1 - Cellular pathology Flashcards
pathology
the scientific study of causes and effects of disease
Pathological processes
- Adaptation - may result in abnormal cell growth
- Cell death - lack of adaptation
- Abnormal cell growth - such as metaplasia or dysplasia or neoplastic growth
- Healing - stimulated by a pathological stress such as physical injury, collagen deposition in scar tissue
- Genetic and immune factors - affect a cell/organ ability to adapt to environmental stresses leading to different susceptibilities to disease
Normal cell structure and function
• Functional units of living organisms
• Human body is a clone of 10^13 cells
• Adaptable to changing environment
- within physiological limits
Regulation of Metabolic Function
- Fasting - fatty acids mobilised from adipose tissue
- Calcium lack - calcium mobilised from bone matrix
- Liver enzymes induced to metabolise drugs
Pathological stimuli cause cellular stresses
- Osmotic stress (water and electrolyte/salt concentrations)
- temperature stress
- oxygen / energy deprivation
- Injury, infection
- any disruption of homeostasis…
cell stress response
decreased activity from ‘housekeeping’ genes (normal structural proteins)
increased activity from Cell stress genes (cell-organising/ protective functions)
e.g. heat shock proteins (HSPs), NF-kB, AP-1
-> high degree of evolutionary conservation
-> essential to cell survival
Protection in times of cellular stress
- Heat shock proteins (HSPs) act as chaperones: protect proteins, assist refolding, prevent protein aggregation
- Ubiquitin – targets protein for destruction by specific proteases (proteasome)
- Chronic stress = visible aggregates of constituents known as inclusion bodies e.g. Lewy body in nerve cells
Adaptive response during cell stress
- Alterations in metabolism and structure
- Improves survival in adverse environment
- Inability to adapt may result in cell death
- Cells vary in their ability to survive
Physiological adaptive responses
Morphological change – metaplasia, Restitutive Wound Healing
Increased cellular activity
Decreased cellular activity – cell/tissue atrophy
Hyperplasia
increase in number of tissue cells due to increased cell division, e.g. endometrial lining during menstrual cycle
Hypertrophy
increase in size of existing cells, matched by increase in functional capacity e.g. skeletal muscle fibres of athletes
Colonic epithelial hyperplasia
The normal colon has a smooth lining of single layer epithelial cells and short crypts.
Epithelial hyperplasia increases the number of cells present resulting in deeper crypts.
Prostate hyperplasia
Benign prostatic hyperplasia (BPH) • 20% of males age 40 • 70% at age 60 • 90% at 80 • Hyperplasia of prostate cells • BPH not risk factor or precursor for prostatic carcinoma
Transient hyperplasia
useful defence and repair mechanism
- allows increase functional capacity
Persistent hyperplasia
increased risk of mutation, survival/uncontrolled growth
Irreversible cell damage
Leads to pathological death • Apoptosis (programmed cell death) • Necrosis Cell targets include: • Cell membranes • Mitochondria • Cytoskeleton • Cellular DNA
Apoptosis
Responsible for elimination of unwanted/damaged cells
Four phases:
1) Induction/signalling - anti-apoptotic proteins Bcl-2
2) Effector - ‘point of no return’ = mitochondrial permeability
3) Degradation - proteases (caspases) = morphology
4) Phagocytic - cell fragments are engulfed and removed
Apoptosis is a normal cell process
• Intestinal cell turnover
• Immune system – removal of autoreactive immune cells
• Embryogenesis and development
- larval forms & evolutionary background
Apoptosis as a pathological disease
• Under-active pro-apoptotic pathways and/or over-active anti-apoptotic pathways can promote cancer
Necrosis
Triggers: any acute stressor e.g. metabolic stress, hypoxia, absence of nutrients, trauma
Common molecular mechanisms that result in necrosis:
• Reduction in ATP swelling of internal membranes (‘cloudy swelling’), reduced biosynthesis
• Increased cytosolic calcium (Ca++) = activate protein kinases, phospholipases
• Reduction in ability to scavenge ROS (reactive oxygen species)
• Plasma membrane integrity and cytoskeleton compromised
• Cells swell, lyse and burst
Examples pathological stimuli that cause necrosis
• Hypoxia - reduction or absence of normal oxygen supply to an organ
• Specific chemical agents - carbon tetrachloride (CCl4) or paracetamol
• Hypoxia = death of an area of tissue = INFARCTION
Myocardial Infarction = Heart attack
Cerebral infarct & brain necrosis
Hypovolaemic shock
• Reduction in blood available for the heart to pump
Loss of blood - Haemorrhage
Loss of plasma - severe burns
Loss of sodium and intravascular water
Symptoms of hypovolaemic shock
- restlessness and confusion
- pale, cold, sweaty skin
- rapid, weak pulse and low blood pressure
- drowsy and confused, may comatose
- multiple organ failure = Death
Cellular effects of hypovolaemia
- Inadequate cardiac output -> reduction in oxygen supply ->Switch to anaerobic metabolism ->
- Increase in metabolic waste products e.g. lactic acid, CO2
- Loss of Na+/K+ pump = Cellular swelling
- Long term – insufficient energy supply ->
Cellular necrosis
Response to hypovolemic shock (body)
- Increase respiratory rate and blood glucose
- Increase in heart rate and vasoconstriction
- Release of postaglandins and hormones eg Adrenaline
Response to hypovolemic shock (clinical)
- Deal with cause
- If <25% blood volume lost = restored by compensatory mechanisms; i.v. infusion of fluids
- If >25% blood volume lost = blood/plasma transfusion
Ischaemia
Reduction or absence of normal oxygen supply to an organ
Hypoxia
Reduction in circulating blood volume
Hypovolaemia
Inadequate blood supply
Apoptosis vs. Necrosis
Shrinking of cytoplasm vs Swelling of cytoplasm
Condensation of nucleus vs Swelling & disintegration of organelles
Blebbing of plasma membrane, maintains integrity vs Loss of plasma membrane integrity
Formation of membrane-bound vesicles vs Loss of membrane integrity
Tightly regulated process vs Loss of ion homeostasis
Energy (ATP) dependant – does not occur at 4oC vs Passive process - occurs at 4oC
Very little inflammatory response vs Cell contents release = Inflammatory
response
Gel electrophoresis (apoptosis)
Non-random degradation of DNA = ladder pattern on agarose gel electrophoresis
Gel electrophoresis (necrosis)
Random digestion of DNA = smear on agarose gel electrophoresis
