-
four aspects of disease
- eitology (cause)
- pathogenisis (mechanism of disease)
- molecular/morphologic change (mechanical and visual tests)
- functional consequence (clinical)
-
8 causes of cellular injury
- Oxygen depreivation (everyone needs O2)
- Chemical (bad things getting you)
- Physical
- Infectious
- Immune (you getting yourself)
- Genetic
- Aging
- Nutritional imbalance (either too much or too little)
-
Cellular adaptation
- hypertrophy
- hyperplasia
- atrophy
- metaplasia
-
- Boxcar nuclei
- large and more dense nucleus means increased need for protein production
- blue is bad = hypertrophy or cancer
-
Physiological vs pathological hypertrophy
- Physio --> pregers, subceullar hypertrophy in response to barbituates and alcohol,
- Patho--> Left ventricular hypertrophy (responds to growth factors, agonists and mechanical stretch)
-
Physio and patho hyperplasia
- Physio --> liver regrowth in response to damage
- Patho --> BPH, Post menapausal endometrial hyperplasiam, cancer
-
Physio vs path atrophy
- Physio --> embroynic development , uterus after parturition
- Patho --> decreases in workload, innervation, blood supply, nutrition, stimulation and increases in pressur
-
Cachexia
- patho atrophy--> due to chronic inflammatory cytokine and TNF production's supression of appetite
- Cancer wasting
-
muscle atrophy due to disuse
-
Metaplasia
- No physiological
- Pathological due to external stimulus cytokines, growth factors, extracellular matric components
-
- squamous cell metaplasia in response to smoking/stimuli in respiratory tract
- may lead to neoplasia = cancer
-
- squamous to columnar metaplasia
- barretts esophagus
-
Reversible cell injury morphological change
Swelling and fatty change
-
Morphology of cell swelling
- Plasma membrane - blebbing -blunting -loss of microvilli
- Mitochondrial changes - swelling - appearance of small amorphous densities
- Dilation of the ER - Detachment of polysomes - myelin formation
- Nuclear alterations - disaggregation of granular and fibrillar elements
-
Macrospocic of cellular swelling
- pallor
- increase turgor
- increased weight of organ
-
Types of necrosis
- Coagulative Necrosis
- Liquefactive Necrosis
- Gangrenous Necrosis
- Caseous Necrosis
- Fat Necrosis
- Fibrinoid Necrosis
-
Coagulative necrosis:
- Caused by ischemia (called an infarct) --> except brain which is liquifactive
- perserved archtecture for days or weeks
- eosinophilic --> pink
- firm texture
-
-
Liquefactive necrosis of the brain
-
Liquiefactive necrosis
- Hypoxic death of cells within central nervous system
- necrotic tissue is a creamy yellow
- tissue is turned into liquid mass through cell digestion
-
Gangrenous necrosis
- ischemia plus bacerial infection of the limbs
- coagulative and liquefactive
-
-
cacseous necrosis
- Granuloma necrosis
- Inflammation enclosed lysed cells and amorphous granular debris
- Think TB
-
inflammation surrounded pink necrotic area
-
Fat necrosis
- when fat is broken down by lipases
- fatty acid plus calciu equals fat soponification
- dystrophic calcification
- can be enzymatic or due to trauma
-
- fat necrosis on the right side
- vague cells lines, left side intact
-
- fibrinoid necrosis
- immune complex deposition and fibrin leaks causes pink necrotic arterial wall
-
mechanisms of necrotic cell injury
- Depletion of ATP
- Mitochondrial damage
- Calcium influx and loss of homeostasis
- Accumulation of oxygen derived free radicals (oxidative stress)
- Defects in membrane permeability
-
Depletion of ATP
- Caused by reduced O2, mitochondrial damage, and toxins
- Liver better able to handle O2 than brain due to glycogen storage (longer glycolysis run)
- Failures of PUMPS, PROTEIN SYNTHESIS/RECYCLING AND ORGANELL MEMBRANE DAMAGE
-
Defects in membrane permeability
- ROS peroxidation
- o Hypoxia/ATP exhaustion decreased synthesis
- o Increased Ca2+ phospholipase and protease breakdown or skeleton and membrane
- o Causes mitochondria/lysosomal membrane damage, MPTP, apoptosis, lysing enzymes.
- o General plasma membrane damage means loss of osmotic balance, metabolite, and cell content
-
Mitochondrial damage
- o Caused by increases in cytosolic Ca2+, ROS, toxins, mutation or deprivation of O2
- o MPTP mitochondrial permeability transition pore (excitotoxicity ,ischemia and reperfusion injury) leaks small molecules out
- o Leaking activates apoptosis
-
Calcium influx and loss of homeostasis
- o Caused by infectious agent, organelle break with stores released or bad
- o Closely linked to mito-damage, can cause mito damage and be caused by mito damage
- o Activation of digestive enzymes
-
Accumulation of oxygen derived free radicals (oxidative stress)
- o Caused by, normal respiration, WBC cytotoxic agent, drug detox (CCL4 to CCL3), UV radiation, NO, metals being oxidized
- o Damages by peroxidation of membranes(lipids), modification of proteins and DNA lesions
- o Antioxidants superoxide dismutase, glutathione peroxidase, catalase, vita A, C, E
-
Damage to DNA & proteins
o If damage it too sever it goes through apoptosis
-
Most consistent irresibility of cell death
- Can’t reverse mitochondria dysfunction
- Membrane function disturbances
-
Hypoxia vs ischemia
- Hypoxia means no O2 avaliable
- Ischemia is the inability to bring O2 to site (this compromises both arobic and anaerobic ATP production)
- Ischemia is worse because not only O2 but all transports are down
-
Reprefusion injury
- Occurs when blood flow is restored and normally cells continue to die
- due to increase in ROS, inflammation, compliment system activation continue clear out cells that were tagged (IgM deposition)
-
Chemical injry
- Direct = by the actual chemical
- indrect = by the product of P450 oxidase system of a chemical (CCl4-an radial after p450) EtOH and acetaminophen
-
Physiological Apoptosis
- Embyogenesis
- Hormone cycles: Endometrial breakdown; prostatic atrohy after castration (castration was not physiological but the atrophy in response is)
- Cell population control: lymphocyte selection and neutrophil post infection
-
Pathological Apoptosis
- Atrophy
- Viral infection
- DNA and protein damage
-
Morphology of Apoptotic cells
- cell shrinkage
- Chromatin condensation and fragmentation--> peripherally
- Cytoplasmic blebs
- Apoptotic bodies that are still enclosed by membrane
|
|
