Cellular Response to Stress

Example of labile cells

Skin, GI, reproductive, urinary, exocrine epithelial cells, haematopoietic stem cells

Example of Stable cells

Liver, kidney, lung, pancreas epithelial cells, smooth muscle cell, fibroblast, endothelial cells

Example of permanent cells

Cardiac/skeletal myocytes, neurons

What is hyperplasia

Increase in the NUMBER of cells only in non-permanent cells

What is the difference between physiological and pathological adaptions

Physiologic: Due to normal stressor

Pathologic: Due to abnormal stressor

What is hypertrophy

Increase in cell SIZE; physiologic = from increased workload

what is the difference between the two pictures

Left is normal; right is hypertrophy

What is atrophy

Decrease in size of cell that once was NORMAL size

When would physiologic and pathologic atrophy occur

Physiologic: Common during early development (thymus)

Pathologic: Loss of stimulus to organ

Describe this image

A = atrophy of muscle, B = normal muscle

What is metaplasia

Change of epithelium to another type (normal appearance but abnormal in location)

Compare these two images, which is abnormal

Top image shows transitional epithelium in bronchiole; bottom image is normal

What is abnormal in this image

Esophagus showing change from stratified squamous into simple columnar with goblet cells (arrow) → Intestinal metaplasia

What pathologic change has occurred for A to change to B

Metaplasia

What are the causes of cell injury

Oxygen deprivation, physical agents, chemical agents, infectious agent, immunologic reaction, genetic abnormalities, nutritional imbalance

What are cellular responses to cell injury

Integrated stress response (ISR), unfolded protein response (ER stress), autophagy

What is integrated stress response

Stress → Activation of kinase enzymes → Phosphorylation of elF2a → Global protein translation stops + ATF4 activation → ATF4 lead to apoptosis/survival

What is ER stress

Protein folding demand exceed protein folding capacity of ER

What are the mechanisms of unfolded protein response

Reduce protein synthesis, increase chaperones, eliminate misfolded proteins

What is autophagy

Cell eats its own contents to recycle or clear debris

Steps of autophagy

Nutrient deprivation → Initiation → Elongation → Maturation of autophagosome → Fuse with lysosome → degradation

What are the signs of reversible cell injury

Generalized cell swelling, blebbing of plasma membrane, ribosome detachment from ER, chromatin clumping, fatty change

What is the difference between necrosis and apoptosis

Necrosis = accidental cell death; apoptosis = programmed cell death

What is the sequence of necrosis

Denaturation of cellular protein → Leakage of contents → Inflammation → Enzymatic digestion

What mechanisms lead to necrosis

Hypoxia/ischemia, ROS

What mechanisms lead to apoptosis

Radiation mutation, mutation, cell stress, infection

Process of necrosis caused by mitochondrial damage

O2 low → MT cannot make ATP → ATP dependent Na pump function decrease → Active transport system failure → cell swelling

How does membrane damage occur in necrosis

Low ATP from MT dysfunction → low phospholipid synthesis → Lipid bilayer and lysosome breakdown → Ca increase → Lipase/protease activation → Membrane breakdown

What are the signs of necrosis on histology

Eosinophilia and nuclear changes

Types of nuclear changes

Karyolysis, pyknosis, karyorrhexis

What does this show

Nuclear condensation → Pyknosis

What does this show

Fading of chromatin basophilia → Karyolysis

What does this show

Pyknotic nuclei become fragmented → Karyorrhexis

What are the types of necrosis

Coagulative, liquefactive, gangrenous, caseous, fat, fibrinoid

What is coagulative necrosis

Caused by ischemia; cells are dead but architecture is preserved

What is liquefactive necrosis

Tissue → Liquid; caused by microbes that stimulate leukocytes to accumulate and release enzymes to digest tissue

What is the difference between wet and dry gangrene

Dry = ischemia (coagulative necrosis); wet = ischemia + bacterial infection (liquefactive necrosis)

What is caseous necrosis

Cheesy debris; caused by TB infection

What is fat necrosis

Release of pancreatic lipase into peritoneum → Binds with Ca to form chalky white areas

What is fat saponification

FFA (from breakdown of TG into FFA and glycerol) + Ca → Soap

What is fibrinoid necrosis

Caused by immune reaction involving blood vessels

What are the steps of apoptosis

Cell shrinkage + chromatin condensation → Nuclear fragmentation and membrane blebbing → Apoptotic body formation

What do the arrows represent

Nuclear condensation and fragmentation → Sign of apoptosis

What are the physiologic and pathologic causes of apoptosis

Physiologic → Eliminate cells that aren’t needed

Pathologic → Eliminate cells beyond repair

Extrinsic apoptosis pathway

FasR and FasL binding → FADD + procaspase 8, 10 into DISC → Caspase 8 and 10 activate → Activation of caspase 3,6,7 → Apoptosis

Intrinsic apoptosis pathway

Stress → Activation of BH3 → BAX BAK release → BAX BAK make hole in MT inner membrane → release cytochrome C → APAF1 oligomerization → Apoptosome → Activate procaspase 9 → Caspase 3,6,7 activation

How is BAX BAK activated

Caspase 10 cleave BID → tBID → BAX BAK

Process of necroptosis

Extrinsic apoptosis → Inhibit caspase 8 → Necrosome activate → MLKL activate

Process of Pyroptosis

Inflammasome formation → Caspase 1 formation → IL-1B activation

Process of ferroptosis

Oxidative stress → Fe catalyze ROS → Lipid peroxidation → Membrane damage

What type of necrosis is this

Fat necrosis

What type of necrosis is this

Caseous necrosis