9/18 Flashcards
Inflammation
Accumulation of fluid, plasma proteins, and WBCs that is initiated by physical injury, infection, or a local immune response
Attempts to remove harmful substances and initiate the healing process
Primary and Secondary Lymphoid Organs
Primary: bone marrow and thymus, where immune cells develop and mature
Secondary: where lymphocytes respond to invading pathogens, spleen, lymph nodes, tonsils
Innate vs. Adaptive Immunity
- Innate: respond rapidly and are not specific for a particular insult/infection
NK cell, neutrophil, mast cell, etc.
Inflammation
- Adaptive: immune response by B and T cells that recognize specific pathogens and generates memory immune responses
Inflammation in Sterile Injuries
Danger Associated Molecular Patterns (DAMPs): intracellular molecules released by damaged cells like HSPs, HMGB1, and DNA
Necrotic cardiomyocyte releases DAMPs after ischemic injury to result in endothelial cell activation, peripheral neutrophil activation, and mast cell degranulation
Two Types of T Cells
2 types of Glycoproteins expressed on the surface
CD4 T Cells: helper T cells, protect us by helping other immune cells work better
CD8 T Cells: cytotoxic T cells, protect us primarily by killing infected and malignant cells
Function of T Cells
Make contact with other cells and inducing them to change
CD8 T cell: kill virally infected cells after contact
CD4 TH1 cell: release cytokines to activate macrophages which can in turn release cytokines
CD4 TH2 cells: release cytokines to B cells to get plasma cell that releases antibodies
Lymphocyte Circulation
B and T cells travel through body in blood and lymph, leave blood through capillaries in lymph nodes
If encounter antigen recognized by its receptor in the lymph node it will stay and become activated
If not then leave lymphoid organ via efferent lymph vessel to the thoracic duct which empties into the left subclavian vein, returning the lymphocyte into circulation
Spleen Anatomy
Red pulp: old/damaged RBCs are removed from circulation
White pulp: where innate and immune cells reside, can respond to pathogens in the blood that is being filtered
Asplenia: lack a spleen, at increased risk of infection by encapsulated bacteria
Cyclin-Dependent Kinases Operation Pathway
Cdk start with ATP and are inactive until binding of phase-specific cyclins then get partially activated, get change in shape of the T loop
Cdk becomes fully activated by phosphorylation from CAK (Cdk activating kinase)
Additional phosphorylation by Wee1 kinase inactivates it, can be counteracted by Cdc25 phosphatase to return to being active
Cycling binding is the limiting event for the activation of CDKs, cycling expression levels vary with phases and kinase activity varies cyclically in turn
Mechanism of action of Cdk inhibitors (CKI)
- Cip/Kip proteins: inhibit the kinase activity of CDK/cyclin complexes
p21, p27, p57
- INK 4 proteins: inhibit the interaction between cyclins and CDKs
p15, p16, p18, p19
- Ubiquitin Ligase: SCF helps degrade p27 CKI
- Ubiquitin Ligase: APC (anaphase promoting complex) destroys M cycling and terminates M phase
Escape from G1 Phase
Mitogen binds to mitogen receptor to activate MAP kinase pathway and induce expression of Myc
Myc increases cyclin D expression to increase G1-Cdk activation, also raises SCF ubiquitin expression to increase p27 degradation and have higher G1/S-Cdk activity
G1-Cdk and G1/S-Cdk phosphorylates retinoblastoma (Rb) to prevent it from locking up E2F (powerful transcriptional activator of genes for S phase like G1/S-cyclin), get positive feedback since increase G1/S-cyclin expression
Cell active and mitogen depravation doesn’t impair proliferation
Alteration in E2F/Rb pathway are common in cancer
Regulation of S Phase
Need to ensure only copy DNA once
Pre-replicating complex: forms during G1 and gone by G2 and M phase, composed of origin replication complex (ORC) plus Cdc6 and MCM
S-Cdk triggers S phase, destroys Cdc6 via SCF/ubiquitin and phosphorylates MCM
S-Cdk high during G2 but reduced after M phase, M-Cdk phosphorylates Cdc6 and McM to prevent additional DNA replication during M phase
During G1 Cdc6 accumulates and the pre-RC is formed but not active since low S-Cdk activity, in the next state S-Cdk is high but Cdc6 is inactivated so the pre-RC is active but not formed
DNA Regulation Checkpoint
M-cyclins stockpile during G2/M
Unfinished replication forks somehow send negative signal to M-Cdk, activates a kinase that inhibits the Cdc25 phosphatase and allows Wee1 to keep M-Cdk in inactive state
Start of M phase Regulation
Inactive M-Cdk becomes activated
M-Cdk activates Polo kinase which activates Cdc25, which activates M-Cdk and causes a positive feedback loop to further activate Polo kinase
M-Cdk also inhibits its own inhibitor (Wee1)
M-Cdk induces assembly of the mototic spindle, chromosome condensation, nuclear envelope breakdown, actin-myosin cytokinesis, and distribution of membranous organelles to daughter cells
Regulation of Sister Chromatid Separation
Anaphase-promoting complex (APC) ubiquitin Ligase activated by M-Cdk cohesin complex keeps chromatids bound at the centromere
At end of metaphase APC targets securin that inhibits securin, a protease that degrades the cohesin complex
Spindle-Attachment Checkpoint
Sensor that detects attachment of kinetochores to microtubules, failed attachment generates negative signal to block anaphase
Mad2 binds unattached kinetochores and blocks Cdc20-APC induced destruction of securin by sequestering Cdc20 away from APC
M-Cdk and Polo kinase release Cdc20 from Mad2 when all kinetochores become attached to the spindle
DNA Damage Checkpoint
DNA damaged by X-rays induces phosphorylation of p53 to remove Mdm2 (the inhibitor for p53)
Active p53 increases transcription of p21 (a Cdk inhibitor protein), which then inactivates G1/S-Cdk and S-Cdk
Basic Blood Vessels
Large arteries: aorta, elastic
Medium arteries: learn in anatomy, up to 8 layers of smooth muscle
Arterioles: one or two layers of smooth muscle, empty into capillaries, contract smooth muscle to control blood flow into capillaries which increases the vascular resistance
Capillaries: smallest vessels, gas and nutrient exchange in the tissues
Venules: move blood from capillaries into small veins, 0.1 mm diameter
Small veins: less than 1 mm diameter
Medium veins: most of what will learn in anatomy, diameter up to 10 mm
Large veins: diameter over 10 mm, hepatic portal vein and superior/inferior vena cava
Basic Structure of Arteries and Veins
- Tunica Intima
A: Endothelium- single cell layer of squamous epithelial cells, lines lumen
B: Basal lamina- thin layer of extracellular tissue made of collagen, proteoglycans, and glycoproteins
C: Subendothelial layer of LCT- in arteries/arterioles this layer contains the internal elastic membrane - Tunica Media: circumferentially arranged smooth muscle cells, thicker in arteries than veins, goes from internal to external elastic membranes
- Tunica Adventitia: made of CT, longitudinally oriented collagen and some elastic fibers, thicker in veins than arteries
Vasa vasorum: Large veins/arteries have a network of blood vessels to supply blood to the cells of the vessel wall
Nervi vascularis: network of autonomic nerves that control the contraction of smooth muscle
Three Types of Capillaries
- Continuous Capillaries: found in muscle, skin, brain, and spinal cord
Endothelial plasma membranes are continuous, tight junctions only allow passage of small molecules, pinocytosis transports larger molecules, have pericytes associated with it
- Fenestrated Capillaries: found in endocrine glands and sites of fluid/metabolite absorption (gallbladder, kidney, and GI tract)
Have pinocytotic vesicles, fenestrations may form when pinocytotic vesicles opens on each side of capillary
Fenestrations may have a thin nonmembranous diaphragm-like structure across its opening, GI tract changes wall thickness and fenestration number during absorption
- Discontinuous Capillaries (sinusoids): found in liver, spleen, bone marrow
Larger and more irregular in shape than other capillaries, larger gaps and more variable in size than fenestrae with discontinuous basement membrane
Liver: Kupffer cells are macrophages, Ito cells store Vitamin A
Two important underlying concepts of capillaries
- Vasomotion
Capillary blood flow, vasodilating factors like NO or low oxygen cause smooth muscle in wall of arteries to relax to get increased blood flow/pressure to the capillaries and some plasma fluid is driven into the surrounding tissue, occurs in peripheral edema
Vasoconstriction of arteriole smooth muscle from norepinephrine or ANS can result in decreased capillary blood flow/pressure, might prevent hypovolemic shock during blood loss
- Density of Capillary Network:
Determines total SA for exchange between blood/tissue and is related to metabolic activity
Liver, kidney, and skeletal/cardiac muscle have extensive capillary networks
Arteriovenous Shunt (AV anastomoses)
Skin, nose, lips, fingertips, penis/clit
Specialized arterioles supply the AV shunt: coiled, thick muscle layer, rich innervation
AV shunt arteriole contraction sends blood to a capillary bed while relaxation sends blood to venule and bypassing the capillary bed
Skin: opening the shunt reduces blood flow to Capillaries and conserves heat
Penis: close AV shunt to direct flow into corpora cavernosa to start erection
Postcapillary venules
Collect blood from Capillaries, characterized by pericytes
Endothelium is the main site of action for vasoactive agents like histamine and serotonin, cause extravasation
Specialized in lymph nodes called high endothelial venules, prominent cuboidal morphology
Lymphatic Capillaries
Numerous in LCT under skin and mucus membranes
Endothelial tubes that lack continuous basal lamina so permeable, open nature supported by anchoring filaments
As lymphatic channels become larger the vessel wall becomes thicker due to the presence of smooth muscle and CT
Vascular Endothelium
Simple squamous epithelium, long axis in direction of blood flow, adhesion molecules and receptors on luminal surface
Activated by bacterial/viral antigens, cytotoxins, complement products, lipids, hypoxia
Release: cytokines, lymphokines, GFs, coagulation factors, vasoconstrictor/dilator
Endothelial Cell Functions
- Selective Permeability: hydrophobic molecules do transcellular transport, hydrophilic molecules need active/facilitated transport or do paracellular transport across tight junctions
Transcellular transport involves pinocytosis (no clathrin) or receptor-mediated endocytosis (use clathrin)
- Prevent thrombosis: have anticoagulant factors like thrombomodulin to prevent coagulation of liquid to solid, have antithrombigenic factors like prostacyclin/tissue plasminogen activator to impair platelet aggregation
Normal Endothelium prevents platelet adherence but damaged Endothelium causes platelets to release prothrombogenic factors like von Wilebrand and plasminogen-activator inhibitor
- Mediates vasoconstriction: endothelins act as autocrine/paracrine activators on endothelial/smooth muscle cells, increased levels of Endothelin-1 (ET-1) does hypertension, atherosclerosis, heart failure, and other more
Endothelins, ACE, prostaglandin H2, thromboxane
- Mediates Vasodilation: NO and prostacyclin
Shear stress of flowing blood along surface causes endothelial cells to release NO that diffuses into tunica media to relax smooth muscle
3 Types of Leukocytes
- Lymphocytes: B cells, T cells, NK
- Granulocytes: neutrophils, eosinophil, basophils
- Monocytes: dendritic cells, macrophages
Hematopoietic Stem Cell
Gives rise to all blood cells in the bone marrow, pluripotent, CD34 (cluster of differentiation) is a surface marker for identification
Become: common lymphoid, myeloid, and erythroid megakaryocyte progenitor
Erythropoiesis
Generation of red blood cells, occurs primarily in bone marrow
Early fetal development: occurs in mesodermal cells of the yolk sac then liver/spleen
Erythropoietin promotes generation of erythrocytes from erythroid megakaryocyte progenitor, given to anemic patients, cytokine in fibroblasts in kidney
Cytokines
Help with differentiation of immune cells, affect behavior of other cells and allow communication
Thrombopoietin
Cytokine that promotes development of megakaryocyte sand then platelets (thrombocytes)
