normal cell (homeostasis) can be stressed and if it can not adapt what occurs?

-reduced oxidative phosphorylation

-atp depletion-no energy in the cell

-cellular swelling-Na/K pump brings in water

-aka hydropic swelling

hypoxia: deficiency of oxygen decreased aerobic oxidative respiration

ischemia: loss of blood flow compromises the supply of oxygen and metabolic substrates (glucose)

give one mode of injury that could cause ischemia

coronary artery artherslerosis

it is a decrease in oxygen carrying capacity often seen in:

-anemia

-methemoglobinemia

-CO poisoning-inhibits cytochrome oxidase in ETC

CO and CN posoning

watershed areas  - ant cerebral and mid cerebral

subendocardial tissues

-renal cortex and medulla-straight portion of the prox tubule in cortex

-mechanical trauma

-extreme temps

-changes in atmospheric press

-radiation

-electric shock

-oxygen in high concentration

-poisons- mercury (SH group) and CN

-pollutants

-carbon tetrachloride

-acetaminophen

-alcohol

exagerated immune response-anaphylaxis and autoimmune

protein-calorie def

vitamin def

nutritional xs

anorexia nervosa

type

duration

deverity

**small doses of toxin or brief periods of ischemia may produce reversible injury

type

state

adaptability of the injured cell

**cells nutritional and its hormonal status and its metabolic demands

aerobic respiration

integrity of the cell membrane

protein synthesis

cytoskeleton

integrity of the genetic apparatus of the cell

depletion or decreased ATP is most often seen in hypoxic or chemical injuries

1.  oxidative phosphorylation of ADP -normal situation

2.  glycolytic pathway -reserve mechanism

-fall in intracellular pH due to increase production of lactic acid

-impaired Na/K pump

-detachment of ribosomes

-failure of the Ca-Atpase pump (irreversible)

1. enzyme activation-phospholipase increases cell membrane permeability

2.  re-entry of calcium into the mitochondria leads to formation of mitochondrial permability transition pores

-detachment of ribosomes from rough ER reduction in protein synthesis

can be potentially reversible

proteins may become misfolded - often these are modified chaperones leading to cell death

this is seen in alzheimers

increases in cytosolic Ca

oxidative stress

activation of phospholipase A2

results in formation of mitochondrial permability pores

leakage of cytochrome c

apoptosis

ATPases- depletes ATP

phospholipases- damages the cell memb

proteases- cell memb damage

endonucleases-fragmentation of DNA

accumulation of oxygen derived free radicals are formed how

celles generate energy by reducing molecular oxygen to water

free radicals are the intermediates in this process

what are the intermediates that are formed when reducing molecular oxygen to water

ie. free radicals

superoxide

hydrogen peroxide

hydroxyl radical

lipids

 proteins

nucleic acids

free radicals can be formed via this liver enzyme system

what drugs will cause this free radical formation in the liver

cytochrome P450

carbon tetrachloride

acetaminophen

**these cause liver necrosis

chemical and radiation injury

ischemia reperfusion injury

liver necrosis by drugs

retinopathy of prematurity

iron overload

cellular aging

microbial killing by phagocytes

antioxidants-Vitamins A,C,E

trace elements- iron and copper binds to oxygen free radicals

enzymes-catalase, superoxide dismutases, glutathione peroxidase

vitamins- C, E, and beta carotene

defects in membrane permeability (ionic damage)

membrane damage affects what

mitochondria

 plasma membrane

other cellular membranes

mitochondrial dysfunction

plasma memb damage

1. inability to revers the mitochondria dysfunction-mitochondrial transition pores

2.  altered membrane function-ion channels disrupted-ca influx/k efflux

necrotic cells are more eosinophilic appear glassy, cytoplasmic vacuolation

calcification and foramtion of myelin figures

always pathologic

what are the nuclear changs seen with necrosis and define them

pyknosis-condensation of the chromatin-nucleus small

karyolysis- lysis/dissolution of the nucleus-extruded or faded out nucleus

karyorrhexis- fragmentation of the nucleus

**pyknosis can be found in both apoptosis and necrosis

the other 2 are only seen in necrosis

preservation of cell outlines

increasing intracellular acidosis - denaturation of enzymes and proteins

follows hypoxic death of most cells

***except CNS

MI

focal, bacterial, fungal infection

hypoxic cell death in CNS

transformation of the tissue into a liquid viscous mass

lysosomal enzymes released by necrotic cells-neutrophils(infective)

1.  dry necrosis-limb lost of blood supply-diabetes

2.  wet necrosis: bacterial infection superimposed-coagulative necrosis is modified by liquefactive action of bacteria

-small bowel  entrapment-anearobic bacteria

distinctive form of coagulative necrosis- term used for inflammation -collection of macrophages

seen in TB formation of caseating granulomas

gross- cheesy white

micro- granulomas

areas of fat destruction following release of activated pancreatic lipases into substance of pancreas and peritoneal cavity

the activated lipases split triglyceride esters-release fatty acids that will combine with calcium to form chalky white areas-fat saponofication

*acute pancreatitis

seen in necrosis and apoptosis

blood flow is restored to ischemic areas this in turn causes  an overload of O2 causing even more formation of free radicals in turn causing necrosis or apoptosis

 the free radicals cause mitochondrial permeability - leak cyto c - apoptosis

cytokine mediated - inflammatory response- necrosis

programmed cell death

cells destined to die activate enzymes that degrade the cell

cell membrane is retained

NOT associated with inflammation

programmed cell death in embrygenisis

hormone dependent involution- menstrual cycle

 cell deletion in proliferating cells - GI tract cells

removal of neutrophils in inflammation (first line of defense)

cell death following injury such as radiation, cytotoxic anticancer drugs

viral induced cell injury - viral hepatitis

pathologic atrophy in parenchymal organs following duct obstruction

cell death in tumors-cytotoxic CD 8 T lymphocytes

cell shrinkage!!

chormatin condensation along nuclear border

cytoplasmic blebs

phagocytosis of apoptic cells or cell bodies

protein cleavage- activation of caspases-normally present in cells in the inactive form when they become activated they have a cascade reaction leading to apoptosis

caspases activate DNAses-degrade DNA

DNA breakdown in Apoptosis by DNAses

broken into large pieces

DNA is cleaved by calcium and magnesium endonucleases into oligonucleosomes

the apoptic cells express phosphotidylserine on the surface of their plasma membranes

these are then recognized by macrophages-eating

no inflammation caused here despite the macrophages

1.  initiation phase

a. extrinisic

b.  intrinsic

2.  execution phase

explain the extrinsic pathway of the intiation phase

extrinsic pathway-death receptor pathway

1. death receptors - TNFR-1 and Fas (integral memb proteins)

2. these receptors are activated

3. activation of the caspase 8 

4. apoptosis

**this can be blocked by FLIP seen in AIDS

this is the mitochondrial pathway

results from increased mitochondrial permeability and release of pro-apoptotic cells

growth factors stimulate production of anti-apoptotic members of the Bcl-2 family in the mitochondrial membrane

the Bcl-2 will be turned off and replaced with Bak, Bim, Bax increasing mitochondrial perm

release of cyto C which binds with Apaf-1

Apaf-1 activates caspase 9

apoptosis

mediated by proteolytic cascade

caspases divided into 2 groups

initiator- 8, 9

execution- 3, 6

AST-diffuse liver necrosis; viral hep

ALT- diffuse liver necrosis; viral Hep

CK-MB- acute MI of myocarditis (coagulative necrosis)

Amylase and lipase- acute pancreatitis (fat necrosis)

1. hyperplasia

2. hypertrophy

3. atrophy

divided into:

1. hormonal- proliferation of glandular tissue-breasts

2. compensatory- regeneration of liver following hepatectomy

increase in local prod of growth factors

increased number of growth factors on responding cells

activation of particular intracellular signaling pathway

1. unopposed estrogen on the endometrium-endometrial carcinoma

-seen in estrogen replacement therapy for osteoporosis-post menapausal

2.   prostatic hyperplasia

increase in size of cells resulting in increase in size of organ

no new cells

-hypertrophy of muscle cells

-physiologic growth of the uterus in pregnancy

**both hypertrohy and hyperplasia can occur

-left ventricular hypertrophy associated with hypertension (increase in afterload)

-smooth muscle hypertrophy associated with prostatic hyperplasia

*urinary bladder hypertrophy and enlarged prostate(hyperplasia)

--prostate enlarged compressing the urethra so backflow into the bladder causing hypertrophy

stimualation of transduction  pathways

-growth factor stimulation: TGF-B, insulin like growth factor 1, fibroblast growth factor

increased protein translation

increased gene expression -c-fos, c-jun in the heart

swith of contractile proteins from adult form to fetal forms

-in cardiac hypertrophy

a. mechanical triggers stretch

b. trophic triggers- IGF-1

shrinkage in size of the cell by loss of cell substance

adaptive response

- decreased workload-prolonged immobilization of limb

-loss of innervation-skeletal muscle atrophy-leprosy

-inadequated nutrition-marasmus

-loss of endocrine stimulation-hypopitiutarism

-aging

-pressure -thick secretions in cystic fibrosis cause atrophy of the pancreas

imbalance between protein synthesis and degradation

increased catabolism of cell organelles

stimulation of ubiquitin proteasome pathway

brown atrophy-due to accumulation of LIPOFUSCIN within the lysosomes (wear and tear)

**lipofuscin seen in synovial joints of the elderly

reversible change in which one adult cell type is replaced b]y another adult cell type

give the 5 cases where you see metaplasia

1.  columnar to squamous-squamous metaplasia of brionchial mucosal lining in chronic smokers

2.  squamous to columnar-distal end of esophagus-Barretts Esophagus

3.  intestinal metaplasia-seen in pylorus and antrum in the presence of H. Pylori and characterized of goblet cells

4.  transitional epithelium to squamous- chronic inflammation of the urinary bladder mucosa, usually caused by the schistosoma  hematobium

5.  connective tissue metaplasia- formation of cartilage, bone, or adipose tissue in tissue which does not normally posess them

-myositis ossificans-sometimes seen in soft tissue following blunt trauma

-chondroid metaplasia

esophageal squamous epithelium is replaced with intestinal like columnar epithelium following gastric reflux

**risk of malignancy-adenocarcinoma of distal portion of esophagus

**adenocarcinoma-malignancies from glandular epithelium (columnar)

**will see columnar creeping onto squamous

  what is the mechanism of metaplasia

-reprogramming stem cells

-differentiation of stem cells along a particular lineage

-brought about by various cytokines growth factors

ex: smokers-ciliated columnar to squamous

-this is reversible

normal cellular constituents-water, lipids, proteins, and carbs

abnormal substance (exo or endogenous)

pigment

fatty change-abnormal accumulations of triglycerides within the parenchymal cells

-liver, heart, and muscle

-liver is enlarged, yellow and greasy

-microvesicular (sm droplets of fat) and macrovesicular fatty change(one huge droplet of pushing nuclei to the periphery)

-Oil Red O stain is used

1.  toxins-alcohol: prevents oxidation of FAs so     they start accumulating - also aspirin can cause this in pediatric age- Reyes syndrome

2.  protein malnutrition-bloated belly and enlarged liver

3. diabetes mellitus

4. obesity-nonalcoholic steatohepatitis (NASH)

5. anoxia-oxid of FFAs - acc of lipid

-associated with Rh incompatability in newborns-so you will get this after destruction of RBCs

-fat soluble unconjugated bilirubin deposits in basal ganglia nuclei of brain

-jaundice - scleral icterus-physiological jaundice of newborns due to the hypoxemia in womb so the RBCs need to be broken down

*organs not mature yet

cholesterol and cholesterol esters can be forms of intracellular accumulations what diseases/sxs are seen with this

-arthersclerosis

-xanthomas-acquired and hereditary hyperlipidemias-fat not metab properly

-sites of inflammation and necrosis-cell destruction by phospholipases

**macrophage take up cholesterol then deposit in the BV smooth muscle causing narrowing of the lumen

focal accumulation of cholesterol laden macrophages in lamina propria of gall bladder

seen in Niemann-Pick disease type C

-appear as eosinophilic droplets, vacuoles, or aggregates in cytoplasm

-Russell bodies-immunoglobin accumulation in plasma cells

renal problems-body doesnt want to lose proteins-reabsorption droplets in proximal tubules

chronic infection-plasma + immunoglobins

Alzheimers - amyloidosis-defect in protein folding

alteration within cells or in extracellular spaces

not specific marker for cell injury

extracellular hyaline seen in old scars, long standing hypertension

histologically you will see the "onion peel" appearance with glomeruli damaged

diabetes melitus- glycogen seen in epithelial cells of the PCT (cells become insensitive to insulin, leading to deposition  of glycogen)

glycogen storage disease-Von Gierkes-deficiency if glucose-6-phosphatase

carbon-air pollutants

anthracosis-black discoloration of lungs-maybe seen in chronic smokers of 40-50 years

coal workers-pneumoconiosis-large amt of carbon in inspired air

1.  lipofuscin

2.   melanin

3.  hemosiderin

wear and tear, aging pigment

composed of polymers of lipids and phospholipids  complexed with protein

**Brown atrophy

**seen in cardiac muscle-see a golden brown in b/t muscle striations

non Hb derived brown black pigment

Addisons disease

melanotic skin lesions

malignant melanoma

-hemorrhages in tissue(local xs)-hematoma

-hemosiderosis-systemic iron overload

1. dystrophic calcification

2.  metastatic calcification

seen in areas of necrosis

atheromas, damaged heart valves-lesions become calcified

histo: psammoma bodies-seen with meningiomas, papillary carcinoma of thyroid and papillary carcinoma of ovary

rheumatic heart disease-bacteria integrates with the cells to change the heart cells-causing distortion of the valves-incompitant

-PTH increase

-destruction of bone tissue-advanced malignancies

-vitamin D related problems

-renal failure

**you will see an increase in serum calcium-hypercalcemia

the reaction of the vascularized living tissue to loval injury

closely linked to the process of repair/it is a protective response

destroys

dilutes

and walls off

1. vascular reaction-seen in BVs

2.  cellular reaction-associated with BVs

1.  eosinophils-allergy

2.  heterophils-polymorpholeukocytes

3.  lymphocytes-chronic inflammation

4.  platelets

5.  monocytes-chronic inflammation

*once monocytes leave the BV it becomes a macrophage

1.  mast cells-never in circulation

2.  fibroblasts-for collagen formation

3.  macrophages-(monocytes)

4.  proteoglycans

5.  collagen fibers

6. elastic fibers

1. acute inflammation

2. chronic inflammation

acute inflammation is defined as what?

what are its characteristics?

 defined as rapid in onset and is relatively short duration-lasts mins to hours

characterized by exudation of fluid, plasma proteins, and emigration of leukocytes

**exdudation of fluids-dynamic forces are upset so fluid moves from inside to outside the vessel

 chronic inflammation is defined as what?

what are the characteristics?

longer duration and characterized by the presence of lymphocytes and macrophages

*associated with the proliferation of blood vessels, fibrosis, and tissue necrosis

vascular and cellular responses of acute and chronic inflammation are mediated by chemical factors derived from what

plasma proteins

cells

**cytokines

1.  heat-BVs dilated and blood going there, also the cause of redness

2.  redness

3.  swelling-exudation of fluid-moving out from BVs-edema

4.  pain- due to the mediators (prostaglandins)

5.  loss of function-  fall injuring an ankle causes swelling thus pain

rubor-redness

calor-heat

both due to vasodilation of arterioles

mediated by histamine

pain-due to prostaglandins and bradykinin

prostaglandins-sensitizes the specialized nerve endings to the effects of bradykinin

acute inflammation has 3 major components what are they?

1. alteration in vascular caliber-increased blood flow

2.  structural changes in microvasculature-escape of plasma proteins-endothelial cells lining BVs contract causing intracellular space formation-permitting escape and emigration of leukocytes

3.  emigration of leukocytes-look for site of injury

movement of fluid of low protein concentration

* ultrafiltrate of the blood

what are the differences between exudate and transudate?