1. Cellular Injury & Adaptation

name the types of cell adaptation to environmental stress

hypertrophy

atrophy

hyperplasia

aplasia

hypoplasia

metaplasia

what is etiology?

causes of disease

what is pathogenesis?

mechanisms of disease

what is hypertrophy?

increase in organ/tissue size due to increased size of cells

on a cellular level, hypertrophy results in what?

increased protein synthesis

increased size or number of intracellular organelles

cellular adaptation due to increased workload

what are examples of hypertrophy?

skeletal muscle - increased mass associated with exercise

cardiac muscle - enlargement of L ventricle in hypertensive heart disease

nerve tissue

what is hyperplasia?

increased organ/tissue size due to increased number of cells

what are examples of hyperplasia?

breast during pregnancy - glandular proliferation

pathologic hyperplasia (can progress to dysplasia and cancer) - endometrial hyperplasia (exception is benign prostatic hyperplasia, which does not increase risk for prostate cancer)

what is dysplasia?

abnormal growth and development of cells within a tissue or organ

true or false: hyperplasia and hypertrophy often occur together

true

e.g. uterine enlargement in pregnancy is caused by both hypertrophy and hyperplasia of uterine smooth m. cells

true or false: an increase in stress leads to increase in organ size

true

what is aplasia?

failure of cell production

“no development” (started but didn’t get far)

true or false: primordial tissue is present in aplasia

true

what is an example of aplasia?

aplastic anemia - bone marrow stem cells present but fail to produce sufficient blood cells

what is agenesis?

cell production never started

primordial tissue absent, organ not formed at all, earlier developmental failure

what is an example of agenesis?

unilateral renal agenesis (during embryogenesis)

what is hypoplasia?

decrease in cell production

(hypoplasia = “under development,” started and got further than aplasia but not all the way)

how does hypoplasia affect organ size?

small size

what is an example of hypoplasia?

streak ovary in Turner syndrome during hypoplasia

(fibrous tissue with little or no germ cells, degree of development may be defined as aplasia or hypoplasia)

(not a Q) kidney agenesis vs aplasia vs hypoplasia

what is atrophy?

decreased organ or tissue size due to decrease in size and number of cells

true or false: atrophy refers to a reduction in size after normal, matured growth has been attained

true

what causes decrease in number of cells in atrophy?

apoptosis

what causes decrease in size of cells in atrophy?

ubiquitin-proteasome degradation of cytoskeleton

autophagy of cell components

what are some causes of atrophy?

decreased hormonal stimulation (e.g. vaginal atrophy in menopause)

denervation (nerve injury in trauma, destruction of NMJ)

decreased nutrients/oxygen/blood supply

disuse

aging

(not a Q) atrophy

what is metaplasia?

replacement of one differentiated tissue by another

metaplasia usually occurs between what cell types?

usually one surface epithelium to another (squamous, columnar, urothelial)

why does metaplasia occur?

new metaplastic tissue better able to handle new stress

can metaplasia be reversed with the removal of the driving stressor?

yes

what are examples of metaplasia?

Barrett esophagus

squamous metaplasia

HPV infection of uterine cervix

how does Barrett esophagus occur?

esophagus normally lined by squamous epithelium (suited to handle friction of food bolus)

new stressor: acid reflux from stomach causes metaplasia

new cell type becomes mucin-producing columnar cells (better able to handle stress of acid)

(not a Q) Barrett esophagus

how does squamous metaplasia occur?

bronchus is normally comprised of columnar epithelium

new stressor: chronic irritation from long-term tobacco use causes metaplasia

new tissue: squamous epithelium

(not a Q) squamous metaplasia

why does metaplasia occur with HPV infection of the uterine cervix?

glandular cells are normally lined by ciliated columnar epithelium

new stressor: HPV infection

new tissue: squamous epithelium

(not a Q) pathologic adaptations

name the 3 types of cellular injury

hypoxic cell injury

free radical cell injury

chemical cell injury

what may cause hypoxic cell injury?

cellular anoxia or hypoxia

name the mechanisms of hypoxic cell injury

ischemia

anemia

carbon monoxide poisoning

decreased perfusion (types of shock)

pulmonary disease

what organelle is affected first in hypoxic cell injury?

mitochondria

what occurs in the early stage of hypoxic cell injury

decreased oxidative phosphorylation and ATP synthesis

what are some consequences of decreased oxidative phosphorylation and ATP synthesis in early hypoxic cell injury?

failure of Na+/K+ pump

cellular and organelle swelling

increased buildup of Ca2+ in cell due to malfunction of Ca2+ pump

stimulation of phosphofructokinase activity (increased anaerobic glycolysis → lactic acid accumulation → decreased intracellular pH → denatures proteins and clumps nuclear chromatin)

what occurs in the late stage of hypoxic cell injury?

membrane damage (plasma membrane/organelles)

what are some consequences of membrane damage in late-stage hypoxic cell injury?

loss of membrane phospholipids

cell blebs (cell-surface deformity)

additional Ca2+ entering cell

intracellular enzymes/proteins released from necrotic cells into circulation

what is the “point of no return” in hypoxic cell injury?

cell death

what causes cell death in hypoxic cell injury?

irreversible damage to cell membrane

massive Ca2+ influx → calcification of mitochondria

true or false: vulnerability to irreversible hypoxic injury is dependent on tissue/cell type

true

how much time does it take for neurons to become vulnerable to irreversible hypoxic injury?

3-5 minutes

what types of neurons are most susceptible to irreversible cell death due to hypoxic injury?

Purkinje cells of cerebellum

neurons of hippocampus

how much time does it take for myocardial cells and hepatocytes to become vulnerable to irreversible hypoxic injury?

1-2 hours

(think 90-minute window for “door to balloon” for heart attack)

how much time does it take for skeletal muscle to become vulnerable to irreversible hypoxic injury?

4-6 hours

(limb tourniquet application recommended for max 4-6 hours before necrosis sets in)

what are free radicals?

molecules with a single unpaired electron in its outer orbital

what forms free radicals?

free radicals are the activated products of oxygen reduction reactions

name the mechanisms through which free radicals may cause cellular injury

peroxidation of lipids

oxidation of DNA and proteins

DNA damage implicated in aging and oncogenesis

name the mechanisms that generate free radicals

normal metabolism

oxygen toxicity

ionizing radiation

UV light

drugs/chemicals (e.g. barbiturate intoxication)

re-perfusion after ischemic injury

name the mechanisms that degrade free radicals

intracellular enzymes

exogenous/endogenous antioxidants

metal carrier proteins

spontaneous decay

what is an example of chemical cell injury?

liver cell membrane damage caused by carbon tetrachloride (organic solvent used in dry cleaning in 1900s)

CCl₄ converted to CCl₃ → cell injury

what are the types of cell death?

necrosis

apoptosis

what 3 things may happen to chromatin in cell death?

pyknosis

karyorrhexis

karyolysis

what is pyknosis?

condensation of chromatin in nucleus

in what type of cell death does pyknosis occur?

more characteristic in apoptosis but also happens in necrosis

what is karyorrhexis?

destructive fragmentation of nucleus

in what type of cell death does karyorrhexis occur?

apoptosis and necrosis

what is karyolysis?

complete dissolution of chromatin

in what type of cell death does karyolysis occur?

only necrosis

does NOT occur in apoptosis

name some characteristics of necrosis

enlarged cell size

pyknosis → karyorrhexis → karyolysis

disrupted plasma membrane

enzymatic digestion

frequent adjacent inflammation

name some characteristics of apoptosis

reduced cell size

fragmentation of nucleus into nucleosome-sized fragments

intact plasma membrane but altered structure

intact cellular contents, may be released in apoptotic bodies

no adjacent inflammation

is necrosis pathologic or physiologic?

invariable pathologic (culmination of irreversible cell injury)

is apoptosis pathologic or physiologic?

often physiologic (means of eliminating unnecessary cells)

may be pathologic after some forms of cell injury

what is necrosis?

degradative and inflammatory reactions occurring after tissue death

what is autolysis?

cellular degradation caused by intracellular enzymes

what is heterolysis?

cellular degradation by enzymes derived from extrinsic sources (bacteria or leukocytes)

name the types of necrosis

coagulative necrosis

liquefactive necrosis

caseous necrosis

gangrenous necrosis

fibrinoid necrosis

fat necrosis

what occurs in coagulative necrosis?

tissue remains firm, cell shape/organ structure preserved

nucleus disappears (pyknosis, karyorrhexis, karyolysis)

what preserves cell shape/organ structure in coagulative necrosis?

coagulation of proteins

what causes coagulative necrosis?

ischemia

what are examples of coagulative necrosis?

heart or kidney necrosis (supplied by end arteries with limited collateral circulation)

anemic infarcts (white appearance)

(not a Q) coagulative necrosis

what is liquefactive necrosis?

necrotic tissue becomes liquefied by autolysis

enzymatic lysis of cells/protein

what causes liquefactive necrosis?

ischemia

what are examples of liquefactive necrosis?

CNS/brain

abscess (pus, localized collection)

(not a Q) liquefactive necrosis

what is caseous necrosis?

a combination of coagulative and liquefactive necrosis

architecture not preserved but tissue not liquefied

what causes caseous necrosis?

granulomatous inflammation

infection of T lymphocytes, macrophages, and cytokines

what does caseous necrosis visually look like?

cottage cheese-like (caseous) appearance

what is an example of caseous necrosis?

tuberculosis

(not a Q) caseous necrosis

what is gangrenous necrosis?

not a distinctive pattern of cell death; refers to necrosis of a limb/bowel

what are the subtypes of gangrene?

wet gangrene

dry gangrene

what does wet gangrene involve?

includes infective heterolysis and liquefactive necrosis

what is usually involved in wet gangrene?

bacterial infection

what does dry gangrene involve?

includes coagulative necrosis without liquefaction

what causes dry gangrene?

usually ischemia without bacterial infection

true or false: vascular occlusion in lower extremity or bowel is a common cause of gangrene

true

(not a Q) gangrenous necrosis

what is fibrinoid necrosis?

deposition of fibrin-like proteinaceous material in arterial walls

what is fibrinoid necrosis associated with?

immune-mediated vascular damage

what may cause fibrinoid necrosis?

malignant hypertension

vasculitis

(not a Q) fibrinoid necrosis