Session 2 - Cell Injury 2 Flashcards
Cell Injury 2
Defintions of cell death (3)
Oncosis - Changes before death
Necrosis - Changes after death
Apoptosis - Programmed cell death
What is necrosis?
Morphological changes following death largely due to action of enzymes
When plasma and organelle enzymes are damaged -> cell contents are released and inflammation is seen
How long after death do necrotic changes develop?
4-12 hours
What types of necrosis exist? (4)
Coagulative
Liquefactive (Colliquitive)
Caseous
Fat
When is coagulative necrosis seen?
When protein denaturation is the dominant feature -> leads to solidity of dead cells Most common (ischaemia) e.g. pancreas Forms a ghost outline (only seen for a few days before acute inflammation)
When is liquifactive (colliquitive) necrosis seen?
When the release of active enzymes, partiularly proteases, is the dominant feature of dead cells -> dead tisse tends to liquefy
When there is large numbers of neutrophils (abscesses) -> therefore bacterial infections
Seen in brain due to poor stromal support
When is caseous necrosis seen?
Seen in infections (especially TB)
Amorphous debris appearance (looks cheesy macroscopically)
Associated with granulomatous inflammation
When is fat necrosis seen?
Seen in destruction of adipose tissue
Most common after acute pancreatitis -> during inflammation there is release of lipases
Free fatty acids can react with calcium to from chalky deposits (visible on x-rays and macroscopically)
Can occur after direct trauma to fatty tissue (differential for breast cancer)
What is gangrene in terms of necrosis?
It is NOT a necrosis - describes necrosis visible to naked eye
Can be dry (coagulative) or wet (liquefactive) (wet can lead to septicaemia)
Can be see most commonly in ischaemic limbs
What is infarction in terms of necrosis?
It is NOT a necrosis - it is a cause of necrosis, most often ischaemic. e.g. death by ischaemic necrosis is an infarct
What causes infarctions?
Thrombosis or embolism
external compression of vessel
twisting of vessels
What is a white infarct?
White (anaemic) infarct - occurs in solid organs after occlusion of an end artery -> prevents haemorrhaging
e.g. heart, spleen, kidneys
white appears as coagulative necrosis histologically
What is a red infarct?
Red (haemorrhagic) infarct - occurs due to:
dual blood supply (collateral)
numberous anastomoses
loose tissue
previous congestion (more blood than usual)
raised venous pressure (transferred to capillary bed)
What determines the consequences of an infarct?
Alternative blood supply?
How quickly ischaemic occured
How vulnerable a tissue is to hypoxia
Oxygen content of the blood
What is apoptosis?
Programmed cell death - can be physiological -> occurs when cells are no longer needed, damaged and in embryogenesis.
Features of apoptosis - light microscope
Shrunken Eosinophilic Chromatin condensation Pyknosis Karyorrhexis
Features of apoptosis - electron microscope
Cytoplasmic blebbing
Fragentation into membrane bound apoptotic bodies
No leakage of cell contents (therefore no inflammation)
Describe the intrinsic apoptosis pathway
Triggered by DNA damage, withdrawal of growth factors or hormones.
p53 detects and triggers increased mitochondrial permeability -> cytochrome C is released.
Cytochrome C intereacts with APAF1 and caspase 9 to form an apoptosome which activates caspase 3
Describe the extrinsic apoptosis pathway
Triggered by death ligands (TRAIL and Fas) which bind to death receptors (TRAIL-R) which activates downstream caspases.
Both intrinsic and extrinsic meet at the downstream caspase activation and cause degradation -> apoptotic bodies form, and induce phagocytosis.
What prevents cytochrome c release from mitochondria?
BcI-2
When do we see abnormal cellular accumulations?
When metabolic processes become deranged - often with sublethal or chronic injury
What abnormal cellular accumulations are there?
Normal cellular constituents e.g. water, lipids, proteins, carbohydrates Abnormal substances (exogenous or abnormal endogenous products of metabolism) Pigments
What lipid accumulations are there?
Steatosis (fatty change) - accumulation of TAGs. Often seen in liver (fat metabolism)
Caused by alcohol, diabetes, obesity and toxins.
In mild cases no effect on cell function.
Cholesterol - accumulates in SMC and macrophages in atheroma. Also seen in hyperlipidaemia (xanthoma, xantholasma, corneal arcus)
What protein accumulations are there?
Mallory’s hyaline - seen in hepatocytes in alcholic liver disease - they are altered keratin filaments
Incorrectly folded a1-antitrypsin
What exogenous pigments are there?
- carbon/coal dust - inhaled and phagocytosed macrophages in lung tissue - seen as blackened lung tissue or blackened peribronchial lymph nodes
- tattoos - [igments phagocytosed by macrophages within the dermis
What endogenous pigments are there?
- lipofusin - brown pigment seen in aging cells (signs of ROS injury)
- Haemosiderin - derived from haemoglobin - yellow/brown and contains iron (often seen as a bruise). Can be seen in haemolytic anaemias, blood transfusions and haemochromatosis (increased absorption of dietary iron). Can result in severe liver, heart and pancreas damage.
- Bilirubin - bile pigment - yellowing of the skin in haemolytic anaemia or abnormal liver function
What is calcification and what types of calcification are there?
Abnormal deposit of calcium salts in tissues
Dystrophic or Metastatic
What is dystrophic calcification?
Occurs in an area of dying tissue, atherosclerotic plaques, damaged heart valves and TB lymph nodes.
No abnormality of calcium metabolism or serum calcium concentration.
Causes organ dysfunction.
What is metastatic calcification?
Calcium is deposited in normal tissue in hypercalcaemia -> asymptomatic. Four causes: More PTH Destruction of bone Vit D disorder Renal failure
Describe cellular aging
As cells age, they accummulate damage. Also can accumulate lipofuscin and abnormally folded proteins. Replication ability declines - repilicative senscense. This is due to telomeres shortening. (germ cells and stem cells have telomerase which maintains telomere length - cancer cells produce telomerase)
What are the major effects on the liver by alcohol? (3)
Fatty change - steatosis - hepatomegaly (reduced transport of fat out of cells)
Acute alcholic hepatitis - alcohol and its metabolites are toxic -> focal hepatocyte necrosis, formation of Mallory bodies and neutrophilic infiltrate - can cause fever, liver tenderness and jaundice. (usually reversible)
Cirrhosis - 10-15% of alcholics - hard, shrunken liver appears histologically as micronodules of tegenerating hepatocytes surrounded by bands of collagen. Irreversible and sometimes fatal
Who are more susceptible to paracetamol overdose? (4)
Alcoholics
Malnourished people
People on enzyme inducing drugs
HIV positive or AIDS patients
How to determine when to prescribe NAC?
4 hours after overdose serum concentration of paracetamol is measured and plotted.
24 hours later INR is measured (PT) to assess liver damage. (liver produces clotting factors). When PT increases its indicative of liver damage.
What does aspirin do?
Acetylates platelets cylcooxygenase and prevents thromboxane A2 production. -> petechaie may be present
Aspririn also stimulates the respiratory centre which results in respiratory alkalosis - compensatory acidosis occurs. Aspirin then contributes to acidosis via lactate, pyruvate and ketone body production.
Can see GI bleeding in acute erosive gastritis.
