cellular adaptations and cell death

week 2 ctb

homeostasis

• cells must survive with a tight set of parameters

  • pH

  • temperature

  • oxygenation

• changes to these parameters can lead ot loss of homeostasis

  • cells may adapt

  • cells may die

• if capacity to adapt is exceeded, injury occurs

  • reversible to a point

  • irreversible injury leads to cell death

proliferative capacity of cells

• permanent cells

  • non proliferative

  • terminally differentiated

• stable cells

  • usually non proliferative

  • capable of proliferating if required

• labile cells

  • proliferative

  • continuously dividing 

adaptive changes

• hypertrophy

• hyperplasia

• atrophy

• metaplasia

hypertrophy

• increases in individual cell size

• gain of cellular substance

• as a result of increased functional demand

• as a result of specific endocrine stimulation

hypertrophy-pathological

• pathological hypertrophy of heart

• in response to increased haemodynamic loads

• heart muscle enlarged

• compromised myocardial blood supply can lead to:

  • reversible injury

  • irreversible injury + cell death

hyperplasia

• increase in cell number

• physiological- uterine endometrum

• pathological: BPH

hyperplasia- physiological

• hormonal hyperplasia

  • glandular epithelium of breast in puberty/pregnancy

• compensatory hyperplasia 

  • residual tissue grows after removal/loss of part of an organ

atrophy

• decrease in cell size

• loss of cellular substance

• atrophy in sufficient cell number- organ atrophy

causes:

• decreased workload

• diminished blood supply

• loss of endocrine stimulation

• ageing

metaplasia

• change in cell type

• one adult cell type replaced by another cell type

• an adaptive response

• normal protective mechanisms may be lost

• cell function often compromised

dysplasia

• abnormal development of cells within a tissue or organ

• failure of normal development

• features include:

  • nuclear enlargement

  • loss of nuclear polarity

  • increased cell division

neoplasia

• a mass formed by autonomous proliferation of cells that persists after cessation of the stimulus that provoked the change

• compared with normal cells, neoplastic cells have disordered phenotype, function and behavious

• benign neoplasms show least cytological variation from parent tissue and do not invade surrounding structures

• malignant neoplasms show substantial cytological changes- invade surrounding tissues and are harmful

causes of cell injury

• hypoxia/ischaemia (oxygen deficiency, redued blood supply)

• genetic defects (mutations causes LOF of GOF or faulty proteins)

• physical agents (trauma, extremes of temperature, radiation)

• toxins (pollutants, insecticides, CO)

• infection (viruses, bacteria, fungi)

• nutritional imbalances (specific vitamine deficiencies)

• immunologic reactions (autoimmune reactions, chronic inflammation)

mechanisms of cellular injury

• membrane destruction

• protein denaturation

• disrupt metabolic processes

• DNA damage

hypoxia/ischaemia

• reduction in level of oxygen available/inadequate blood supply

• lack of oxygen limits aerobic respiration

• inadequate ATP leads to reduction in cellular function

• due to inadequate oxygen supply or inadequate oxygen delivery

• ischaemia leads to loss of nutrient delivery and build up of toxins

• due to embolism or systemic cardiac failure

chemicals and drugs

• simple chemicals

  • glucose

  • salt

  • damage electrolyte and fluid balance

• poisons

  • arsenic

  • cyanide

  • mercury

• frequent exposure to:

  • CO

  • pollutants

  • alcohol

  • therapeutics

infectious agents

• bacteria

• viruses

• parasites

particularly significant in cases of:

• immunocompromisation

• malnutrition

physical

divided into:

• mechanical trauma

  • shape of colliding object

  • force of collision

  • site of injury

• thermal injury 

  • burns

  • hyper/hypothermia

• electrical injury

  • low/high voltage current

• injury produced by ionising radiation

  • x rays

sustainable healthcare

• climate change: global cause of environmental disease

• WHO estimates 250000 deaths between 2030 and 2050 due to climate change

• CV, cerebrovascular diseases

• food/water borne infectious diseases

• vector-borne infectious diseases including malaria and dengue 

• malnutrition

nutritional

• dietary insufficiency- injury at cellular level due to interference in normal metabolic pathways

• dietary excess- abnormal conc of molecules that may affect metabolic pathways

• scurvy

  • vit C deficiency

  • ascorbic acid is involved in a number of biochemical reactions

  • involved in collagen synthesis

  • deficiency results in impaired wound healing, defective tooth formation, impaired osteoblast function

cellular response to stress and injury

• response to injury commonly results in activation of response pathways

  • integrated stress response

  • unfolded protein response

  • autophagy

• can trigger cell death

integrated stress response

• intracellular signalling pathways

• modulate gene expression and protein synthesis

• adaptation to cell injury

• activated by stress sensing kinases

• results in cell survival, recovery, restoration of homeostasis or cell death

unfolded protein response

• accumulation of misfolded proteins in the ER

• results in:

  • increased production of chaperones

  • enchance degradation of abnormal proteins

  • slows protein translation

• ageing

• viral infections

• neurodegenerative disorders

autophagy

• cell eats its own contetns

• cytoplasmic materials delivered to lysosome for degradation

• survival mechanism for nutrient deprivation

cell death: apoptosis

• programmed cell death

• activation of specific genes

• pathologic or physiologic

• no inflammatory response

• usually single cells

• membrane integrity retained

• cell shrinkage and formation of apoptotic bodies

cell death: necrosis

• pathologic

• cell disintegrates

• inflammatory response

• groups of cells

• membrane integrity lost

• cell swelling and lysis

necrosis

• accidental cell death

• severe injury to many cellular components

• severe mitochondrial damage

• rupture of lysosomal and plasma membranes

• local inflammatory response

• main causes: ischaemia, microbial toxins, burns, chemical and physical injury

types of necrosis

1. coagulative necrosis

2. liquefactive

3. caseous

4. fat

5. fibrinoid

coagulative necrosis

• architecture of dead tissue preserved for some days

• firm texture

• injury denatures structural proteins and enzymes

• proteolysis blocked

• necrotic cells eventually broken down by lysosomal enzymes from infiltrating leukocytes

liquefactive necrosis

• digestion of dead cells

• transformation of tissue to viscous liquid

• bacterial or fungal infections

• pus

caseous necrosis

• tuberculosis 

• cheese-like appearance

• fragmernted or lysed cells

• granular debris enclosed within a collection of macrophages

fat necrosis

• focal areas of fat destruction

• release of activated pancreatic lipases

• acute pancreatitis

fibrinoid necrosis

• vascular damage

• antigens and ABs deposited in artery walls

apoptosis

• precise set of molecular pathways

• defined genes and biochemical pathways

• once initiated, it’s irreversible

• serves to eliminate cells with intrinsic abnormalities

• promotes clearance of cell fragments without inflammatory reaction

physiological apoptosis

• removal of cells during development

• involution of hormone dependent tissues

• cell turnover in proliferating populations

• death of cells that have ‘served their purpose’

pathologic apoptosis

• DNA damage

• misfolded protein accumulation

• infections

• atrophy due to obstruction

morphologic changes during apoptosis

• cell shrinkage

• chromatin condensation

• cytoplasmic blebs and apoptotic bodies

• phagocytosis

mechanism of apoptosis

• results from activation of enzymes called caspases

  • pro-enzymes

• activated by 

  • mitchondrial (intrinsic pathway)

  • death receptor (extrinsic pathway)

intrinsic pathway: mechanism of apoptosis

1. mitcohondria contain proteins that can induce apoptosis: cytochrome C

2. anti-apoptotic proteins maintain mitochondrial membrane integrity 

3. deprivation of survival signals leads to dimerisation of pro-apoptotic factors BAK and BAX

4. BAK and BAX dimerise and insert into mitochondrial membrane, forming channels

5. permeabilisation of mitochondrial membrane releases cytochrome C

6. caspase activation is triggered, leading to apoptosis

extrinsic pathway: mechanism of apoptosis

1. death receptors on cell surface are capable of triggering apoptosis

2. members of the tumour necrosis family containing death domains

3. Fas is a prototypic death receptor

4. Fas ligand (FasL) is expressed on activated T lymphocytes

5. recognition of Fas-expressing cells leads to crosslinking of Fas and binding of adaptor proteins

6. caspase activation