Cell pathology

refers to the underlying causes and modifying actors that are responsible for the initiation and progression of disease

mechanism of development and progression of the disease

hypoxia and ischemia

hypoxia: oxygen deficiency in tissue

ischemia: reduced blood supply -> low o2 and low nutrients + biuld up of toxic metabolics

cells return to normal function if damaging stimulus is removed

e.g. cellular swelling, fatty change

in cell injury with increased permeability of p.m.

apperent at level of whole organ (difficult to see with light microscope)

causes pallor increased turhor and increased organ weight

manifested by apperance of triglycerode containing lipid vacuoles in the cytoplasm

1. inability to restore mitochondrial function

2. loss of structure and functions of the plasma membrane and intracellular membranes

3. loss of DNA and chromatin structural integrity

NECROSIS:

ischemia, exposure to toxins, infection, trauma

uncontrollable accidential cell death

APOPTOSIS:

regulated cell death

less severe cell injury

apoptosis also occures in healthy tissue

cell death in which cellular membranes fall appart an d cellular enzymed leat out ultimately digest the cell

1. pyknosis

2. karyolysis

3. karyorrhexis

characterized by nuclear shrinkage and increased basophilia

-> DNA condensed into dark shrunken mass

basophilia fades because of digestion of DNA by DNAse activity

pyknotic nucleus can undergo fragmentation

increased eosinophilia

-> increased binding of eosin to denatured cytoplasmic proteins and loss of basophilic ribonucleic acid in the cytoplasm

fibirnoid necrosis which is detected only by histologic examinaton

characteristics of infarcts (areas of necrosis caused by ischemia) in all solid organs EXEPT THE BRAIN

• underlying tissue architecture is preserved for at least several days after death of cekks in the tissue

• injury denatures not only structural proteins but also enzymes -> blocking proteolysis of the dead cells -> eosinophilic anucleated cells may persist for days or weeks

• leukocytes are recruited -> cellular debris removed by phagocytosis

in focal bacterial and funfal infections

• in hypxic death of cells in the CNS

• dead cells are completly digested -> viscous liquid removed by phagocytes (formation of abcess)

No distinctive pattern

• limb that has undergone coagulative necrosis in multiple tissue layers

• when bacterial infection is superimposed morphologic appearance change to liquefactive necrosis resulting in wet gangrene

most often in foci of TCB

• cheeslike -> friable yellow white appearance of the area

• architecture completely obliterated and no cellular outlines

• necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in H&Estained tissue sections

• caseous necrosis is often surrounded by a collection of macrophages and other inflammatory cells; this appearance is characteristic of a nodular inflammatory lesion called a granuloma.

Focal areas of fat destruction -> release of activated pancreatic lipases

• acute pancreatitis

• pancreatic enzymes leak out of acinar cells and ducts and liquefy the membranes of fat cells in the peritoneum

• outline of dead fat cekks can often be seen, calcium soups stain blue with H&E stains

in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels , also in severe hypertension

• Deposited immune complexes and plasma proteins that leak into the wall of damaged vessels produce a brightpink, amorphous appearance on H&E preparations called fibrinoid (fibrinlike) by pathologists

• Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples

• Cardiac muscle-contains a unique isoform of the enzyme creatine kinase and of the contractile protein troponin

• Hepatic bile duct epithelium - enzyme alkaline phosphatase

• Hepatocytes - transaminases

• Irreversible injury and cell death in these tissues elevate the serum levels of these proteins, which makes them clinically useful markers of tissue damage

Pathway of the cell death i nnwhich cells activate enzymes -> degrade the cells DNA and proteins

• rehǵulated by biochem. pathway controll balance of activation of caspase

• mitochondrial pathway and death receptor pathway

responsible for apoptosis in most physiologic and pathologic situations

• When mitochondrial membranes become permeable,cytochrome c leaks out into the cytoplasm, triggering caspase activation and apoptotic death.

• A family of more than 20 proteins, the prototype of which is Bcl-2, controls the permeability of mitochondria.

• Many cells express surface molecules, called death receptors, that trigger apoptosis

• Most of these are members of the tumor necrosis factor (TNF) receptor family, which contain in their cytoplasmic regions a conserved “death domain”

• The prototypic death receptors are the type TNF receptor and Fas (CD95).

by phagocytes

no inflammatory reaction

initiated by engagement of TNF receptors -> receptor interacting protein (RIP) kinases are activated -> dissolution of the cell

=> features of necrosis AND apoptosis

activation of cytosolic danger sensing protein complex (inflammasome) -> activation of caspases -> productio of proinflammatory cytokines

=> Apoptosis AND inflammation

lysosomal digestion of the cells own components

• survival mechanism during ischemia or starvation and some types of myopathies

restoration of blood flow to ischemic tissue can result in tissue inury because:

• increased generation of ROS

• influx of leukocytes and plasma proteins

cellular abnormalities that are induced by ROS

phagocytic leukocytes (neutrophils and macrophages)

There also are nonenzymatic and enzymatic systems, sometimes called free radical scavengers, serving to inactivate free radicals:

•  Superoxide - superoxide dismutase (SOD)

• Hydrogen peroxide - Glutathione (GSH) peroxidases

• Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide

•  Endogenous or exogenous anti-oxidants (e.g., vitamins E, A, and C and β-carotene) may either block the formation of free radicals or scavenge them after they have formed.

accumulation of misfoldeed proteins lead to apoptosis

abnormalities that increase the production of misfolded proteins or reduce the ability to eliminate them:

• gene mutations that lead to the production of proteins that cannot fold properly

• aging, which is associated with a decreased capacity to correct misfolding

• infections, especially viral infections, when large amounts of microbial proteins are synthesized within cells, more than the cell can handle

• increased demand for secretory proteins such as insulin in insulin-resistant states;

• changes in intracellular pH and redox state.

responses to stimulation of hormones or endogenous chemical mediators to the demands of mechanical stress

responses to stress to modulate their structure and function to escape injury

e.g. squamous metaplasia of bronchial epithelium in smokers

increase in cell size

NO NEW CELLS

can also be pathological (prostate hypertrophy due to high levels of testoterone)

Increase in number of cells

physiologic (puperty breasts) and pathologic (chushings)

stiulated by growth factors

1. hormonal ->exemplified by proliferation of glandular epi. of f. breasts during puperty

2. compensatory -> residual tissue grows after removal/loss of an organ

exessive hormonal growth factor stimulation

shrinkage of size of cells -> diminished function

caused by:

• decreased workload

• loss of innervation

• diminished blood supply

• inadequate nutition

• loss of endocrine stimulation

• aging

physiologic and pathologic

change of one adult cell type tp another

replacing less stress resistant tissue with more resistant by reprogramming of stem cells (transdifferentiation)

e.g.:

• rugged stratified squamous epi. instead of specialized epi. in smoker lungs

• stratified squamous epi. to gastric/intestinal type columnar epi. im lower esophagus due to chonic gasrtic reflux

• bone formed in to soft tiss. in foci of injury

-> The influences that induce metaplastic change in an epithelium, if persistent, may predispose to malignant transformation

1. inadequate removal and degradation

2. exessive production of an andogenous substance

3. deposition of an abnormal exogenous material

process in a wide variety of disease states, is the result of an abnormal deposition of calcium salts

calcium metabolism is normal but deposits in injured or dead tiss. (areas of necrosis)

• It is virtually ubiquitous in the arterial lesions of advanced atherosclerosis.

• Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in elderly persons

(1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of parathyroid hormone–related protein by other malignant tumors

(2) destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia,or diffuse skeletal metastases)

(3) vitamin D–related disorders including vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor)

(4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism

can occure everywhere but mostly in intertestinal tiss of vasculature kidneys lungs and gastric mucosa

telomeres shorten

type

duration

severity

VEGF new blood vessels

increase of glucose uptake & glycolysis

aerobic glycolysis -> warburg effect

• Reduced activity of plasma membrane ATP- dependent sodium pumps =swelling

• increase in anaerobic glycolysis= lactic acid enviroment

  
  

• Detachment of ribosomes from RER and dissociation of polysomes = reduction of protein synthesis

• Increase of ROS

• Damage to mitochondrial and lysosomal membrane= cell death

  
  

• radiation

• enzymatic metabolism of exogenous chemicals

• inflammation

• reperfusion

• necrosis

• apoptosis

• necroptosis

• cystic fibrosis

• familial hypercolesterolemia

• Tay-sachs disease

• Alzheimer

• parkinson

• huntington

heart & skeletal muscles

pathologic setting

• liver

• heart

• skeletal muscle

• kidney

• toxins (alcohol)

• protein malnutrition

• diabetis mellitus

• obesity

• anoxia

• refers to the observation that cancer cells and rapidly proliferating normal cells tend to favor metabolism via aerobic glycolysis rather than the much more efficient oxidative phosphorylation pathway irrespective of oxygen status

• Aerobic glycolysis is less efficient than oxidative phosphorylation in terms of adenosine triphosphate production (2 vs 36 molecules of ATP), but leads to the increased generation of additional metabolites (proteins, lipids, nucleic acid) needed for cell growth and divisio

• diagnosed by PET scan