MOD Flashcards
List the main methods of cell injury
- Hypoxia
- Toxins
- Heat
- Cold
- Trauma
- Radiation
- Micro-organisms
- Immune mecha`nisms
What is Hypoxia
Hypoxia is reduced O2. It is often due to Ischaemia, the interruption of blood supply. Ischaemia is used as a model for understanding the pathogenesis of cell injury:
Reversible Changes:
o Oxidative phosphorylation decreases
o Amount of ATP decreases
o Increased amount of anaerobic glycolysis, decreasing pH (Lactate)
o Low ATP means Na+ accumulates in the cell
o This means the cell swells via osmosis
o Detachment of ribosomes also leads to a decrease in protein synthesis
Irreversible Changes:
o Massive accumulation of cytosolic Ca2+
o Several enzymes activated resulting in cell death
Different cells react differently, e.g. a neurone can only withstand Ischaemic conditions for a few minutes, whereas fibroblasts can last for hours.
What are the structural changes seen in hypoxia
Structural Changes
Structural changes can be seen under the electron microscope
Reversible o Swelling o Chromatin clumping o Autophagy o Rinosome dispersal o Blebs (Little bumps on membrane surface where cytoskeleton has detached)
Irreversible o Nuclear changes o Lysosome rupture o Membrane defects o Endoplasmic reticulum lysis
LO 1.2 Define Necrosis and Apoptosis
Necrosis – Changes that occur after cell death in living tissue
Apoptosis – Programmed cell death
LO 1.3 Discuss Coagulative Necrosis
o More protein denaturation than enzyme release
o Cellular architecture is somewhat preserved, creating a ‘ghost outline’.
o Tends to be due to Infarcts (Infarct in the brain = Liquefactive)
LO 1.3 Discuss Liquefactive Necrosis
o More enzyme release than protein denaturation
o Tissue is lysed and disappears
o Tends to be due to infection
LO 1.3 Discuss Caseous Necrosis
o Tissue appears amorphous
o “Half way” between Coagulative and Liquefactive
o Caseous necrosis in the lung is very likely to be TB.
LO 1.3 Discuss Fat Necrosis
Occurs when cell death occurs in adipose tissue
LO 1.3 Discuss Gangrene
o Clinical term for grossly visible necrosis
‘Dry’ gangrene
o Coagulative
o E.g. umbilical cord after birth
‘Wet’ gangrene
o Liquefactive
o Infection -> Neutrophils -
> Proteolytic enzymes
What is an Infarct
Necrosis due to ischaemia
Can be white or red, depending on how much haemorrhage there is
White Infarct
o E.g. kidney
o Occlusion of end artery, no peripheral blood vessels, leaving the area entirely without blood
Red Infarct
o E.g. Bowel
o Occlusion of blood vessel leads to build up of blood, which all haemorrhages at once. Increased pressure decreases blood flow, leading to ischaemia and infarct.
LO 2.1 Discuss the major causes and biological purposes of acute inflammation
Acute inflammation is the response of living tissue to injury, initiated to limit the tissue damage.
Causes of Acute Inflammation:
o Microbial infections - E.g. Pyogenic Organisms
o Hypersensitivity reactions (acute phase)
o Physical agents
o Chemicals
o Tissue necrosis
LO 2.2 List the macroscopic features of acute inflammation
Calor – Heat
Rubor – Erytherma (Redness)
Tumor – Oedema (Swelling)
Dolor – Pain
And Loss of function
LO 2.3 Characterise the microscopic features of acute inflammation, including how they are brought about and relate to the macroscopic ones
- Vasodilation
Small adjacent blood vessels dilate with increased blood flow. - Gaps form in endothelium
Endothelial cells swell and retract; there is no longer a completed intact internal lining. - Exudation
Vessels become leaky. Water, salts and small plasma proteins leak through. (Exudate) - Margination and Emigration
Circulating neutrophils adhere to swollen endothelial cells. (Margination.)
Neutrophils then migrate through the vessel basement membrane. (Emigration). - Macrophages and Lymphocytes
Migrate in a similar way to Neutrophils.
LO 2.4 Briefly mention some of the chemical mediators of acute inflammation
Vasodilation -Histamine, Prostaglandins, C3a, C5a
Inc. Vascular Permability -Histamine, Prostaglandins, Kinins
Emigration of Leukocytes - Leukotrienes, IL-8, C5a
LO 2.5 Discuss the action of neutrophils
Neutrophils phagocytose microorganisms, by making contact, recognising and internalising them. Phagosomes are then fused with lysosomes to destroy the contents.
Neutrophils move to the site of injury by chemotaxis. An activated neutrophil may also release toxic metabolites and enzymes, causing damage to the host tissue.
LO 2.6 Discuss the systemic consequences of acute inflammation
Decreased appetite, raised heart rate, altered sleep patterns and changes in plasma concentration of Acute Phase Proteins, such as C-Reactive Protein (CRP), Fibrinogen and 1-antitrypsin.
The spread of micro-organisms and toxins can lead to Shock, a clinical syndrome of circulatory failure (See CVS Session 12)
Fever Endogenous pyrogens (substances that produce fever) IL-1, TNFA and prostaglandin are produced.
Leukocytosis
IL-1 and TNFA produce an accelerated release from marrow. Macrophages, T-Lymphocytes produce colony-stimulating factors.
LO 2.7 What may happen after the development of acute inflammation?
- Complete resolution
- Continued acute inflammation with chronic inflammation (Abscess)
- Chronic inflammation and fibrous repair, probably with tissue regeneration
- Death
Resolution
All mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution in exudate or inhibition.
Gradually all of the changes of acute inflammation reverse, and the vascular changes stop. Neutrophils no longer marginate, and the vessel permeability and calibre returns tot normal.
Therefore, the exudate drains via the lymphatics, fibrin is degraded by plasmin/other proteases and the neutrophils die.
Damaged tissue may then be able to regenerate, but if tissue architecture has been destroyed, complete resolution is not possible.
LO 2.8 Describe some possible complications of acute inflammation
Swelling
Blockage of tubes, e.g. bile duct, intestine
Exudate
Compression, e.g. cardiac tamponade
Serositis
Loss of fluid
E.g. burns
Pain and loss of function
Especially if prolonged
LO 2.9 Give a few clinical examples of acute inflammation - Skin Blister
Caused by heat, sunlight, chemicals
Pain and profuse exudate
Collection of fluid strips off overlying epithelium
Inflammatory cells relatively few, therefore exudate is clear
Resolution or scarring
LO 2.9 Give a few clinical examples of acute inflammation - Abscess
Solid Tissues
Inflammatory exudate forces tissue apart
Liquefactive necrosis in centre
May cause high pressure, therefore pain
May cause tissue damage and squash adjacent structures
LO 2.9 Give a few clinical examples of acute inflammation - Pericarditis
Inflammation of serous cavity
Pericardium becomes inflamed and increases pressure on the heart
LO 2.10 Discuss inherited disorders of the acute inflammatory process - general
Disorders of Acute Inflammation are rare diseases, but illustrate the importance of apparently small parts of this complex web of mechanisms.
Examples include: o A1 anti-trypsin deficiency o Inherited complement deficiencies o Defects in neutrophil function o Defects in neutrophil numbers
LO 2.10 Discuss inherited disorders of the acute inflammatory process - Hereditary Angio-Oedema
o Hereditary Angio-Oedema is caused by a deficiency of C1 inhibtor.
o C1 is a complement protein that cleaves C2 and C4 to form C3.
o C1 inhibitor does not only inhibit C1, but Bradykinin too. Uninhibited Bradykinin vastly increases the permeability of endothelia, causing Oedema.
o Hereditary Angio-Oedema is treated with C1 inhibitor infusion or fresh frozen plasma.
LO 2.10 Discuss inherited disorders of the acute inflammatory process - α1-antitrpysin Deficiency
o α1-antitrpysin inhibits Elastase.
o Without this inhibition elastase breaks down lung/liver tissue
o Causes emphysema and Liver Sclerosis.
LO 2.10 Discuss inherited disorders of the acute inflammatory process - Chronic Granulomatous Disease
o Recessive sex linked
o Immune phagocytes can’t form ROS
o Can’t kill some bacteria without ROS
o Granulomas formed in an attempt to contain the bacteria
What is chronic inflamation
Chronic response to injury with associated FIBROSIS
LO 3.1 Discuss how Chronic Inflammation Arises
- May ‘take over’ from acute inflammation
o If damage is too severe to be resolved within a few days… - May arise de novo
o Some autoimmune conditions (E.g. RA)
o Some Chronic Infections (E.g. viral hepatitis)
o “Chronic low-level irritation” - May develop alongside acute inflammation
o In severe, persistent or repeated irritation
LO 3.2 List the effects of Chronic Inflammation
o Fibrosis Gall bladder (chronic cholecystitis), chronic peptic ulcers, cirrhosis
o Impaired function
Chronic Inflammatory Bowel Disease
Rarely, increased function, e.g. mucus secretion, thyrotoxicosis
o Atrophy
Gastric mucosa, adrenal glands
o Stimulation of immune response
Macrophage-Lymphocyte interactions
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Macrophages
Important in acute and chronic inflammation
Various levels of activation
Functions
o Phagocytosis and destruction of debris and bacteria
o Processing and presentation of antigen to the immune system
o Synthesis of cytokines, complement components, clotting factors and proteases
o Control of other cells via cytokine release
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Lymphocytes
Sometimes called ‘chronic inflammatory cells’
Functions
o Complex, mainly immunological
o B Lymphocytes (Plasma Cells) differentiate to produce antibodies
o T Lymphocytes involved in control (CD4+) and some cytotoxic (CD8+) functions
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Eosinophils
Allergic reactions
Parasite infections
Some tumours
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Fibroblasts/Myofibroblasts
Recruited by macrophages, make collagen
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Giant’ Cells
Giant cells are multinucleate cells made by the fusion of macrophages, through the process of frustrated phagocytosis. There are several types recognised:
Langhans -> Tuberculosis
Foreign Body Type
Touton -> Fat Necrosis
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Chronic Cholecystitis (Fibrosis)
Repeated obstruction of the gall bladder with gallstones. Repeated acute inflammation leads to chronic inflammation and fibrosis of the gall bladder wall.
Treated with the surgical removal of the gall bladder.
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Gastric Ulceration (Fibrosis)
Acute gastritis (alcohol, drugs) Chronic gastritis (Helicobacter pylori)
Ulceration occurs because of an imbalance between acid production and mucosal defence.
H. pylori triple treatment:
o PPI Inhibitor – E.g. Omeprazole
o 2 Antibiotics – E.g. Clarithromycin / Amoxicillin
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Inflammatory Bowel Disease (Impaired Function)
Inflammatory disease affecting the large and small bowl. Patients present with diarrhoea, rectal bleeding and other symptoms.
Ulcerative colitis o Superficial o Diarrhoea o Bleeding o Treat with immunosuppression, surgical removal of the large bowel (colectomy)
Crohn’s disease
o Transmural
o Strictures
o Fistulae (Abnormal connection between two epithelia)
o Treat with lifestyle modifications, diet/hydration, immunosuppression
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Liver Cirrhosis (Fibrosis + Impaired Function)
Chronic inflammation with fibrosis leading to disorganisation of architecture and attempted regeneration -> Cirrhosis.
Common causes of cirrhosis: Alcohol Infection with HBV/HCV Immunological Fatty liver disease Drugs and toxins
Liver cirrhosis cannot be reversed, so treatment involves lifestyle changes to prevent further damage, and transplantation of a new liver if necessary.
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Thyrotoxicosis (Increased Function)
Graves disease
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Rheumatoid arthritis
Autoimmune disease
Localised and systemic immune response
Localised chronic inflammation leads to joint destruction
Systemic immune response (Can affect other organs and cause amyloidosis)
LO 3.5 Describe and give examples of Granulomatous Inflammation
Chronic inflammation and immune responses overlap.
Immune diseases cause pathology by chronic inflammation
Chronic inflammatory processes can stimulate immune responses
Granulomas form when the immune system walls off something that it is unable to eliminate, for example bacteria, fungi and other foreign material. Granulomas arise with persistent, low-grade antigenic stimulation and hypersensitivity.
Main Causes of Granulomatous Inflammation
Mildly irritant foreign material
Infections
o Mycobacteria: Tuberculosis, leprosy
o Syphilis
o Some fungi
Unknown causes
o Sarcoid
o Wegener’s Granulomatosis
o Crohn’s disease
Tuberculosis
Caused by mycobacteria
Produces no toxins/lytic enzymes
Causes disease by persistence and induction of cell-mediated immunity
Outcomes of Granulomatous Inflammation
- Arrest, fibrosis, scarring
- Erosion into bronchus
- Tuberculous empyema (collection of pus)
- Erosion into blood stream
LO 4.1 Understand and describe Fibrous repair - the first step
Initiate fibrous repair by combining to form granulation tissue.
- Cell Migration
Inflammatory Cells
o Phagocytosis of debris: Neutrophils, macrophages
o Chemical Mediators: Lymphocytes, macrophages
Endothelial Cells
o Angiogenesis
Fibroblasts/Myofibroblasts
o ECM proteins e.g. collagen
o Wound contraction
What is Fibrous repair
The replacement of functional tissue by scar tissue
LO 4.1 Understand and describe Fibrous repair - the second step
- Angiogenesis
The development of a blood supply is vital to wound healing, to provide access to the wound for the above cells, and to deliver oxygen and other nutrient.
o Endothelial proliferation induced by proangiogenic growth factors such as VEGF
o Preexisting blood vessels sprout new vessels
o These mechanisms are exploited by malignant cells
o Endothelial proteolysis of basement membrane
o Migration of endothelial cell via chemotaxis
o Endothelial proliferation
o Endothelial maturation and
tubular remodelling
o Recruitment of periendothelial cells
LO 4.1 Understand and describe Fibrous repair - the third step
- ECM production/remodelling
o Supports and anchors cells o Separates tissue compartments (e.g. basement membrane) o Sequesters growth factors o Allows communication between cells o Facilitates cell migration
What are the 3 main stages of fibrous repair
Key Components:
- Cell migration
- Blood vessels – angiogenesis
- ECM production/remodelling
Describe the actual steps of fibrous repair as a whole
- Inflammatory cell infiltrate
Blood clot forms
Acute inflammation around the edges
Chronic inflammation – Macrophages and lymphocytes migrate into the clot - Clot replaced by granulation tissue (A combination of capillary loops and myofibroblasts).
Angiogenesis – Capillaries and lymphatics sprout and infiltrate
Myo/fibroblasts migrate and differentiate.
ECM is produced by myo/fibroblasts
3. Maturation Comparatively long lasting Cell population falls Collagen increases, matures and remodels Myofibroblasts contract – Reduces volume of defect Vessels differentiate and are reduced Left with fibrous scar
Describe the control of fibrous repair
Inflammatory cells are recruited by chemotaxis
Angiogenesis is due to angiogenic cytokines
Fibrosis is due to macrophages releasing pro-fibrotic cytokines causing fibroblast proliferation.
LO 4.2 What is Regeneration
Regeneration – The replacement of dead or damaged cells by functional, differentiated cells. Differentiated cells are derived from stem cells.
What are Stem Cells
Stem cells have potentially limitless proliferation, daughter cells either remain as a stem cell to maintain the stem cell pool or differentiate to a specialised cell type. In early life stem cells develop into many different cell types.
Unipotent – Can only produce one type of differentiated cell – E.g. epithelia
Multipotent – Can produce several types of differentiated cell – E.g. Haematopoietic
Totipotent – Can produce any type of cell – I.e. embryonic stem cells
Describe the propensity of different cell types to regenerate
- Labile Cells
E.g. Epithelial or haematopoietic cells
Normal state is active cell division: G1 – M - G1
Usually rapid proliferation - Stable cells
E.g. Hepatocytes, osteoblasts, fibroblasts
Resting state: G0
Speed of regeneration variable - Permanent cells
E.g. Neurones, cardiac myocytes
Unable to divide – G0
Unable to regenerate
Describe the factors controlling regeneration
Growth factors
o Promote proliferation in the stem cell population
o Promote expression of genes controlling cell cycle
o Hormones, oestrogen, testosterone, growth hormone
o Autocrine, paracrine and endocrine cells from many cell types, inflammatory, mesenchyme etc.
o Proteins, PDGF, EGF etc
Contact between basement membranes and adjacent cells
o Signalling through adhesion molecules
o Inhibits proliferation in intact tissue
o Contact inhibition
o Loss of contact promotes proliferation
o Exploited in cancer
LO 4.3 Describe and discuss the healing of a clean incised skin wound
Healing by Primary Intention
Incised wound
Apposed edges
Minimal clot/granulation tissue
Epidermis regenerates
Dermis undergoes fibrous repair
Sutures out at 5-10 days. Approx 10% normal strength.
Maturation of scar continues up to two years
Minimal contraction and scarring, good strength
Risk of trapping infection -> Abscess
LO 4.4 Describe and discuss the healing of a large skin defect
Healing by Secondary Intention
Infarct, ulcer, abscess or any large wound
Quantitative differences o Unapposed wound edges o Large clot dries to form ‘scab’ o Epidermis regenerates from the base up o Repair process produces much more granulation tissue
Comparison with primary intention:
o Produces more contraction to reduce volume of defect
o Produces a larger scar; not necessarily weaker
o Takes longer
LO 4.5 Discuss factors influencing the efficacy of healing and repair - local factors
Local Factors
1. Type, size, location of wound
2. Apposition, lack of movement
o Skin wounds, bone fractures, severed nerves
3. Blood supply: Arterial, venous
4. Infection: Suppuration, gangrene, systemic
5. Foreign material: dirt, glass, sutures, necrotic tissue
6. Radiation damage
LO 4.5 Discuss factors influencing the efficacy of healing and repair - General Patient Factors
General Factors 1. Age 2. Drugs (steroids) and hormones 3. General dietary deficiencies e.g. protein 4. Specific dietary deficiencies o Vitamin C – Alpha chain hydroxylation o Essential amino acids 5. General State of Health o Chronic diseases, e.g. diabetes, RA etc 6. General Cardiovascular status
LO 4.6 Describe and discuss special aspects of haling and repair in various tissues
Cardiac Muscle
o Fibrosis
Bone
o Callus formation
Liver
o Acute damage -> Regeneration
o Chronic damage -> Cirrhosis
Live hepatocytes have some regenerative capacity, but hepatocyte architecture does not regenerate. The imbalance between hepatocyte regeneration and the ability to regenerate architecture leads to cirrhosis and nodules.
Peripheral Nerve
o Wallerian degeneration
o Proximal degeneration, distal proliferation (~1mm/day)
CNS
o No regenerative capacity
o Glial cells can proliferate -> Gliosis
Muscle
o Cardiac / Smooth -> Permanent tissues. Will be replaced by a scar
Vascular smooth muscle has some, limited, regeneration
o Skeletal
Limited regenerative capacity due to satellite cells
LO 5.1 Define and discuss Haemostasis
Haemostasis is the body’s response to stop bleeding and loss of blood.
Successful Haemostasis depends on:
o Vessel wall - Constricts to limit blood loss
o Platelets
- Adhere to the damages vessel wall and to each other
-Form platelet plug
o Coagulation System
- Cascade, series of inactive components -> active components
- 1ml of blood can generate enough Thrombin to convert all of the fibrinogen in the body to fibrin, so tight regulation is required
- Balance of procoagulant and anticoagulant forces
o Fibrinolytic System
LO 5.2 Discuss the regulation of the coagulation system
Thrombin positively feeds back on factors V, VIII and XI - Thrombin inhibitors o Anti-thrombin III* o Alpha 1 anti-trypsin o Alpha 2 macroglobulin o Protein C/S*
*Inherited deficiencies in antithrombin III or Protein C/S -> Thrombophilia and thrombosis
Fibrinolysis
The breakdown of fibrin, by Plasmin.
Fibrinolytic therapy is widely used, e.g. Streptokinase, which activates Plasminogen. They are known as clot/thrombus busters. This is a very drastic treatment, used only in a serious situation, e.g. coronary artery occlusion or thrombus cutting off circulation to a limb.
LO 5.3 Define Thrombosis
Thrombosis – The formation of a solid mass of blood within the circulatory system during life
What are the factors affecting thrombus formation
Virchow’s Triad
Changes in blood flow
o Stagnation, turbulence
Changes in vessel wall
o Atheroma, injury, inflammation
Changes in blood components
o Smokers, pregnancy
Compare arterial and venous thrombi
Arterial Thrombi Pale Granular Lines of Zahn Lower Cell Content
Venous Thrombi Deep Red Soft Gelatinous Higher Cell content
LO 5.4 Discuss the effects of thrombosis
Arterial
- Ischaemia
- Infarction
- Depends on site and collateral circulation
Venous
- Congestion
- Oedema
- Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure)
- Infarction
