Pathology Basics Flashcards
Cell injury; irreversible changes
- Plasma membrane damage (phospholipid membrane degradation);
- leakage of cytosolic enzymes
- Ca+ influx - Lysosomal rupture/autolysis
- Nucleus:
- shrinkage (pyknosis)
- fragmentation (karyorrhexis
- fading (karyolysis) - Mitochondria permeability/vacuolization increases. (swelling alone is reversible)
What causes nuclear fragmentation (karyorrhexis)
Endonuclease mediated cleavage
What is a sensitive indicator of apoptosis
DNA laddering
Apoptosis pathways
Intrinsic (mitochondrial) pathway
Extrinsic (death receptor) pathway
-Both pathways activate caspases (cytosolic proteases)
Intrinsic pathway stimuli
Internal stimuli;
- DNA Damage/stress
- Cytokines (decreased IL-2 after an immunological reaction)
- Injurious stimuli: Toxins, radiation, hypoxia
Extrinsic pathway stimuli
External stimuli; (2 pathways)
A. Extracellular Transmembrane ligands/receptor interaction;
- FASL binding to FAS (CD95)
- TNF-a binding to its receptor
B. T-cell release of perforin and granzyme B
Mitochondrial pathway is regulated by which family of proteins?
BCL-2.
Proapoptotic: BAX and BAK
Antiapoptotic: BCL-2 and BCL-xL
What is the function of BAX and BAK on the mitochondrial membrane?
Form pores in the membrane which allows the release of cytochrome C (leads to activation of caspases)
What is the function of BCL-2 on the mitochondrial membrane?
Keeps the membrane impermeable to keep cytochrome C from leaking out.
BCL-2 overexpression leads to decreased cascade activation which promotes tumor growth. Which malignancy is associated with this overexpression?
Follicular lymphoma t(14;18)
Extrrinsic pathway is regulated by which family of proteins?
TNF (tumor necrosis factor) family;
FAS (CD95)
What is the importance of FAS-FASL interaction in the thymic medulla?
FAS-FASL is important for the elimination of self-reacting T-cells. Normally, self reacting T-cells under go apoptosis. FAS mutation increases the number of self-reacting T cells in the circulation.
What autoimmune syndrome is associated with defective FAS-FASL interaction?
Autoimmune lymphoproliferative syndrome.
Leukocyte extravasation steps
- Margination/rolling
- Adhesion
- Transmigration
- migration
Margination/rolling: Molecules present on the blood vessel wall that serve as “speed bumps” so that rolling leukocytes can slow down to exit the blood vessel and to the site of injury.
Blood vessel:
E-selectin (in endothelial cells)
P-selectin (in platelets and endothelial cells)
Leukocyte:
L-selectin
Silly-Lewis
Adhesion molecules
Blood vessel:
- ICAM (CD54)
- VCAM (CD106)
Leukocyte:
1. CD11/18 integrins;
(LFA-1 and MAC-1)
2. VLA-4 integrin
Transmigration/Diapedesis; leukocyte squeezes through endothelial cells and exits blood vessel. Which molecules are involved in this step?
PECAM-1 (CD31)
Migration: leukocyte is guided to site of injury by ________________
Chemotactic signals
Although macrophage are the dominant mediators of chronic inflammation, they are also present in the late stages of acute inflammation (peak 2-3 days after onset) what is the role of macrophage in acute inflammation?
Influence the outcome of acute inflammation (4 outcomes; Resolution, healing by scarring, abscess formation or progression to chronic inflammation) by secreting cytokines.
Outcomes of chronic inflammation?
Scarring, amyloidosis or neoplastic transformation
Which mediators activate macrophage to create a pro inflammatory response?
INF-gamma (secreted by TH1), TNF
Which mediators activate macrophage to induce an anti-inflammatory response?
IL-4 and IL-13 (Secreted by TH2)
Oncogenes that encode Receptor Tyrosine Kinases. (With the associated neoplasm)
RET
HER2
ALK
Oncogenes that encode Non-Receptor Tyrosine Kinase
JAK2
BCR-ABL
Oncogenes that encode transcription factor
MYCL1
N-MYC
C-MYC
Oncogene that encodes serine/threonine kinase
BRAF
Oncogene that encodes GTPase
KRAS
Oncogene that encodes cytokine receptor (Stem cell growth factor receptor)
C-KIT
Tumor supressor gene that help repair damaged DNA
BRCA1/BRCA2
Which tumor supressor genes prevent cells from dividing too fast (inhibit G1 to S phase progression)
- Rb (Inhibits E2F; transcription factor)
- TP53 (Activates P21 which is a cyclin dependent kinase inhibitor that slows down the cell cycle)
- CDKN2A (P16)
Which tumor supressor gene that inhibits hypoxia inducible factor 1a
VHL
Which tumor supressor gene encodes a transcription factor that regulates urogenital development?
WT1
Tumor suppressor gene that is a major antagonist of PI3K activity
PTEN (phosphatase and tensin homolog) negatively regulates the Pi3k/AKT pathway
Tumor supressor gene that codes for Hamartin protein and Tuberin protein respectively
TSC1 and TSC 2
Tumor supressor gene that codes Ras GTPase activating protein
NF1 (Neurofibromin)
Negative regulator of B-catenin/WNT pathway
APC
Carcinogens that cause hepatocellular carcinoma
- Aflatoxins (aspergillus)
2. Ethanol
Carcinogens that cause angiosarcoma
Vinyl chloride (pipes, plumbers) Arsenic (Herbicides, metal smelting;iron)
Angiosarcoma: cancer that forms in the lining of blood vessels or lymph vessels. Common sites; skin, scalp, neck. Most common occupational association: Vineyard workers (arsenic) and plumbers (vinyl chloride)
Carcinogens causing lung cancer
- Radon (airborne radioactive gas that accumulates in basements)
- Asbestos (Old roofing material, shipyard workers)
- Arsenic (Herbicides, metal smelting;iron)
Cancer caused by radiation exposure from medical imaging equipment, Gamma rays, UV light
Papillary thyroid carcinoma (exposure to ionizing radiation)
Most carcinomas spread through lymphatics with the exception of these four that spread via hematogenous route.
Follicular thyroid carcinoma, Choriocarcinoma, Renal Cell Carcinoma, Hepatocellular Carcinoma.
Phases of wound healing
- inflammatory- up to 3 days after wound
- Proliferative - 3 days to weeks
- Remodeling- 1 week to more than 6 months.
Cells and characteristics most likely seen in day 1 of wound healing
Cells: Platelets, neutrophils, macrophage
Characteristics:
1. Clot formation
- Migration of neutrophils to site of injury (step 4 of leukocyte extravasation)
- Macrophage clear debris 2 days later
Cells and characteristics in proliferative (growth of new tissue) phase of wound healing
Cells: Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophage
Characteristics:
- Clot lyses and is replaced by Granulation tissue
- Collagen type 3
- Epithelialization ( to form a barrier between wound and environment)
- angiogenesis
- wound contraction (mediated by myofibroblasts)
Cells and characteristics seen in Remodeling/ maturation phase of wound healing.
Cells: Fibroblasts
Characteristics:
- Collagen 1 (replaces collagen 3 increasing tensile strength)
- Collagenases (require zinc to function) break down collagen 3
- No zinc = no collagenases = collagen 3 doesn’t break down = delayed wound healing and decreased tensile strength.
Part of kidney most susceptible to ischemia
Medulla
- Straight part of proximal tubule
- Thick ascending limb
