Pathology Flashcards
What is hypoxia? What are some causes? How does it lead to cellular injury? What are some other causes of cellular injury?
Cell injury causes: inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations
Low O2 delivery to tissue.
Decreased O2 leads to decr. oxid. phosphor leading to decr. ATP, which leads to cellular injury.
Causes include ischemia, hypoxemia, and decreased O2 carrying capacity
What is anemia? What are the PaO2 and SaO2 like? What is the pathophys of carbon monoxide poisoning? PaO2/SaO2? What are some common causes? Classic finding? Early sign of exposure? Sign of significant exposure? What is the pathophys of methemoglobinemia? PaO2? SaO2? What cuases it? Classic finding? Treatment?
Decrease in RBC mass-PaO2 normal, SaO2 normal
Co binds hemoglobin tighter than O2 can. PaO2 normal and SaO2 decrease.
Smoke from fire; car exhaust; gas heaters
Cherry red skin
Early-headache; significant=coma and death
Iron in heme is oxidized to Fe3+, which cannot bind oxygen. PaO2 normal and SaO2 decr.
Oxidant stress (sulfa and nitrate drugs) or in newborns
Cyanosis with chocolate colored blood
IV methylene blue
Describe how hypoxia leads to irreversible cellular injury. Describe the histology of it.
Low ATP leads to poor functioning of:
Na-K pump, leading to build up of sodium and water in cell.
Ca pump, leading to incr. Ca in cell
Aerobic glycolysis, leading to anaerob. leading to lactic acidosis which results in low pH and denaturing of proteins and DNA
Loss of microvilli and membrane blebbing
Swelling of RER leads to loss of ribosomes and less proteins
What is the hallmark of irreversible injury? What are the results?
membrane damage
PM damage leads to cytosolic enzymes in serum
More calcium in cell
Mitochondrial membrane damage leads to leakage of cytochrome C leading to apoptosis
Loss of ETC
Lysosome membrane damage releases hydrolytic enzymes which are activated by calcium.
All this leads to cell death.
What is the morphologic hallmark of cell death? How does it occur? Waht are the two mechanisms?
Hallmark is loss of the nucleus, which occurs via pyknosis (nuclear condensation), fragmentation (karyorrhexis), and dissolution (karyolysis).
Necrosis and apoptosis.
What is apoptosis? What is the morphology? What is the basic mechanism? Decribe the intrinsic mitochondrial pathway, extrinsic receptor ligand pathawy, and the cytotoxic Cd8 T cell mediated pathway.
ATP dependent genetically programmed cell death involving single cells or groups of cells
Dying cell shrinks, more eosinophilic cytoplasm
nucleus condenses (pyknosis) and fragments
Apoptotic bodies fallf rom cell to macrophages
Intrinsic: Cell injury, DNA damage, or decr. hormonal stim leads to inactivation of Bcl-2 which no longer blocks Bax/Bak whichs allows cytochrome C to leak from inner mitochondrial matrix into cytoplasm and activate caspases.
Extrinsic receptor ligand pathway: FAS ligand binds FAS death receptor on target cell (CD95), which activates caspases (Negative selection of thymocytes)
TNF binds TNF receptor leading to caspases
Cytotoxic CD8: Perforins create pores, granzyme secreted which activates caspases. `
How are free radicals produced in the body? How do they cause cellular injury? How are they eliminated?
Oxid. phosph=cytochrome C oxidase
Ionizing radiation, oxidative burst, metals (copper/iron), drugs and chemicals (P450 system)
Peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis
Antioxidants, enzymes (SOD, Glutathione peroxidase, catalase-peroxisomes), metal carrier proteins
How does CCl4 lead to free radical injury? What is the result? What is it used for?
Dry cleaning
Conv. to CCl3 by P450 in hepatocytes
Cell injury with swelling of RER–>ribosomes detach, which impairs protein synth
Decreased Apolipoproteins leads to fatty change in liver
What is amyloid? Where is it located? What are the shared features of amyloid
Misfolded protein in EC space that damages tissues
Different proteins but have:
beta pleated sheet configuration
Congo red staining with apple green birefringence when viewed microscopically under polarized light
What is primary amyloidosis? Which protein? Derivation? Association? Secondary amyloidosis protein? Derivation/causes? What is FMF? Pathophys? Symptoms?
Wha are the classic clinical findings in systemic amyloidosis? Diagnosis? Treatment?
AL amyloid from Ig light chain
Associated with plasma cell dyscrasias (mult. myeloma)
AA amyloid from serum amyloid associated protein
Chronic inflammatory states, cancer, FMF (familial meditt. fever)
FMF is a dysfunction of neutrophils leading to episodes of fever and acute serosal inflammation (mimics appendicitis, arthritis, MI) leading to high SAA
Nephrotic syndrome
Restrictive cardiomyopathy or arrhythmia
tongue enlargement, malabsorption, and HSM
Tissue biopsy=abdom. fat pad, rectum
Transplantation
What protein is involved in senile cardiac amyloidosis? Symptoms? familial amyloid cardiomyopathy? Non insulin dependent DM? alzheimers? Dialysis associated amyloidosis? Medullary CA of the thyroid?
Non mutated serum transthyretin
Asymptomatic
Mutated serum transthyretin deposits in heart –>restrictive cardiomyopathy (afr. amer)
Amylin (from insulin) deposits in islets of pancrea
A-beta amyloid (from Beta amyloid precursor protein (APP)) deposits in brain forming amyloid plaques.
Beta 2 microglobulin deposits in joints (carpal tunnel)
Calcitonin (produced by tumor cells) deposits in tumor (tumor cells in amyloid background)
How do TLRs lead to acute inflammation? AA metabolites? Mast cells? Hageman factor?
TLRs are present on cells of innate immune system. Activate by PAMPs (LPS to CD14/TLR4)
Activation leads to upregulation of NF-kappa B, a transcription factor leading to immune mediators which are secreted
AA released from phospholipid membrane by PLA2 and then acted on by COX or 5 lipooxygenase
Cox produces PGI2, D2, and E2 which mediate vasodilation and incr. vasc. permeability.
E2 also produces pain and fever
5 lipoxygenase leads to LTB4 which attracts and activates neutrophils and LTC4, D4, and E4 which mediate vasoconstriction, bronchospasm and incr. vasc. perm.
Activated by trauma, IgE crosslinking, and C3a and C5a lead to histamine release which mediates vasodil. and vasc. perm. Later, it release LTs.
Inactive proinflammatory produced in the liver. Actived on exposure to SEC or tissue collagen. It activates coag and fibrinolytic systems, complement, and bradykinin (vasodilation, vasc. perm., and pain)
What are the 4 cardinal signs of inflammation? How are each mediated?
Redness and warmth (vasodilation)
Swelling (vasc. perm)
Pain (bradykinin and PGE2 sensitize nerve endings)
Fever (pyrogens (LPS)) causes macrophages to release IL-1 and TNF, which increase. PGE2 near hypothalamus which raises set temp.
What causes margination? Rolling? Adhesion? Transmigration and chemotaxis, Phagocytosis? How is phagocytosed material destroyed? How is it resolved?
Vasodilation=neutrophils to periphery in postcapillary venules
P-selectin (WP bodies-histamine) and E selectin (TNF and IL-1) on endothelial cells interact with sialyl lewis X on neutrophils
ICAM and VCAM are upregulated by endothelial cells due to TNF and IL-1). Integrins expressed due to C5a and LTB4.
Leukocytes migrate across endothelium (containing PECAM-1) of postcapillary venules then go through chemotaxis following IL-8, C5a, and LTB-4
Opsonization by IgG and C3b
Oxidate burst or O2 independent killign (lysozyme, major basic protein)
Undergo apoptosis and disappear within 24 horus of resolution
When do macrophages arrive/predominate? Waht are 4 outcomes are how do macrophages accomplish them?
Predominate after neutrophils (2-3 days)
Resolution (IL-10 and TGF-beta)
Continued inflammation (IL-8)
Abscess-Fibrogenic growth factors
Chronic inflammation-function as APCs
