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PO2

driving force for diffusion of O2 into tissue

SaO2

percent heme groups occupied by O2

Cyanosis

decreased O2 saturation (SaO2); O2 content

Oxygen

electron acceptor in oxidative pathway

Hypoxia

inadequate O2 leads to ATP depletion

Ischemia

decreased arterial (or venous) blood flow

Respiratory acidosis

retention of CO, always decreases PaO2

Ventilation defect

impaired delivery of O2 to alveoli; intrapulmonary shunting of blood (e.g., RDS)

Perfusion defect

absent blood flow to alveoli; increased alveolar dead space (e.g., pulmonary embolus)

Diffusion defect

O2 cannot cross alveolar-capillary interface; interstitial lung disease (e.g., sarcoidosis)

Methemoglobin

↓ SaO2; heme Fe+3; oxidizing agents (sulfur/nitro drugs); Rx with IV methylene blue

Clinical methemoglobinemia

cyanosis not corrected by O2; chocolate colored blood

Carbon monoxide

↓ SaO2; left-shift O2 binding curve; inhibits cytochrome oxidase

Causes carbon monoxide poisoning

car exhaust, space heaters, smoke inhalation

S/S carbon monoxide poisoning

headache; cherry red color skin

Cyanide

inhibits cytochrome oxidase; systemic asphyxiant

Carbon monoxide + cyanide poisoning

house fires

Left-shifted O2 curve

↓ 2, 3 BPG, carbon monoxide, alkalosis, HbF, methemoglobin, hypothermia

Right-shifted O2 curve

↑ 2, 3 BPG, high altitude, acidosis, fever

High altitude

respiratory alkalosis enhances glycolysis; ↑ synthesis 2,3 BPG

Mitochondrial poisons

damages membrane and drains off protons; alcohol, salicylates

Uncoupling agents in mitochondria

drain off protons; dinitrophenol, thermogenin (brown fat)

Complication mitochondrial poisons/uncoupling agents

hyperthermia

Decreased ATP

impaired Na+/K+ ATPase pump (cellular swelling); reversible

Anaerobic glycolysis

ATP synthesis in hypoxia; lactate ↓ intracellular pH, denatures proteins

Irreversible injury hypoxia

membrane/mitochondrial damage

Mitochondrial damage

release cytochrome c activates apoptosis

Irreversible injury hypoxia

↑ cytosolic Ca2+ activates phospholipase, proteases, endonuclease

Free radicals

unpaired electron in outer orbit; damage cell membranes and DNA

Free radicals

superoxide, hydroxyl, peroxide, drugs (acetaminophen)

Superoxide dismutase

neutralizes superoxide

Glutathione

neutralizes peroxide, drug FRs

Catalase

neutralizes peroxide

Lipofuscin

indigestible lipid of lipid peroxidation; brown pigment increased in atrophy and FR damage

Reperfusion injury in heart

superoxide FRs + calcium

Mitochondrial injury

cytochrome c in cytosol initiates apoptosis

SER hyperplasia

alcohol, barbiturates, phenytoin

Complications SER hyperplasia

increases drug metabolism (e.g., oral contraceptives); low vitamin D

Chediak-Higashi

membrane protein defect in transferring lysosomal enzymes to phagocytic vacuoles

Chediak-Higashi

AR; giant lysosomes

I cell disease

absent enzyme marker in Golgi apparatus (mannose 6-phosphate); empty lysosomes

Rigor mortis

stiff muscles after death due to ATP depletion

Fatty change in liver

MCC alcohol (increase in NADH); DHAP → G3P → TG

Fatty change in liver

VLDL pushes nucleus to side

Causes fatty change

↑ synthesis TG/FAs, beta-oxidation of FAs, synthesis apoproteins/release VLDL

Fatty change in kwashiorkor

↓ synthesis of apoproteins

Ferritin

primary iron storage protein; soluble in blood; serum level reflects marrow storage iron

Hemosiderin

insoluble ferritin degradation product visible with Prussian blue stain

Atrophy

reduction in cell/tissue mass by either loss or cell shrinkage

Brain atrophy

ischemia; Alzheimer's

Exocrine gland atrophy in CF

duct obstruction by thick secretions

Labile cells

stem cells (skin, marrow, GI tract) →←→⇦

Stable cells

in G0 phase (smooth muscle, hepatocytes); can enter cell cycle (growth factors, hormones)

Permanent cells

cannot replicate; cardiac/striated muscle; neurons

Hypertrophy

increase in cell size (structural components, DNA)

LVH

increased preload (valve regurgitation), increased afterload (hypertension, aortic stenosis)

RVH

pulmonary hypertension

Bladder smooth muscle hypertrophy

prostate hyperplasia constricts urethra

Removal of kidney

hypertrophy of remaining kidney

Hyperplasia

increase in number of cells

Endometrial hyperplasia

unopposed estrogen (obesity, taking estrogen)

RBC hyperplasia

increased EPO (blood loss, ectopic secretion, high altitude)

Prostate hyperplasia

increased dihydrotestosterone (DHEA)

Gynecomastia

hyperplasia male breast tissue; normal in newborn, adolescent, elderly

Metaplasia

one adult cell type replaces another cell type

Squamous metaplasia in bronchus

smoking

Intestinal metaplasia in stomach

Paneth cells, goblet cells; H pylori chronic atrophic gastritis

Squamous metaplasia bladder

Schistosoma hematobium infection

Barrett's esophagus

glandular metaplasia of distal esophagus; due to GERD

Dysplasia

atypical hyperplasia and metaplasia are precursors for cancer

Squamous dysplasia in cervix

human papilloma virus

Squamous dysplasia in bronchus

smoking

Necrosis

death of groups of cells

Coagulation necrosis

preservation of structural outline (due to ↑ lactic acid)

Infarction

pale (e.g., heart, kidney); hemorrhagic (e.g., lung, small bowel); dry gangrene

Liquefactive necrosis

brain infarct, bacterial infections; wet gangrene

Caseous necrosis

variant coagulation necrosis; granulomas due to TB/systemic fungi

Granulomas

activated macrophages (epithelioid cells); multinucleated giant cells; CD4 TH1 cells

Epithelioid cells

γ-interferon released by CD4 T cells activates macrophages

Multinucleated giant cells

fusion of epithelioid cells

Granulomas

type IV hypersensitivity

Enzymatic fat necrosis

associated with pancreatitis; soap formation (Ca2+ + fatty acids)

Fibrinoid necrosis

necrosis of immune reactions (immune vasculitis/endocarditis)

Postmortem necrosis

autolysis; no inflammatory reaction

Dystrophic calcification

calcification of damaged tissue; normal serum calcium

Dystrophic calcification

pancreatitis; atherosclerotic plaque

Metastatic calcification

calcification of normal tissue; increased serum calcium or phosphorus

Nephrocalcinosis

metastatic calcification of collecting tubule basement membranes

S/S nephrocalcinosis

polyuria due to nephrogenic diabetes insipidus; renal failure

Apoptosis

gene regulated individual cell death

Signals activating apoptosis

mullerian inhibitory factor, tumor necrosis factor, hormone withdrawal

Signal modulators of apoptosis

TP53 suppressor gene, BCL-2 genes

BCL-2 genes

anti-apoptosis gene; prevents cytochrome c from leaving mitochondria

Caspases

responsible for enzymatic cell death in apoptosis; proteases and endonucleases

Markers of apoptosis

eosinophilic cytoplasm, pyknotic (ink dot) nucleus

Apoptosis

loss Mullerian epithelium in male fetus; thymus involution; killing cancer cells

Histamine

key chemical in acute inflammation; mast cell; arteriole vasodilation; ↑ venular permeability

Rubor acute inflammation

redness; arteriole vasodilation (histamine)

Calor acute inflammation

heat; arteriole vasodilation (histamine)

Tumor acute inflammation

swelling; ↑ vessel permeability (histamine)

Dolor acute inflammation

pain; bradykinin, PGE

Acute inflammation

neutrophil dominant; ↑ IgM

Initial vessel events

transient vasoconstriction → arteriolar vasodilation → ↑ venular permeability

Neutrophil rolling acute inflammation

due to selectins

Integrins

neutrophil adhesion molecules; C5a and leukotriene B, activate; neutrophil margination

CD11/CD18

markers for integrins

Endothelial cell adhesion molecules

activated by IL-1 and TNF

ICAM

intercellular adhesion molecule

VCAM

vascular cell adhesion molecule Leukocyte adhesion molecule defect

Activation neutrophil adhesion molecules

neutrophilic leukocytosis; corticosteroids

Activation neutrophil adhesion molecules

neutropenia; endotoxins

Chemotaxis

directed movement; C5a and LTB4

Opsonizing agents

IgG, C3b; enhance phagocytosis

Neutrophils, monocytes, macrophages

receptors for IgG, C3b

O2-dependent MPO system

most potent microbicidal system; neutrophils, monocytes

ProductionofsuperoxidefromO2

NADPH oxidase with NADPH cofactor; produces respiratory burst

Nitro blue tetrazolium (NBT)

test for respiratory burst

Superoxide dismutase

converts superoxide to peroxide

Myeloperoxidase

lysosomal enzyme that combines peroxide + Cl to form bleach (HOCl)

Microbicidal defects

chronic granulomatous disease childhood (XR), myeloperoxidase deficiency (AR)

Chronic granulomatous disease

absent NADPH oxidase; no respiratory burst

Chronic granulomatous disease

Staphylococcus aureus not killed (catalase positive)

Chronic granulomatous disease

Streptococcus killed (catalase negative)

Myeloperoxidase deficiency

AR; respiratory burst present; no bleach produced

Opsonization defect

Bruton's agammaglobulinemia (XR, decreased IgG)

Phagocytosis defect

Chediak-Higashi (see cell injury); also has defect in microtubule polymerization

COX inhibitors

non-steroidals (non-selective), selective COX-2 inhibitors

PGE2

vasodilation, fever

PGI2

vasodilator; prevent platelet aggregation

Nitric oxide

vasodilator; FR gas from conversion arginine to citrulline

IL-1 and TNF

fever, synthesis acute phase reactants in liver, leukocytosis

IL-6

stimulated by IL-1; stimulates synthesis of acute phase reactants

Acute phase reactants

fibrinogen, ferritin, C-reactive protein

Bradykinin

kinin produced in conversion of factor XII to factor XI

Bradykinin

pain, vasodilator, vessel permeability; cough/angioedema, ACE inhibitors

Anaphylatoxins

C3a and C5a; directly stimulate mast cell release of histamine

Prostaglandin I2

synthesized by endothelial cells; vasodilator, inhibits platelet aggregation

Lipoxygenase

hydroxylation of arachidonic acid

Zileuton

inhibits lipoxygenase

Zafirlukast, montelukast

block lipoxygenase receptor

LTC4, -D4, -E4

bronchoconstrictors

TXA2

synthesized by platelets; platelet aggregation, vasoconstriction, bronchoconstriction

Dipyridamole

inhibits thromboxane synthase

Corticosteroids

inhibits phospholipase A2, activation neutrophil adhesion molecules

Corticosteroids

neutrophilic leukocytosis, lymphopenia, eosinopenia

Fever

right shift OBC; hostile to bacterial/viral replication

Chronic inflammation

monocyte/macrophage; ↑ IgG; repair by fibrosis

Granuloma

cellular immunity; macrophages interact with TH1 class cells (memory cells)

Positive PPD

Langerhan's cells process PPD and interact with TH1 class cells