 Secondary
 Edges are not approximated
 Granulation tissue fills the defect
 Causing some contraction of the wound
(reduction in size) cause of the myofibroblasts (a
component of granulation tissue)
o Delayed wound healing
 Infection (most common cause)
 Vitamin C deficiency: cofactor for hydroxylation of proline and
lysine residues of procollagen for proper cross linking
 Copper deficiency: cofactor for llysyl oxidase to crosslink lysine
and hydroxylysine in collagen synthesis
 Zinc deficiency: cofactor for collagenase to remove type 3
collagen from granulation tissue
 Other causes include foreign body, ischaemia, diabetes, and
malnutrition
o Dehiscence
 Rupture of a wound
 Commonly seen in abdominal surgery
o Hypertrophic scar
 Excess production of scar tissue that is localized to the wound
 Excess type 1 collagen was made
o Keloid
 Excess production of scar tissue that is out of proportion to the
wound
 Characterized by excess type 3 collagen
 Genetic predisposition (more common in African Americans)
 Classically affects earlobes, face, and upper extremities
 Example: after an ear piercing