Cell Injury

• 1. can adapt immediately
• 2. can suffer an injury that is reversable and eventually adapts
• 3. can suffer an injury that is reversable but progresses to death
• 4. Death

• atrophy
• hypertrophy
• hyperplasia
• metaplasia
• dysplasia

• decrease in cell size
• if you dont use a cell it may start to shrink causing this
• due to decreased use, decreased blood supply and/or decreased nutrition

• the thenar muscle in carpeltunnel syndrome
• the motor branch of the median nerve that innervates the thenar muscle to the palm looses its function and because of that the muscle cant become used or activated and then the muscle atrophies due to disuse

• occurs in alzheimer's disease
• cells die and the brain atrophies and everything gets smaller

• aging
• testicular cancer
• orchitis
• excessive alcohol
• hormone imbalance
• testicular tortion

• increase in cell size, NOT due to increased volume or fluid but because of increased protein synthesis in the cell or decreased protein breakdown
• increased protein in organelles

• there is a deposition of more muscle protiens (actin, myosin, troponin, tropomyosin)
• when you deposit more proteins in the muscle fibers they become larger and there is also decreased protein degredation rate so the muscle fibers and therefore the whole muscle becomes larger

• left ventricle increases in thickness due to it working harder
• this usually happens when the ventricle is subject to more workload due to hypertension for example
• the heart has to work harder to pump out blood making it larger

• increase in number of cells
• cells divide fast making a whole bunch of them

• walking barefoot: sole of the foot increases in cell number and the epitheial cell number increases causing hyperplasia
• breast size: number of cells increases in breast feeding with lactation
• prostate: when the male sex hormone acts on the normal prostate it undergoes hyperplasia and the cell number increases which can lead to issues when older
• gums: cyclosporine can cause hyperplasia of gums

• replacement of one cell type with another
• change in form, replacement of adult cells
• you may have constant injury in the environment and cells may adapt but change their form and you have replaced an adult cell with one that doesnt look exactly the same as the original cell that was in that area. 
• happens within the same tissue type
• reversable
• you have some changed cells but some normal cells still remaining

• barrets esophagus
• esophagus is usually covered with normal squamous cell epithelium. when you have acid reflux, the squamous cell epithelium gradually changes into mucous producing epithelium (goblet cells) similar to those in the intestine. the change from normal to goblet is the way the esophagus protects itself from damage by the acid

• deranged cell growth of a specific tissue
• there is uncontrolled cell division in the area in the tissue and the cell form is different
• there may be many cells undergoing mitosis in a deranged manner
• reversable to a certain point, but can progress to neoplasia (cancer)
• the cell shape becomes abnormal, size becomes abnormal, and the organization of the cells becomes abnormal. 
• so the cell type stays the same but the cell organization and morphology changes and it will increase its mitosis

• dysplasia of the cervix as a result of HPV infeciton
• reversable, but can progress to neoplasia

• you can go from a normal ciliated epithelium to a metaplasia state and eventually to dysplasia. 
• you can go normal to meta and back, normal to dysplasia and back or normal to metaplasia to dysplasia and back or to neoplasia

• ciliated epithelium is lost in injury and cells pile up on top of eachother (metaplasia) but they look kind of squamous epitheliumy
• when the injury continues, theres nuclear disorganization, the shape is not uniform, there are abnormal nuclear structures and mitosis progresses at a faster pace- you can see the mitotic cells

• anything that alters the function of the cell can be considered an agent of injury
• internal: metabolic or genetic
• external: physical, chemical, infection mechanical

• hypoxia
• free radicals
• calcium
• chemicals 
• infections

• internal
• nutritional- iron, vitamin, protein or carb deficit
• ie if not enough iron metabolic activity is affected and cells cant work

• lysosomal, peroxisomal, mitrochondrial etc problem
• ie TaySachs (lysosomal disease- lysosomes cant be degraded, takes up whole cell and organ and stops function) or Adrenoleukodystrophy (peroxisome dysfuntion)
• can happen at different levels- ie disorders of certain organelles

• heat, uv, ionizing radiation
• trauma, heat cold

• toxins
• free radicals
• ions
• venoms
• drugs
• chemicals
• medications

injury to cells and tissues that can either undergo resolution and repair if reversable or loss of function and system failure if irreversable

• differs based on the type of cell
• smoke injury: epithelial cells on the skin will not suffer as bad damage as epithelial cells in the trachea
• cells with stored energy reserves: glycogen filled liver cells get damaged less than depleted ones
• tissue specific type of insults: brain and heat cells are more susceptible to ischemia while the liver is more susceptible to chemicals
• time duration of insuts: calf muscles can survive ischemia ~2hrs, while heart can ~30min. brain only 3-4min heirarchy of ischemia.

• hypoxia: oxygen deficiency
• ischemia: impaired blood supply
• infarction: area of necrosis due to ischemia

• injury affects the cell structures- usually the cell goes through a sequence of events, some of which arent visible early on
• structural changes occur in a sequence

• biochemical- things are happening here before you even notice change
• ultrastructural
• light microscopic
• gross level- organ pathology becomes evident and eventually after these changes occur function is lost
• injured cells look different than normal ones which causes tissue pathology and change instructure often affects function

• injury affects cell structures
• structural changes sequence
• similar morphological changes will happen regardless of injury type
• common biochemical pathways are altered that will lead to either adaptation or death
• if death loss of function

• cell membrane: dysfunction of cell membrane activity
• mitochondria: oxidative phosphorylation inhibited and ATP depleted
• nucleus: and genetic material
• protein synthesis: end enzyme production
• calcium homeostasis: bc of biochemical changes
• oxygen effects: ischemia/reactive oxygen species/free radicals

• cell normally has very tight control over how much free calcium stays in the cell bc that amount determines what kind of enzymes are active in the cell
• if Calcium is suddenly available inside the cell, the wrong enzymes become active and can kill the cell by digestion

the result of cellular injury

• causes ATP depletion and deprives cells of oxygen and interrupts oxidative metabolism and ATP generation
• once a cell loses oxygen supply it gets hypoxic, once it gets hypoxic mitochondria function and krebs cycle is affected and your cell depends on glycolysis for 2ATP
• very small amount of energy available so the cell will shut down many processes that arent immediately necessary
• so the cell will get injured and when these are shut down it will die if continued lack of oxygen
• many processes in the cell and reactions that depend on ATP get shut down

• Na K pump, followed by calcium channel
• this leads to influx of Na into the cell followed by water then followed by calcium
• once calcium enters, lysosomal enzymes are activated and damage is irreversable

• can be derived from oxygen species
• produced when you consume oxygen and when injury occurs, so production of these is always something going on
• usually they prefer to combine with lipids, proteins and dna and they can cause molecular injury
• normally you have the energy and antioxidants to fix these things, but when oxygen depleted you dont have the energy to do that anymore

• lipid peroxidation
• oxidative modification of proteins
• DNA effects

• swelling
• fatty change
• free radical generation

• impairs cell function but does not result in cell death
• if NaK pump shut down Na goes in followed by water causing swell
• tissue of damaged organs will appear pale and distorted
• severe swelling can lead to additional ischemia by occlusion of patterns reversable cell injury occur
• swelling can cause increase in the bulk of the organ and put pressure on blood vessels which can cause occlusion of microvasculature which can cause more ischemia
• can become irreversable and lead to further ischemia and infarctions that are visible at the gross level

• accumulation of fat inside of the cell
• can happen when you have production of fat that needs to be sent outside of the cell (ie in the liver)
• if the cell is injured it will still make fat, but wont make proteins to transport it so the fat is stuck inside- fatty liver

• they are entities with unpaired electrons, usually oxygen, that bind and alter chemical bonds in proteins and lipids and DNA to cause damage
• they need to gain or lose an electron
• can cause chain reactions in the cell

• radiation
• redox reactions
• chemicals

• combat free radicals
• react with them and neutralize them to prevent damage
• in our cells we have superoxide dismutase- an enzyme in cells that can react with free radical oxygen and neutralize it
• antioxidants are in the body or can be supplimented in our diet

• SOD converts free radicals to H2O2 and catylase converts that to water
• OR: H2O2 can go through the glutathione pathway to produce water, but it is dependent on iron, vitamin b6, vitamin b12 and folic acid and peroxisomes

• cell swelling
• becomes irreversable if insult continues
• tissue will appear pale and distorted in damaged organs
• severe swelling can lead to additional ischemia by occluding microvasculature

• steatosis-triglycerides accumulate in cells
• lipid vacuoles occur in cytoplasm

liver, kidney, skeletal muscle, cardiac muscle

• a storage disease of triglycerides
• same as fatty change
• in mild cases: reversable.
• if too much it can overcrowd organelles and cause secondary change
• in severe cases: cellular function is deranged due to overcrowding caused by the lipid vaccules. this is irreversable- cirrhosis

• in those who drink a lot of alcohol
• liver appears yellow and becomes soft and greasy
• can lead to cirrhosis

• hypoxia
• ischemic insult leads to rapid damage
• the length of time that ischemia would cause death is dependent on the oxygen needs of the specific cell

• swelling of cell and its components
• clumping of nuclear chromatin
• lipid deposition
• hemosiderin deposition

• used to be used for drycleaning but it was found that it cuases release of many free radicals and damage to ER, mitochondria and membrane
• majorly injures liver and kidneys

• it leads to destruction of the plasma membrane which causes sodium water and eventually calcium influx which wll activate lysosomal enzymes and cause death
• it also causes release of free radicals which denature the ER causing decreased protein synthesis so no lipoportiens that carry fat out of liver and fatty liver disease
• the free radicals also injure the mitochondria so theres less ATP then lactic acid then a pH drop which activates lysosomes causing cell death

• chemical injurer
• metabolized in the liver and by alcohol dehydronase and you produce acetaldehyde which is toxic to mitochondria so you break it down into acetate and free radicals which cause the same damage
• as the alcohol dehydrogenase continues to work you make more and more acetaldehyde and as you drink more you induce the ER enzyme cyp450 so people think they can tolerate more alcohol because this is activated but it also makes more acetylaldehyde and free radicals

• can either destroy cell membrane and get into the cells, inhibit protein synthesis and/or make toxic substances
• microorganisms can invade and harm cells
• these cause direct damage to the cell by damage to membrane and shutting down protein synthesis and also indirect damage through the release of toxins and chemicals

• the effects it can have on the whole body
• fever, pain, loss of function, internal organ changes (ie heart rate)

• disruption of
• protein synthesis
• the internalization of electrolytes from the outside of the cell
• enzyme loss of function
• loss of membrane integrity
• cell death, destruction of nuclear material
• deposition of caclium in the mitochondria.

• binds degredation enzymes and activates them
• activates protein kinases: which cause phosphorylation of protein and chromatin fragmentation
• activates phospholipases with phospholipid degredation and loss: which leads to membrane damage
• activates proteases: this with cell swelling leads to cytoskeletal disassembly

• autolysis and lysosomal rupture (you will have activated lysosomal enzymes that will start digesting the cell)
• cell membrane disruption
• eosinophillic inclusion bodies inside
• nuclear damage
• calcium deposition in mitochondria, cytosol, etc

• normal body substances: lipids, proteins, carbs, melanin
• abnormal endogenous products: those resulting from inborn errors of metabolism
• exogenous products: environmental agents and pigments which arent broken down by the cell. ie caratinoids turn skin orange

buildup causes damage to cell

application of mechanical energy to the body resulting in tearing, shearing or crushing of tissues

• bruise, bleeding in skin
• bruising causes extavasated red cells which leads to phagocytosis of red cells by macrophages which leads to hemosiderin and iron-free pigments

this change in the nature in hemaglobin contributes to the change in color overtime from purple to yellow

blood in enclosed place

• scrape
• skin erosion
• scab

• a rip
• avulsion
• lacerations of different degrees by the effect of force skin might come off from the muscles or you might have a rip in a blood vessel because of mechanical trauma

• bone injury
• elderly are more susceptible and it can lead to many complications in them

• incised wounds
• stab wounds
• puncture wounds
• chopping wounds

depending on the wound- surface edges can be jagged or clean cut, can sometimes be prepared, sometimes cant

• long not deep
• lethal in suicide

penetrating deep

step on a nail for example

axe

have entrance and exit wounds

• contact range entrance wound
• intermediate range entrance wound
• indeterminate range entrance wound

• muzzle presses skin
• you can see the pressing

• away from skin
• tattooing and stippling: gunpowder hits skin at a certain range

• hole plus abrasion that goes along with it
• indeterminate bc you cant determine the distance it was fired from
• ie a gun at a distance or closer but the person has protection such as a pillow

• clean edges
• shored exit wound: bullet stopped by a chair support

• caused by a failure of cells to recieve or use oxygen
• any of the following can do it: suffocation, strangulation, chemical asphyxiants, drowning

reduction of oxygen ~16%

• loss of blood supply to brain
• hanging, ligature, and manual strangulation

• cyanide
• hydrogen sulfide

cerebral hypoxia

• deficiency: missing nutrient necessary to the cell
• intoxication or poisoning: toxin that interferes in cell physiology
• trauma: physical injury and loss of cells structural integrity

• decreased oxygen in air
• decreased hemaglobin
• decreased oxygen transported to cells
• disease of the respiratory and/or cardiovascular system

• lead: affects nervous system
• Carbon monoxide: deprives body of oxygen
• ethanol: affects central nervous system

dysfunction depends on toxin and cell type

• physical disruption of cells
• ie abrasion, cutting, burns, microorganisms, etc

• cell death by autodigestion in an organ or tissues that is still part of a living person
• swell and spill phenomenon 
• often interferes with cell replacement and affects tissue regeneration
• gangrene occurs when a considerable mass of tissue undergoes necrosis
• the rest of the body undergoes a phenomenon inflammatory response

the cell swells up and the contents spill out into the extracellular environment

• hypoxia
• ATP production decreases
• NaK and calcium channels shut down
• na and water move into the cell, K moves out
• osmotic pressure increases
• more water moves into the cell
• cisterrae of endoplasmic reticulum distend, rupture, and rofm vacules
• extersive vacuolation
• hydropic degeneration

• progressive loss of nuclear chromatin
• rupture of the nuclear membrane
• breakdown of the plasma membrane
• mitochondrial damage
• nuclear changes

• pyknosis: condensation of chromatin and shrinkage of the nucleus. nuclear membrane alteration
• karyorrhexis: fragmentation of the nucleus
• karyolysis: dissolution of the nucleus

they occur in this order

• cell injury
• cytoplasmic damage
• nuclear damage (karryorhesis and karyolysis)
• contents spillage which triggers leukocytes to go to area
• biomarkers released to plasma

• K+ released by dead cells: high extracellular K levels affect brain and heart activity
• enzymes released into blood- the biomarkers of necrosis: creatine kinases, lactic dehydrogenase, aspartate aminotransferase 
• release of protein or protein breakdown products into the blood- ie troponin

• its in skeletal and cardiac muscle
• when cardiac muscle is injured this is released from the cells that burst and serves as a biomarker

• coagulative
• liquifactive
• caseous
• gangrene

• all of these are descriptive in the sense of what happens to the cells when they are going through autolysis
• depending on what enzymes and ions and surrounding environment the debri that results from cell death will look different in histology slides or to the naked eye

• coagulation or proteins
• caused by metal poisons
• affects the heart and kidney
• the enzymes that digest the cellular contents get inactivated and then dont digest them completely
• the proteins get coagulated and form gel like structures

• dissolution by proteases
• soft tissue
• affects brain
• if you have an organ or tissue where a lot of protein digesting enzymes are in abundance the autolysis starts to happen and the proteases digest the material and make it liquid, so the necrotic area becomes soft

• digested material and undigested material that gets clumped together
• soft and cheesy
• coagulation, deposits undigestable
• lungs

• lots of tissue degeneration
• dry: from ischemia
• wet: from infections and pus due to neutrophils
• gas: clostridium infection

• ischemia that slowly develops
• slow decrease in the availability of blood and oxygen and gradual loss leads to slow death in the tissues that blood and o2 cant reach
• blood flow has been slowed for a long period of time before necrosis is visable (ie advanced diabetes)

• advanced diabetes
• on the skin surface following arterial obstruction
• particularly liable to affect the limbs, esp the toes- mumification of limbs and toes for example

• occurs in organs that are generally wet and gangrene happens at a faster rate than dry
• formation of pus happens due to PMN invsion
• necrosis caused by sudden stoppage of blood flow

• commonly found in small intestine, appendix, lung, and uterus and can be limbs
• ie intestinal ischemia

• like wet gangrene but on top of that there is clostridium infection which produces gas bubbles
• anaerobic bacteria produce a toxic gas
• this is an acute, painful and often fatal type of gangrene

• war wounds- battle ground injuries
• deep infected wounds
• muscle damage

• coagulative: kidney infarct
• liquifactive: cerebral infarct
• caseous: tuberculosis
• dry gangrene: diabetes
• wet gangrene: intestines

• thrombosis or embolism
• strangulated hernia
• volvus
• intussusception- a piece of intestine telescopes into the next piece and the blood supply gets obstucted.

• a form of liquefactive necrosis, but what happens is you can have digestion of fat and fatty acids are generated
• that combined with calcium makes calcium soap which results in a white chalky area described as fat necrosis

• acute pancreatitis
• release of digestive lipases into the abdominal cavity
• destruction of mesenteric fat by enzymes
• fatty acids are released and combine with calcium to form a soap- calcium saponification
• dystrophic calcifiaction of liquified adipose cells
• a lesion with white calcium inside, opaque and chalky

• abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium and other minerals
• types: dystrophic and metastatic

• calcification that takes place in dead or dying tissues
• a common location for this is the cardiac valves
• calcifying endocarditis (valves become calcified)
• radiodense white plaques on valves

• you start depositing calcium in normal living tissue
• occurs in tissue other than bone ie muscle, kidney, etc

• inflammation and lysis
• ulceration, isolation
• reorganization of tissue
• area of the dead cells is encapsulated and calcified
• immunological damage 
• you may lose function of the organ

• programmed cell suicide
• they kill themselves when theyre old, produced in excess, are worn out, developed improperly, or have genetic damage
• induced by a mechanism resident in the cells
• an active process that needs energy

• cells do not swell and burst in apoptosis like they do in necrosis
• no debri left behind in apoptosis- cellular material is degraded by activation of caspases (suicide enzymes)
• the disintegrated material is phagocytosed by either phagocytes or surrounding cells in apoptosis

• shrinking of cell structures
• condensation and fragmenation of nuclear chromatin
• separation of nuclear fragments and cytoplasmic organelles into apoptotic bodies
• engulfment of apoptotic fragments by phagocytic cell

• atrophy of thymus: adrenal cortex makes corticosteroids. as more are produced they travel through the blood and induce the thymus cells to kill themselves
• webbed toes and fingers: die by apoptosis in fetal development
• brain cells: extras are killed off other wise thered be too many cells an not enough neruoconnections

• programmed genes
• cellular clock
• death genes
• DNA damage to genes that control differentiation, development and aging
• accumulation of too many free radicals
• mitochondrial damage

• determine how well and how fast we age and our lifespan
• genetic: clock genes
• diet: malnutrition, obesity
• diseases: atherosclerosis, diabetes
• genetics: werner's syndrome
• social conditions: friends, activities
• supporting organizations

death of an entire person

• postmortem changes
• algor mortis
• livor mortis
• rigor mortis
• postmortem autolysis

• normal tissues in a dead body
• distinguished from necrosis by being diffuse
• not associated with inflammatory response

reduction in body temperature following death

settling of the blood in the lower portion of the body

the limbs of the corpse become stiff

• autolysis of organs 
• digestion of cells by enzymes released from lysosomes makes the organ become looser