Week 1 Flashcards
The most common type of genetic variation among humans is ___ and they can help predict a persons risk of a particular disease or their response to certain medications
There is also ___, which are different numbers of large contiguous stretches of DNA, but less is known
^**These are important for determining the function of genes and the elements that regulate them throughout the genome in order to serve as markers for disease risk for multigenic complex disease
SNPs (Single-nucleotide-polymorphisms)
CNVs (Copy-number-variations)
____ are tightly packed and transcriptionally inactive forms of chromatin and ___ are loosely packed and transcriptionally active forms of chromatin
** DNA is wound around an octomeric histone core, and this core (which consists of 8 histones each) makes up. Single nucleosome… The nucleosomes are connected to each other via DNA linkers and H1 linker histones, and these linked nucleosomes are what make up chromatin (if it is tightly packed = heterochromatin, and if it is loosely packed = euchromatin)… These chromatin then make up the chromosome
Heterochromatin, Euchromatin
Proteins act as enzymes, structural components, and signaling molecules but only make up 1.5% of the genome
The other 98.5% of the non-protein coding sequences include
1) Promoter and Enhancer regions that provide the binding site for ____
^** Promoters initiate gene transcription and enhancers are regulatory elements that can modulate gene expression over distances
2) Binding sites for factors that organize and maintain higher order chromatin structures
3) Can regulated gene expression even though they aren’t translated into proteins and include ___ and ____
4) Jumping genes that are implicated in gene regulation and chromatin organization called ___
5) Chromosome ends called ___ and chromosome tethers called centromeres that are special structural regions
Most genetic variation is associated with these non-protein-coding regions of the genome, and it’s called ____
1) TFs
3) Micro-RNAs and Long Noncoding RNAs
4) Mobile genetic elements (aka transposons)
5) Telomeres
Polymorphisms
Heritable changes in gene expression (aka in a chromosome) that is not caused by alterations in DNA sequencing is called ___
The relative state of DNA unwinding, to make them active or inactive, is done via histone modification
Histones can be methylated (lysine and arginine), acetylated (lysine), or phosphorylated (serine) and DNA can be ____, which normally leads to transcriptional ____ (activation or inactivation?)
^** However, note that these modifications are reversible
Histone ___ tends to open up and activate transcription (Via HATs) vs Histone ____ tends to condense and inactivate transcription
^ HDACs deacetylase and therefore lead to inactivation.
**^ MicroRNA is both epigenetically regulated (most), but could also be classified as a polymorphism
Epigenetics
Methylated, inactivation
Acetylation, Methylation
Micro RNA (miRNA) are transcribed but not translated and once cleaved by ___ and then compelxed with ___, the miRNA perform ___transcriptional ____ of the mRNA gene expression in order to breakdown the mRNA and block its translation (aka gene silence)
If the RISC complex matches the target mRNA perfectly, it ___ the mRNA and if it is an imperfect match, it ____ the mRNAs ability for translation… Both lead to gene silencing
^*LncRNA (Long Noncoding RNA is another noncoding regulatory RNA that can silence or increase transcription etc.)
DICER, RISC, Posttranscriptional silencing
Cleaves, represses
___ is normally restricted to the inner face (cytoplasm face) and contains a ____ charge, but if it flips to the extracellular face (which occurs during apoptosis) it becomes an “eat me” signal for phagocytes
Phosphatidylserine, negative
Name if it is expressed out the extracellular surface (outer leaflet) or cytoplasmic surface (Inner leaflet) or both for the cell membrane
1) Phosphatidylcholine
2) Phosphatidylethanolamine
3) Phosphatidylserine
4) Sphingomyelin
5) Gylcolipids
6) Cholesterol
7) Phsophatidylinositol
1) Outer
2) Inner
3) Inner
4) Outer
5) Outer
6) Both
7) Both
Remember, small/nonpolar/hydrophobic molecules can cross the lipid membrane via passive diffusion
If the molecules are hydrophilic, larger than 75 KDs, or charged then they must use ____ proteins that create a hydrophilic pore to cross the membrane or ___ proteins that bind the solute and change conformation to cross the membrane
Certain small molecules, like vitamins/GPI molecules/CAMP proteins/SRC kinases/Folate receptors, can be taken up in ___ via endocytosis (also called potocytosis aka cellular sipping), which are non-coated plasma membrane invaginations associated with taking up extracellular fluid, membrane proteins, some receptors, etc.
Two other forms of endocytosis are pinocytosis (aka cell drinking) or receptor mediated endocytosis (surface receptor ligand pairs) and both of these involve ___-coated pits and vesicles
LDLs are taken up via ____
Channel, Carrier
Caveolae
Clathrin
Receptor mediated endocytosis
There are three major classes of cytoskeletal proteins
1) ___ microfilaments, which form from the ___ protein G-actin and these G-actin momoners noncovalently polymerize into long ___ called F-actin that intertwine to form double-stranded helices with a defined polarity
^** One example of the F-actin is myosin in muscle cells
2) _____ filaments have characteristic tissue-specific patterns of expression that can be useful for assigning a cell of origin for poorly differentiated tumors (ex: Vimentin, Desmin, Neurofilaments, Cytokeratins, etc)
^** Found mainly in a polymerized form within cells and impart tensile strength and allow the cells to bear mechanical stress
3) ___ that act as connecting cables for “molecular motor” proteins that use ATP to move vesicles, organelles, or other molecules around cells along microtubules
1) Actin, Globular, Fillaments
2) Intermediate
3) Microtubules
____ filaments are important for tensile strength and allows the cells to bear mechanical stress
^** They also form the major structural proteins of the skin and hair
___ A, B, and C are important for maintaining nuclear morphology and regulating normal nuclear transcription
___ is found in mesenchymal cell like fibroblasts or endothelium
___ is found in muscle cells, forming the scaffold on which actin and mysoin contract
Neurofilaments are found in axons of neurons for strength and rigidity
Glial fibrillary acidic proteins are found in glial cells and around neurons
Cytokeratins are found in many cells and can be used as cell markers
Intermediate
Lamin
Vimentin
Desmin
Cell-cell interactions occur via junctions to provide mechanical links and enable surface receptors to recognize ligands on other cells and are organized into 3 basic types
1) ____ seal adjacent cells together to create a continuous barrier that restricts the paracellular (between cells) movement of ions and other molecules. They also segregate the apical vs basolateral domain to maintain cell polarity
2) ___s mechanically attach cells and their intracellular cytoskeletons to other cells or to the extracellular matrix (ECM)
^ Cell-ECM = Hemidesmosome, Cell-Cell broad band = Belt desmosome, Cell-Cell small and rivet like = Spot desmosome
3) ___s mediate the passage of chemical or electrical signals from one cell to another (like in cardiac myocytes) aka signaling is between adjacent cells via hydrophilic connexons that permit the movement of small ions (like calcium), various metabolites, and potential second messengers like cAMP, but not large macromolecules
1) Tight junctions (aka occluding junctions)
2) Desmosomes (Anchoring junctions)
3) Gap junctions (Communicating junctions)
Cell-Cell desmosomal junctions are formed by homo-typic association of transmembrane glycoproteins called ____ and for ___-desmosomes the transmembrane adhesion molecule is called E-cadherin, which is associated with intracellular actin microfilaments that can influence cell shape/motility
In hemidesmisomes, the transmembrane connector proteins are called ___ and these also attach to intracellular intermediate filaments to functionally link the cytoskeleton to the ECM
Cadherin, Belt
Integrins
New proteins destined for the plasma membrane or beyond, are synthesized in the ___ via membrane-bound ribosomes on the cytosolic face of the RER (to translate the mRNA into proteins) and assembled in the ___
^** Cis Golgi recycles proteins back to the ER and Trans golgi sorts proteins and lipids and dispatches them to other organelles or secretory vesicles destined for extracellular release
**Proteins intended for the cytosol are synthesized on free ribosomes
___ molecules retain proteins in the ER until the modifications (like protein folding or disulfide bonds forming or oligosaccharides attached) are complete and proper conformation is achieved. If this fails, the protein is retained and degraded in the ER
^** If to many misfolded proteins accumulate, the ER stress response occurs (also called UPR- Unfolded protein resposne) that triggers cell death
** The SER isn’t very important except for synthesizing steroids, catabolizing lipid soluble molecules, and sequestering intracellular calcium
RER, Golgi
Chaperone
____ are intracellular organelles that contain degradative enzymes (acid hydrolases) that permit the digestion of a wide range of macromolecules
^**Fuse with endosomes and phagosomes
____s are specialized cell that selectively chews up denatured proteins, releasing peptides
Proteasomes degrade ___ proteins via tagging them with ____ molecules
Lysosomes
Proteasomes
Cytosolic, ubiquitin
*** Pinocytosis or receptor mediated endocytosis leads to the internalization of contents inside a vesicle, and the vesicle matures and acidifies, which is called an ___ (Early endosome -> Late endosome -> EndoLysosome)
Macrophages or neutrophils can take microbes into a cell via ____ and once internalized is called a phagosome (Phagosome -> Phagolysosome)
Both of these vesicles (endosome or phagosome) can meet with a lysosome in a process called ____ to facilitate the degradation of the internalized contents*
___ is the endcytotic transport of solute and/or bound ligand from one face of a cell to another
Endosome
Phagocytosis
Heterophagy
Transcytosis
Senescent organelles and large denatured protein complexes are shuttled into lysosome in a process called ___ (Senescent organs or Denatured proteins -> Initiation complex and nucleation complex promotes the nucleation of the autophagosomal membrane -> Elongation and closure of the autophagosomal membrane via the microtubule-associated protein light chain 3 aka ___ -> Mature Autophagosome -> Fusion with endosome that turns into a lysosome aka an autophagolysosome -> Degradation via lysosomal enzymes)
^** Autophagy is an adaptive response, triggered by nutrient depletion (to preserve cell viability by allowing the cell to cannibalize itself to survive) or certain intracellular infections (aka host defense against certain microbes)
Autophagy
LC3 **(Useful as a marker for cells undergoing Autophagy)
If there is an external cellular injury (toxic, ischemia, or trauma), mitochondria can be damaged and this leads to the insertion of ____ pores that allow the dissipation of the ___ potential so that ATP can’t be produced and the cell dies in a process called ____
Discussed later, but if mitochondria are damaged via intrinsic pathways (DNA damage or Intracellular stress) or also extrinsic pathways (Cytotoxic T cells or Inflammatory Cytokines) the mitochondria become leaky and ___ leaks into the cytosol of the cell, where it forms a complex with other prtoeins that eventually induce ____
^** Failure of programmed cell death = malignancy and Premature cell death = Neurodegenerative disease
Membrane permeability transition pores (in the outer membrane), Proton, Necrosis
Cytochrome C, Apoptosis
Vitamin D and steroid hormones bind to ___ receptors that are transcription factors that are activated by lipid-soluble ligands that can easily cross the plasma membrane
Transmembrane proteins with extracellular domains that bind soluble secreted ligands are called ___ receptors
Intracellular
Cell-surface
Cellular receptors are grouped into several types based on the signaling mechanisms they use and the intracellular biochemical pathways they activate
1) ___s are integral membrane proteins that cross-link once a ligand binds and activates intrinsic tyrosine kinase domains located in their cytoplasmic tail (Insluin, Epidermal growth factor, PDGF)
2) ___ have no intrinsic catalytic activity and instead phosphorylate specific motifs on the receptor or other proteins (Rous Sarcoma Virus - SRC and include SH2 and SH3 domains)
3) ____s are 7-transmembrane domain that causes cAMP or IP3 downstream to be activated (pharmacologic targets)
4) ___ receptors bind lipid soluble ligands and the complex can bind directly to nuclear DNA (Breast cancer)
5) ____ recognizes a ligand on a distinct cell and then gets cleaved, and the intracellular fragment enters the nucleus and forms a transcription complex
6) Wnt protein ligands can influence cell development via a pathway involving Frizzled, which when activated releases intracellular ___ that then migrates to the nucleus and acts as a TF
^** Lrp5 and 6 act as coreceptors for the WNT/Frizzled pathway ((LDL receptor related proteins)
1) Receptor tyrosine kinases
2) Non-RTKs
3) G-proteins
4) Nuclear
5) Notch
6) B-Catenin
For RTKs, a ligand binds to the receptor -> Dimerization and auto-phosphorylation of the tyrosine residues -> Bridging protein attatches RTK to inactive ___ with GDP bound -> GDP is then dissociated and GTP binds to activate the RAS -> RAF -> MAPK -> Activates gene transcription -> Cell cycle progression
^** RAS can also activate -> PI3K -> Akt -> mTOR -> Gene transcription
** Also note if a mutation in the ability for RAS to hydrolyze GTP occurs, then it won’t become inacrtive and proliferative signaling can occur
RAS
*** COME BACK TO THIS ONCE CHAPTERS 1-3 ARE COMPLETE
Name the growth factor * THIS IS A LOT, MAYBE THE NEXT CARD WOULD BE MORE USEFUL
1) Comes from activated macrophages, salivary glands, kertinocytes, etc and is mitogenic for keratinocytes and fibroblasts (also stimulates keratinocyte migration and formation of granulation tissue)
2) Comes from activated macrophages, keratinocytes, etc and stimulates the proliferation of hepatocytes (liver cells) and other epithelial cells
3) Comes from fibroblasts, stromal cells in the liver, and endothelial cells and enhances proliferation of hepatocytes and increases cell motility
4) Comes from mesenchymal cells and stimulates the proliferation of endothelial cells (lines interior surface of blood vessels and lymphatic vessels) and increases vascular permeability
5) Comes from platelets, macrophages, endothelial cells, smooth muscle cells, and keratinocytes and is chemotactic (movement in response to a chemical stimulus) for neutrophils, macrophages, fibroblasts, and smooth muscle cells; along with activates and stimulates proliferation of fibroblasts and endothelial cells; and finally it stimulates ECM protein synthesis
6) Comes from macrophages, mast cells, endothelial cells, etc and is chemotactic and mitogenic for fibroblasts and stimulates angiogenesis and ECM protein synthesis
7) Comes from fibroblasts and stimulates keratinocyte migration, proliferation, and differentiation
8) Comes from platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, and fibroblasts and is chemotactic for leukocytes and fibroblasts and stimulates ECM protein synthesis and suppresses acute inflammation
1) EGF (Epidermal growth factor)
2) TGF-Alpha (Transforming growth factor-alpha)
3) HGF (Hepatocyte growth factor)
4) VEGF (Vascular endothelial growth factor)
5) PDGF (Platelet-derived growth factor)
6) FGF (Fibroblast growth factor)
7) KGF (Keratinocyte growth factor)
8) TGF-Beta
1) Mutations or amplifications can occur in lung, head, neck, breast, and brain cancers
2) MET is the receptor and over expressed in kidney and thyroid cancer
3) Induces blood vessel development after injury and tumors
4) Recruits cells to sites of tissue injury and inflammation
5) Can lead to acrhondroplasia and malignancies
6) Drives scar formation and applies the breaks on inflammation that accompanies wound healing “pleiotripic with a vengeance”
1) EGF (Epidermal growth factor)
2) HGF (Hepatocyte growth factor)
3) VEGF (Vascular endothelial growth factor)
4) PDGF (Platelet-derived growth factor)
5) FGF (Fibroblast growth factor)
6) TGF-Beta
The Extracellular Matrix has various functions including
1) Mechanical support
2) **Controlling cell proliferation (along with locomotion and/or differentiation) via binding and displaying ___ to their receptors, which can then activate cytoplasmic signal transduction pathways to the nucleus and mediate cell signaling
Or cellular receptors of the ___ family that can interact with the cytoskeleton at ___ complexes to directly transduce signals in the nucleus (cytoskeleton-mediated signals) or these Integrins can also produce intracellular messengers that act on the nucleus as well **
3) Scaffolding for tissue renewal due to the ____ and this also helps establish tissue micro-environments via acting as a boundary between the epithelium and underlying connective tissue for both support and function
2) Growth factors
Focal adhesion, Integrin
3) Basement membrane
For components of the ECM, the interstitial matrix is synthesized via ___
^** It includes Collagens, Elastin, Proteoglycans, and Hyaluronans
The ____ is synthesized by contributions from the overlying epithelium and underlying mesenchymal cells
^** It includes Type 4 Collagen, Laminin, and proteoglycans
Mesenchymal cells (aka Fibroblasts)
Basement Membrane
Fibrillar ____ forms a major portion of the connective tissue in various structures and the process is dependent on ____, so if one is deficient they can have skeletal deformities or bleed easily leading to various diseases like Osteogenesis Imperfecta or Ehlers-Danlos syndrome
___ is able to allow tissues to recoil and recover their shape after physcial deformation. If defective, it can lead to weak aortic walls or skeletal defects like in Marfan Syndrome
^**Collagen and elastin are grouped as fibrous structural proteins
___ forms highly hydrated compressible gels that resist compressive forces and also serves as a reservoir for growth factors secreted into the ECM.
^** They are made up of long polysaccharides, attached to a core protein, linked via hyaluronic acid polymer
Finally, adhesion glycoproteins include Fibronectin, Laminin, and Integrins
Collagens, Vitamin C
Elastin
Proteoglycans
For the cell cycle, starting at G1 we have RNA and Protein synthesis/Cell growth -> Restriction point (If adequate amount of growth factors are present, cell passes through the restriction point) -> G1 checkpoint (corrects any DNA damage before continuing aka chemical modifications) -> S Phase for DNA replication and Chromosome duplication -> G2 phase for Preparation before mitosis (aka premitotic growth) -> G2 checkpoint (verifies completeness of complete genomic duplication aka checks for damaged of unduplicated DNA) -> Metaphase checkpoint (ensures chromosomes are attached to mitotic spindle) -> M phase for mitosis/cell division
The ___-___ complex is necessary for cell cycle progression and the cyclins are proteins that regulate the CDKs and when the complex forms, they can phosphorylate protein substrates (kinase activity) for continuation of the cell cycle
____s bind to G1 and S phase Cyclin-CDK complexes to inactivate the kinase activity of CDK
^** If CDKI checkpoint proteins are defective, damaged DNA can divide and lead to tumors
Cyclin-CDK
CKIs (CDK inhibitors)
Fibroblast growth factors are chemotactant and mitogenic agents for fibroblasts and stimulate ECM protein synthesis and some angiogenesis
FGF can be released when the ECM is damaged, and then the FGFs can bind to ___. These FGF-heparan sulfate complexes can bind to FGF receptors to transduce signals, or they can bind to a cell surface proteoglycan called ___, which has a tail that interacts with the intracellular actin cytoskeleton and can also influence the nucleus
Heparan sulfate, syndecan
Cyclin __-CDK__ and Cyclin ___-CDK___ are active in the G1 phase
Cyclin ___-CDK__ is for the G1-S transition phase
Cyclin __-CDK__ is active in the S phase and Cyclin ___-CDK__ is active in the end of S phase and G2 phase
Cyclin ___-CDK___ is for the G2-M transition phase
___ inhibitors (a class of CDKIs) including P16, P15, P18, and P19 can act on D-CDK4 and D-CDK6 and three other inhibitors including P21, P27, and P57 can inhibit all CDKs
D-CDK4 and D-CDK6
E-CDK2
A-CDK2, A-CDK1
B-CDK1
INK4
___ stem cells are ___potent cells that are present in the inner cell mass of the blastocyst
^** Realize that pluripotent stem cells are equivalent to embryonic stem cells in that they can give rise to any cell type. If one were to take multipotent stem cells and use iPS reprograming factors, they could turn them back into pluripotent cells… But not totipotent cells
*AKA linage goes Toti-Pluri->Multi->Unipotent
Tissue stem cells aka adult stem cells are ____potent
The most common studied adult stem cells are ____ stem cells that can give rise to other blood cells or ___ stem cells that can differentiate into a variety of stromal cells (connective tissue cells of any organ) including Chondrocytes-cartilage, osteocytes-bone, adipocytes-fat, myocytes-muscle, etc
Embryonic, Totipotent (aka they can differentiate into whatever they want)
Multipotent
Hematopoietic, mesenchymal
There are 4 building blocks for pathology including
1) ___, which is the cause
2) ___, which is the biochemical and molecular mechanisms of the development aka the sequence of the event
3) ___, which is the structural alterations induced in the cells and organs of the body
4) Functional consequences of these changes, which is called clinical manifestations aka functional derangement
1) Etiology
2) Pathogenesis
3) Morphology
Normal cells are maintained in homeostasis, and if stressed than the cells can undergo ____, which can result in various outcomes including
1) Increasing the cell and organ size is called ___ and occurs in tissues incapable of cell division.
2) Increase in number called ____ and occurs in tissues whose cells can divide or contain abundant tissue stem cells
^** If a stimulus or injury occurs that causes an increase in demand or increase in stimulation (like growth factors or hormones), than hypertrophy and hyperplasia can occur
3) Decrease in cell or organ size and metabolic activity called ____
^** If a stimulus or injury results in decreased nutrients or stimulation
4) Change in the phenotype of the cells called ___
^** If a stimulus or injury is a chronic irritation (physical or chemical) this can occur
^**Cell injury can be reversible, but if prolonged, it can become irreversible and cell death (necrosis or apoptosis) can occur due to ischemia, infection, or toxins
^*Also note, calcium is often deposited at sites of cell death resulting in pathologic calcification
Adaptation
1) Hypertrophy
2) Hyperplasia
3) Atrophy
4) Metaplasia
Adaptation due to increased workload (Such as in bodybuilders or the uterus of a pregnant women) would induce ___
This adaptation is the result of increased production of cellular proteins (like transcription factors) induced via growth factors, Agonists (ex: hormones), and Mechanical stretch.
These proteins that are produced in myocardial hypertrophy lead to an increase in genes that are expressed only during ___ development (aka induction of embryonic/fetal genes like ANF **AKA GENE ACTIVATION) to ___ mechanical performance and ____ workload, and increase in the synthesis of ___ proteins to ___ mechanical performance, and also more growth factors produced for positive feedback
^** SO REALIZE THAT HYPERTROPHY REQUIRES ___ SYNTHESIS (contractile proteins specifically), GENE ACTIVATION (early fetal genes specifically), AND NEW ORGANELLES**
Hypertrophy
Early, increase, decrease, Contractile, increase
PROTEIN
____ often occurs in conjunction with hypertrophy, but unlike hypertrophy, it occurs in tissues whose cells are able to divide or contain abundant stem cells
It can be physiological or pathological
1) Physiological hyperplasia occurs when there is a need to increase functional capacity of hormone sensitive organs like puberty or pregnancy for breast development; or when there is a need for compensatory increase after damage or resection like in a liver transplant
^** So a liver transplant with the cells regenerating would be classified as ___
2) Pathologic hyperplasia is from excessive or inappropriate actions of hormones or growth factors acting on target cells like in endometrial hyperplasia
^**It is growth factor driven proliferation of mature cells, or it can result from increased output of new cells from tissue stem cells
Hyperplasia
Compensatory hyperplasia
Atrophy can be
1) ___ like in development of the notochord or decrease in uterus size after pregnancy
2) Or it can also be ____ due to decreased workload aka atrophy of disuse (like in a cast), denervation, Ischemia, **inadequate nutrition, loss of endocrine stimulation (like after menopause)*****, and pressure
The goal is to balance the cells metabolic needs with the lower levels of blood, nutrition, trophic stimulation, etc.. To allow the cells to survive even though function is diminished
^** Mechanisms is via ___ protein synthesis and ____ protein degradation (via ubiquitin-proteasome pathway aka Autophagy)
^**Finally, atrophy is often accompanied by increased ___, which is the process in which starved cells eats their own components in an attempt to reduce the nutrient demand to match the supply
Physiological
Pathologic
Decreased, Increased
Autophagy
When one cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment, it is called ___ and the most common is ___ epithelium to ___ epithelium as occurs in the respiratory tract in response to chronic irritation
^** Often sections that have been changed to a different epithelium can be predisposed to metaplasia and thats why respiratory tract cancer is often composed of squamous cells
Can also occur in Barret’s esophagus (Squamous -> Columnar)
Metaplasia occurs via reprogramming stem cells that are known to exist in normal tissues or undifferentiated mesenchymal cells present in connective tissue (It does not occur via changing a phenotype of an already differentiated cell)
Metaplasia, Columnar -> Squamous
When a cell has decreased oxidative phosphorylation (and therefore decreased ATP) and cellular swelling (due to changes in ion concentration and water influx), along with fatty changes (blebbing) the cell is in the ____ stage
If the injury is beyond repair, apoptosis or necrosis can occur
In ___, there is an inflammatory response due to the contents leaking out, but in ____ there is no inflammatory response since no content leaks out
^** Also, necrosis is always pathologic but Apoptosis can be physiologic along with pathologic
Reversible cell injury
Necrosis, Apoptosis
For Necrosis, the cell size ___ (swells or shrinks?), the plasma membrane is ____ (Intact or disrupted?), cellular contents are ___ (Leaked or intact?), inflammation ___(does or does not?) occur, and is ___ (always or sometimes) pathologic
For Apoptosis, the cell size ___ (swells or shrinks?), the plasma membrane is ____ (Intact or disrupted?), cellular contents are ___ (Leaked or intact?), inflammation ___(does or does not?) occur, and is ___ (always or sometimes) pathologic
^** So realize that for morphological features of apoptosis include cell shrinkage, cytoplasmic blebs and apoptotic bodies, and the most important morphological feature is chromatin ____.
Swells, disrupted, leaked, does, always
Shrinks, Intact (with an altered structure), intact (can be released in apoptotic bodies), does not, sometimes (either pathologic or physiologic)
Condensation
For cell injury, at first the injury can be reversible but as cell function declines and duration of injury increases, eventually the cell injury becomes irreversible
First, biochemical alterations lead to cell death. It can then be seen via ___ changes, then after a longer duration ____ changes can be seen, and finally ____ changes can be seen
**Two features of reversible cell injury can be recognized under the light microscope including cellular ____ and ___ change (via the appearance of ___ in the cytoplasm, which are pinched off segments of the ER and is called hydropic change or vacuolar degeneration)
Ultrastructural, light microscopic, gross morphological
Cellular swelling and fatty change, lipid vacuoles
The ___ changes of ___ cell injuries include Plasma membrane alterations (blebbing or loss of microvilli), mitochondrial changes (swelling), Dilation of the ER (myelin figures present), and nuclear alterations (disaggregation of granular and fibrillar elements), along with eosinophilia (due to decreased cytoplasmic RNA)
For irreversible changes leading to necrosis, one is likely to see increased eosinophilia, nuclear shrinkage (pyknosis, karyorrhexis, and karyolysis), fragmentation and dissolution, breakdown of the plasma/organellar membranes, abundant ___ figures (which are dead cells replaced by large, whorled phospholipid masses), and leakage and enzymatic digestion of cellular contents
Ultrastructural, reversible
Myelin figures
3 types of nuclear changes can occur in necrosis
1) ___ is when the basophilia of the chromatin fade and this means DNA has been lost due to nucleosomes
2) ___ is when the nucleus shrinks and basophilia is increased (can also be seen in apoptosis) and therefore chromatin condenses into a solid mass
3) ___ is when then pyknotic nucleus undergoes fragmentation
1) Karyolysis
2) Pyknosis
3) Karyorrhexis
********Name the type of distinct pattern necrosis
1) A type of necrosis in which the architecture of dead tissue is preserved for a span of at least a few days due to the injury denaturing structural proteins and enzymes that BLOCK proteolysis.
^**Effected tissues exhibit a firm texture
^** A localized area of coagulative necrosis is called an ___
^** Often seen from ischemic injury (but not in the CNS)
2) Opposite of Coagulative necrosis, this necrosis is characterized by the DIGESTION of dead cells that transforms the tissue into a liquid viscous mass. Occurs via actions of degradative enzymes and attracted leukocytes
^** Contains a creamy yellow material made of dead leukocytes called ___
^** Occurs in the CNS a lot
3) Necrosis that is not specific, but simply refers to a limb that has lost its blood supply and undergone necrosis.
^** Usually is it due to coagulative necrosis, but if a bacterial infection causes liquefactive necrosis it is called a ___
4) This necrosis if most often associated with infections like tuberculosis and has a yellow-white and “cheese-like” appearance. It appears as an area of structureless collections of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border, known as a ___
5) White, chalky deposits that are focal areas of fat destruction is this type of necrosis and usually occurs due to the release of activated pancreatic lipase into the substance of the pancreas and the peritoneal cavity
6) Necrosis seen in immune reactions involving blood vessels that occurs when complexes of antigens and antibodies are deposited in the walls of arteries. Has a bright pink and amorphous appearance
ALMOST ALL ISCHEMIC NECROSIS IS ____ NECROSIS
1) Coagulative necrosis, Infract
2) Liquefactive necrosis, pus
3) Gangrenous necrosis, wet gangrene
4) Caseous necrosis, Granuloma
5) Fat necrosis
6) Fibrinoid necrosis
COAGULATIVE
Decreased oxygen and nutrients, mitochondrial damage, and the actions of some toxins can lead to the fundamental cause of necrotic cell death, which is a reduction in ____ levels
Various things happen when ATP is decreased including
1) Decreased ATP levels leads to a decreased in the plasma membrane energy-dependent sodium pump, leading to an influx of Ca2+ and ___ and an eflux of __ (since normally the pump brings in 2K for every 3Na) and this causes H20 to follow the net gain of solute, which causes the cell to swell and dilation of the ER
2) Increased rate of ___ in order to maintain the cells energy source by generating ATP via glucose metabolism from glycogen and this ___ glycogen levels (since it uses it up), ___ lactic acid levels (since it is a byproduct), and ____ pH (since lactic acid levels are increasing) and this can cause clumping of nuclear chromatin
3) Structural disruption of the protein synthetic apparatus occurs leading to the detachment of ribosomes from the RER leading to ___ protein synthesis
REALIZE ISCHEMIA OFTEN EFFECTS THE MITOCHONDRIA THE MOST
ATP
Na, K
2) Anaerobic glycolysis, decreases, increases, decreases (more acidic)
3) Decreased
There are three major consequences of mitochondrial damage including
1) The ____ pore causes loss of membrane potential and therefore loss of oxidative phosphorylation and decreased ATP
^** Cyclosporin can block these pores and possible prevent injury due to a graft rejection
2) Decreased oxidative phosphorylation leads to increased production of ___
3) Increased permeability of the outer mitochondrial membrane can result in leakage of Cytochrome C into the cytosol, that can activate caspases and lead to ___
1) Mitochondrial permeability transition pore
2) ROS
3) Apoptosis
Normally, intracellular Ca2+ is very ___, but if ischemia or toxins injur the cell, the concentrations can increase due to release from intracellular stores (like mitochondria and the ER) and increased influx across the plasma membrane
^** This causes an increased in mitochondrial permeability via the pores leading to decreased ATP, and also activation of various enzymes (Phospholipases, proteases, endonucleases, ATPases, Caspases) leading to membrane damage and nuclear damage
Low
Radiation, Toxins, and Repercussion can create ROS and the 4 most important ones are O2- (superoxide), H2O2 (Hydrogen Peroxide), OH (Hydroxyl radical), and ONOO- (Peroxynitrite anion)
There are various mechanisms to prevent ROS from accumulating in the cell including
1) Antioxidants, which include __ and ___
2) Binding of free iron and copper to storage and transport proteins in order to prevent the generation or ROS
3) O2 converted to H2O2 and O2 via the enzyme ___
4) H2O2 converted to H2O and O2 via the enzyme ___ in peroxisomes or ___ in the cytosol and mitochondria
5) Conversion of OH (hydroxyl radical) to H2O by ___
1) Vitamin A and E
3) SOD (Superoxidase dismutase)
4) Catalase, Glutathione Peroxidase
5) Glutathion Peroxidase
If ROS do in fact accumulate, various damaging results occur including
1) ____, which leads to membrane damage
2) ____ of proteins can lead to miss-folding and subsequent breakdown
3) Lesions in the DNA leading to damage and possible mutations
1) Lipid Peroxidation
2) Oxidative modification
There are various mechanisms that can destroy a cell’s membrane including
1) ROS via ___ (when double bonds in unsaturated fatty acids of membrane lipids are attacked by O2 free radicals)
2) ___ phospholipid synthesis
3) ____ phospholipid degradation, which occurs due to the fact that increased cytosolic ___ levels activate ____
4) Increased Ca2+ can also activate ___, which cause cytoskeletal damage to effect the membrane
All these mechanisms can destroy the three most important membranes including ____ membranes that leads to opening of transition pores and decreased ATP, ___ membranes that leads to loss of cellular components and loss of osmotic balance/influx of fluids and ions, and ___ membranes that results in leakage of their enzymes into the cytoplasm that cause digestion of cellular components
1) Lipid peroxidation
2) Decreased
3) Increased, Ca2+, Phospholipases
4) Proteases
Mitochondrial, Plasma, lysosomal
To determine if a injury is reversible vs irreversible, there are two consistent phenomena, which include
1) The inability to reverse ____ dysfunction (lack of oxidative phosphorylation and ATP generation)
2) Profound disturbances in ___ function
**Also note the accumulation of damaged DNA and misfolded proteins can trigger apoptosis
1) Mitochondrial
2) Membrane
___ and ___ injury is the most common type of injury due to reduced blood flow, often from a mechanical arterial obstruction
^** Normally, in just hypoxia, cells can undergo anaerobic glycolysis but if it’s in conjunction with ischemia, the delivery of substrates for glycolysis is compromised so no ATP at all can be produced.
___ is chest pain when your heat muscle doesn’t get enough oxygen rich blood and results in a myocardial infraction
Elevated levels of ___ and ___ are markers for myocardial infractions
Ischemic and Hypoxic
Angina
Troponin and CKMB (Also Lactic acid can show up)
In a ischemia-___ injury, the restoration of blood flow actually exacerbates the injury and causes cell death (even though the restoration of blood flow to ischemic tissue can often promote recovery of cells if they are reversibly injured)
^** This occurs due to new damaging processes that are set in motion during reperfusion, causing the death of cells that might have recovered otherwise and include Oxidative Stress (from leukocytes and endothelial cells), Intracellular Calcium Overload, Inflammation, and Complement System activation (IgM)
Reperfusion
There are two major pathways for apoptosis including the ___ pathway (mitochondrial) and the ___ pathway (Death receptor)
1) For the intrinsic pathway… First, cell injury due to growth factor withdrawal, DNA damage (via toxins, radiation, or ROS), or misfolded proteins activate BCL2 family sensors (referred to as ___-Only proteins), and these sensors realize that the cell is damaged and then antagonize the anti-apoptotic proteins (like BCL2) and activate the pro-apoptotic proteins (BCL2 family effectors) including ___ or ___, which then promote mitochondrial outer membrane permeability which allows Cytochrome C and other Pro-apoptotic proteins to leak into the cytoplasm, where they activate ____, with the main initiator caspase being caspase ___ and the executioner caspase being caspase ___, which then induce apoptosis by activating endonucleases to cut the DNA and breaking down the cytoskeleton.
Cytoplasmic blebs then bud off and form apoptotic bodies, which have ligands for ___ cell receptors so that they can be degraded
Regulators (aka anti-apoptotic proteins) are stimulated via growth factors or other survival signals and include ___ or ___
Intrinsic and Extrinsic
BH3-Only proteins, BAX or BAK, caspases, 9, 3
Phagocytic
BCL2 or BCL-XL
2) For the extrinsic pathway…. The engagement of plasma membrane death receptors (a family of the ___ receptors) occurs.
The best example of this pathway is via the ___ receptor and the ___ ligand that is present on T cells for recognizing self antigens (and eliminate self-reactive lymphocytes) and Cytotoxic T lymphocytes (to kill virus and tumor infected cells)
For this pathway, Fas binds to FasL and brings together a death domain called ___, which binds an inactive form of caspase __ (caspase 10 in humans) and then this inactive caspase turns into an active caspase and then activates executioner caspases, which eventually leads to apoptosis
^** Mutations in Fas or FasL result in autoimmune diseases
TNF
Fas, FasL
FADD, 8
Like we already said, cell injury can activate the ___ apoptotic pathway
1) ____ deprivation (like hormone sensitive cells with no relevant hormones, lymphocytes not stimulated by antigens or cytokines, or neurons with no nerve growth factor)
2) DNA damage via radiation or chemotherapeutic agents, which involves the tumor suppressor gene called ___. Since the protein ___ accumulates in DNA damaged cells, it can arrest the cell cycle at the __ phase and cause apoptosis via activating BAX, BAK, and some BH3-only proteins if the damage can’t be repaired
^** If the TP53 gene is mutated or absent, the cells can’t undergo apoptosis if DNA damage occurs***
Also realize the TP53 can stop the cycle at other points rather than kist G1**
3) Unfolded or misfolded proteins due to decreased energy stores, genetic mutations in proteins or chaperones, viral infections, or chemical insults; normally are ubiquinated and targeted for proteolysis in proteasomes. However, if they accumulate in the ER they can trigger a cellular response called the ___ response, discussed on the next notecard. If the Unfolded protein response fails as an adaptation mechanism (aka the accumulation of misfolded proteins is to large), then apoptosis will occur in a process called ER stress
Intrinsic
1) Growth factor
2) TP53, p53, G1
3) Unfolded protein
Cellular adaptation via the unfolded protein response causes an ___ production of chaperons (to allow mature protein folding), an ___ in proteasomal degradation of abnormal proteins, and ___ in protein synthesis (aka a slowing of protein translation)
Remember, if the protein folding demand becomes greater than the protein folding capacity, the ___ process leads to apoptosis
Increased, increase, decrease
ER stress
___ is programmed necrosis
The process starts with ligation of a receptor by its ligand (TNFR1) or triggered by viral proteins of DNA and RNA viruses
Then the recruitment of 2 unique kinases called __ and ___ (receptor associated kinase 1 and 3) and caspase 8 form a complex, however, ___ (high or none?) activation of the caspase occurs..
^** If it were to be activated, apoptosis would occur
Finally terminal events similar to necrosis including permeabilization of lysosomal membranes, generation of ROS, damage to the mitochondria, and reduction of ATP levels
^** It also induces an inflammatory reaction due to release of contents
Necroptosis
RIP1 and RIP3, none
One of the manifestations of metabolic derangements in cells in the intracellular accumulation of abnormal amounts of various substances and includes 4 main pathways
1) Abnormal ___ aka the inadequate removal of a normal substance, secondary to defects in mechanisms of packaging and transporting these substances can lead to a fatty liver (excess triglycerides or cholesterol aka both are lipids)
^** The most common disease associated with this is ___ change in the ___ due to alcohol abuse; along with nonalcoholic fatty liver disease which is associated with diabetes and obesity
2) Due to genetic or acquired defects in folding, packaging, transport, or secretion of substances, the accumulation of endogenous substances (specifically proteins) appear as rounded, eosinophilic droplets, vaculoes, or aggregates in the cytoplasm
Such as misfolded proteins in ___ deficiency or ___ bodies which are plasma cells constipated with immunoglobin proteins
^** Hyaline cartilage is a descriptive term that refers to an alteration within cells or in the extracellular space that gives a homogenous, glassy, pink appearance in the staining and intracellular accumulations of proteins are one example
3) Failure to degrade a metabolite due to inherited ___ deficiencies and result in diseases called ___ diseases
^** Can result in glycogen deposition if macrophages with defects in lysosomal enzymes that break down glycogen exist
4) Deposition and accumulation of an abnormal exogenous or endogenous pigment when the cell has neither enzymatic machinery to degrade the substance or the ability to transport it to other sites
^*Examples of exogenous substances include anthracosis from carbon or tattoos on the skin
^*Endogenous substances include ____ (a yellow-brown lipid due to free radical injury and lipid peroxidation), ___ (the only brown-black endogenous pigment), or ___ (a hemoglobin derived golden yellow-to-brown granular crystalline pigment that is one of the major storage forms of iron aka hemosiderin forms from excess iron)
1) Metabolism, Fatty change (aka Steatosis) in the liver
2) Alpha1-Antitrypsin, Russell
3) Enzyme, storage
lipofuscin, melanin, hemosiderin
So just to recap, name if the substance is exogenous (comes from outside the body) or endogenous (synthesized within the body itself)
1) Anthracosis (accumulation of carbon) - seen in coal miners
2) Lipofuscin - a yellow-brown lipid indicative of free radical injury or lipid peroxidation
3) Melanin - brown black pigment formed via melanocytes
4) Tattoos on the skin
5) Hemosiderin - Golden yellow-to-brown pigment formed from excess iron
1) Exogenous
2) Endogenous
3) Endogenous
4) Exogenous
5) Endogenous
____ is another word for fatty change and the cells show a well preserved nucleus squeezed into the displaced rim of the cytoplasm about the fat vacuole
^** Occurs from alcohol abuse or diabetes/obesity
Cholesterol can also accumulate in the cells and is seen in atherosclerosis, xanthomas, cholesterolosis (gallbladder disease), and niemann-pick disease (type c)
Intracellular accumulations of ___ appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm and include Russell bodies, misfolded proteins (like in alpha 1 antitrypsin deficiency, amyloidosis, etc…)
^** Intracellular accumulations of protein is an example of a descriptive histological term called ___ deposits
___ is often deposited in diseases like diabetes mellitus or glycogen storage diseases
Pigments can also accumulate in cells and this is discussed in another card
Steatosis
Proteins
Hyalin
Glycogen
Pathologic calcification has two main forms including
___ calcification, which occurs locally in dying tissues (aka occurs in areas of necrosis)
Serum levels of calcium are ___ and in the absence of derangements in calcium metabolism (often a telltale sign of previous cell injury resulting in necrosis and can be a cause of organ dysfunction)***** So in others words, if you see Dystrophic calcification it means there was a previous injury OR it could mean an ongoing organ dysfunction like if you see it in a valvular disease it means some heart problem is going on
^** Like in a valvular disease from artherosclerosis, aging or damaged heart valves, or tuberculous lymph nodes
___ calcification is the deposition of calcium salts in normal tissues and is a result of ____ secondary to some disturbance in calcium metabolism
Macroscopically ___ calcification looks like tiny, white, gritty granules
Microscopically both calcifications look similar with basophilic granules, amorphus granular, and sometimes clumped appearance
Dystrophic
normal
Metastatic, hypercalcemia
Dystrophic
In dystrophic calcifications sometimes so much calcium is deposited that ____ bone can be formed
**** Sometimes, single necrotic cells can act like little grains of sand around which a “pearl” of calcium is deposited and this is called a ___ which are common in ___ carcinomas *****
So if one were to have a thyroid carcinoma and you don’t know if its follicular or papillary and you see psammoma bodies, it is then known to be papillary
Psammoma, papillary
Metastatic calcification results from hypercalcemia secondary to some disturbance in calcium metabolism, with the 4 most common being (Name them)
1) Increased PTH secretion via parathyroid tumors or ectopic secretion of PTH-related protein malignant tumors
2) Secondary to primary tumors of bone marrow (multiple myeloma or leukemia) or diffuse skeletal metastasis (breast cancer), accelerated bone turnover (paget disease), or immobilization
3) Sarcoidosis, toxicity, or abnormal sensitivity to Vitamin D
4) Retention of phosphate leading to secondary hyperparathyroidism
1) Hyperparathyroidism
2) Resorption of bone
3) Vitamin D disorders
4) Renal failure
Cellular aging can result from various mechanisms including
1) ___ damage and defective DNA repair from ROS, Carcinogen exposure, Sporadic erros, etc and eventually leading to mutations
2) Cellular ___ due to the fact that all cells have a limited capacity for replication and eventually become arrested in a terminally nondividing state; which can lead to telomere shortening, activation of tumor suppressor genes (p16) and decreased cellular replication, eventually leading to cell loss
3) Defective protein ___ due to decreases in mechanisms that degrade misfolded proteins (proteasomes) and decreases in mechanisms that maintain proteins in their proper folded conformation (chaperones), eventually leading to decreased cell functions
^** ___ sensing is actually shown to decrease cellular aging due to a ___ in the Insluin/IGF1 signaling intensity, ___ mTOR (mammalian target of rapamycin), and ___ in sirtuins that all lead to altered transcription and eventually an increase in DNA repair and increase in protein hemostasis
1) DNA
2) Senescence
3) Homeostasis
Nutrient, decrease, decrease, increase
Asthma, which can be both an acute and chronic disorder, is due to ___ antibodies released from ____
^**Lymphocytes and macrophages (and possibly antibodies) can also lead to chronic conditions such as arthritis or atherosclerosis
IgE, Eosinophils
For an acute inflammatory response, cells express receptors in the ___ for extracellular microbes, ___ for ingested microbes, and ___ for intracellular microbes
All cells have cytosolic sensors that recognize molecules (uric acid, ATP, DNA, or K+) indicative of cell damage and these cells activate an ___, which then goes on to increase proinflammatory cytokines and adhesion molecules
Plasma membrane, endosomes, cytosol
Inflammasome
The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavity is known as ___ and this fluid is ___ in protein content
___ is another type of fluid low in protien content (most which is albumin)
Exudation, High
Transudate
The acute inflammatory response causes dilation of small vessels to increase blood flow (mainly via histamine on vascular smooth muscles)
^** This is the cause of heat and redness (aka erythema)
Vasodilation is quickly followed by increased permeability in the microvasculature with the outpouring of protein rich fluid
Eventually, the loss of intravascular fluid combined with the dilation of the vessels, leads to a SLOWER blood flow and buildup of red blood cells moving slowly, which is called ___ and as stasis develops, it allows neutrophils and other leukocytes to move peripherally in the vessels
Stasis
For the migration, rolling, and adhesion of leukocytes to the endothelial cells, different ligands and receptors are expressed
On the endothelial cells, ___ and ___ are expressed and on the leukocyte ___ is expressed. The ligands are bound to the opposite cell
^** This has a low affinity for adhesion, but allows the leukocytes to slow down their rolling
These adhesion molecules are expressed due to the secretion from macrophages, mast cells, and endothelial cells of several cytokines including mainly ___ and ___, along with chemokines (*that have a different function discussed below)
Once the leukocytes are slow enough they can undergo firm adhesion by binding to ___ on the endothelial cells via their ___ (which are activated via ___ binding to endothelial cell proteoglycans)
Finally, the leukocytes move through the endothelium into the extravascular site, which is called transmigration (or diapedesis) and this process is facilitated via ____
E-selectin and P-selectin, L-selectin
TNF and IL-1
ICAM (Integrin Ligands), Integrins, chemokines
PECAM-1 (aka CD31)
Once the leukocytes exit the circulation, they move towards the site of injury via a chemoattractants (like cytokines, components of the complement system, arachidonic acid, or metabolites) in a process called ____
Once they reach the microbe or dead cells, the leukocytes become activated and can either phagocytosis the microbes or undergo intracellular killing of the microbes
For phagocytosis, three steps occur
1) Recognition and attachment (microbes bind to their phagocyte receptors including mannose, scavenger, or opsonin receptors)
2) Phagocyte membrane zips up around the microbe to form a ___, which then meets up with a ___ to form a phagolysosome
3) Killing and the degradation of the microbes, which is accomplished via ___ , ___, and lysosomal enzymes/proteins
^** ROS are produced from NADPH oxidase, reducing oxygen to superoxide anion, which spontaneously converts to H2O2, which is converted via MPO (myeloperoxidase) to Hypochlorite and this destroys microbes via halogenation or oxidation (therefore, the H202-MPO-Halide system is the most efficient bactericidal system of neutrophils)
^** NO is produced from arginine by nitric oxide synthase (NOS) and the major NOS involved in killing microbes is iNOS
^** Lysosomal enzymes are contained in primary (azurophilic) or secondary (specific) granules and the enzymes are prevented from destroying healthy tissue via antiproteases like alpha1-antitrypsin
Chemotaxis
2) Phagosome, lysosome
3) ROS and NO
When a cell is injured and a mast cell becomes activated, it releases mainly ___ that causes vasodilation, increases vascular permeability, and endothelial activation (Histamine can also be released from basophils and platelets, along with some serotonin release)
Histamine
There are thee major phagocytotic receptors including
1) The ___ receptor binds to LDL particles and macrophage integrins (MAC-1 aka CD11b/CD18)
2) The ___ receptor binds to terminal manose and fucose residues of glycoproteins and glycolipids
3) The ___ receptor binds to IgG antibodies, C3b complement products, or mannose-binding lectin
Also realize when lipid mediators, chemokines, or N-formylmethionyl peptides bind to their receptors it initiates both integrin activation for adhesion to the endothelium and chemotaxis for migration
1) Scavenger
2) Mannose
3) Opsonin
Arachidonic acid can be cleaved from phospholipids after a stimulus to the cell membrane via the enzyme ____
Once A.A is cleaved, it can be converted to prostaglandins via ___ or 5-HPETE via ___
Phospholipase A2
Cyclooxygenase (COX1 or COX2), 5-Lipoxygenase
For the prostaglandins…
1) ___ causes vasodilation and inhibition of platelet aggregation
2) ___ causes vasoconstriction and promotion of platelet aggregation
3) ___ causes uterine contraction
4) ___ and ___ causes vasodilation and increased vascular permeability
^** PGE2 also plays a role in temp and pain sensation
1) PGI2 (think I = inhibits and I = d I lates )
2) TxA2
3) PGF2a
4) PGE2 and PGD2
The leukotrienes which are created from 5-HPETE include…
1) ___, ___, and ___ cause vasoconstriction
2) ___ is the major chemotactic agent and activator of neutrophils, along with leukocyte adhesion
3) ___, ___, ___ causes increased vascular permeability
Also formed from 5-HPETE are Lipoxin A4 and Lipoxin B4, which play a role in inhibiting ___ via inhibiting neutrophil chemotaxis and adhesion to the endothelium
^** AKA it acts like an off switch
1) LTC4, LTD4, LTE4
2) LTB4
3) LTC4, LTD4, LTE4
Inflammation
NSADIs like ibuprofen, aspirin, or indomethacin inhibit ___ and therefore inhibit prostaglandin synthesis
Steroids inhibit ____
Montelukast, an inhibitor of ___ receptors by acting as an antagonist and can be an important treater of asthma since C4, D4, and E4 can cause bronchospasms
^** Zileuton, which is a lipoxygenase inhibitor is also important in treating asthma
COX1/2
Phospholipase A2
Leukotrienes
Macrophages and monocytes, along with some other cells, release ___ and ___ that plays a critical role in leukocyte recruitment to the endothelium and their migration through the vessels, along with activation of leukocytes and other cells, and finally both have overlapping systemic effects (fever, decreased appetite, increased acute phase proteins, etc.)
^** IL-1 is most important in fevers and TNF is the major player for increasing endothelium dilation
Macrophages and other cells also produce ___, which is important for systemic effects such as the acute phase proteins
___ is produced by T-lymphocytes and is important for recruiting neutrophils and monocytes
^***NOTE THAT ALL OF THESE CYTOKINES/CHEMOKINES ARE INVOLVED IN ____ INFLAMMATION
IL-1 and TNF
IL-6
IL-17
Acute
___ are the most important for leukocyte recruitment to sites of inflammation and migration of the cells in normal tissue (even though some cytokines also have this role)
Chemokines
The ___ system is a collection of soluble proteins and membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions
All thee pathways of complement activation lead to the formation of an active enzyme called ___, which cleaves C3 into ___ and ___
Complement
C3 convertase, C3a and C3b
In the complement system, there are three types of pathways
1) Triggered by fixation of C1 to an antibody like IgM or IgG that has combined with an antigen
2) Triggered by microbial surface molecules (endotoxins or LPS), complex polysaccharides, or cobra venome; In the absence of an antibody
^** AKA microbial cell walls active pathway (so gram negative or gram positive microbes)
3) Plasma mannose binding lectin (MBL) binds to carbs on microbes and directly activates C1
** All these pathways produce ____ and ___, which result in inflammation and chemotaxis to cause recruitment and activation of leukocytes and then destruction of the microbes by the leukocytes
^** These are called anaphylatoxins since they activate histamine as well
___ and its inactive form, act as opsonins to promote phagocytosis of the microbe by neutrophils and macrophages that have cell surface receptors for the complement fragments
The formation of the ___ makes the microbes permeable to water and ions and results in lysis of the microbe
^** C1 inhibitors (C1 INH) block C1, which is the first protein in the classical pathway, and can cause hereditary angioedema.
Also, Decay Accelerating Factor (DAF) prevents the formation of ____ and CD95 prevents the formation of ___and both are linked to the plasma membrane via ____ anchors so if this becomes defective, excessive complement activation and lysis or red cells will occur and the disease PNH (paraxysmal nocturnal hemoglobinuria)
1) Classical pathway
2) Alternative pathway
3) Lectin Pathway
C3a and C5a
C3b (inactive form is iC3b)
MAC
C3 convertase, MAC
TABLE 3-7 PAGE 90 IS A GREAT FUCKING TABLE TO KNOW
SO FUCKING KNOW IT
Kinins, which are vasoactive peptides derived from plasma proteins called kininogens, have vascular reaction and pain responses and one important kinin is ___, which ___ vascular permeability and causes ___ of smooth muscle, ___ of blood vessels, and ___ when injected into the skin
Bradykinin, increases, contraction, dilation, pain
The morphologic hallmarks of acute inflammation reactions are the dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissue
There are also 4 special patterns superimposed on the general features of acute inflammation depending on the disease
1) The exudation of cell poor fluid
^**A skin blister is an example
2) A fibrinous exudate that developed due to large vascular leaks and a local procoagulant stimulus
^** Characteristic in lining of body cavities like meninges, pericardium, or pleura
3) Produces pus
^** Acute appendicitis is an example
4) Local defect/excavation of the surface of an organ or tissue that is produced via sloughing of inflamed necrotic tissue
1) Serous inflammation
2) Fibrinous inflammation
3) Purulent (suppurative) inflammation/abscess
4) Ulcer
1) In serous inflammation, it is marked by the exudation of cell ___ fluid into spaces of injury (so in other words, the fluid is not infected with destructive organisms or lots of leukocytes)
^** Accumulation of fluid in these cavities is called ___
2) In a fibrinous exudate, there are deposits of ___ along the tissue due to the fact that this is associated with a greater increase in vascular permeability so large molecules like fibrinogen can pass out of the blood and be deposited in extracellular spaces.
^** A fibrunous exudate is characteristic of inflammation in the lining of the ___, including the meninges, pericardium, or pleura and if left for to long, it can form scar tissue
3) Purulent inflammation is characterized by the production of ___, which is an exudate consisting of neutrophils, liquefies debris of necrotic cells, and edema
^** The most frequent cause of purulent inflammation is an infection from a ___ that causes ____ tissue necrosis
^** ___ are localized collections of purulent inflammatory tissue
4) Ulcers can only occur when tissue necrosis and resultant inflammation exit on or near the ___ and common in the mouth, stomach, GI tract, or skin of elderly
1) Poor
Effusion
2) Fibrin
Body cavities
3) Pus
Bacteria, Liquefactive
Abscesses
4) Surface
___ and ___ are anti inflammatory mediators that terminate the acute inflammation reaction when it is no longer needed
IL-10 and TGF-Beta
In contrast to acute inflammation, which is characterized by vascular changes, edema, and mainly ___ infiltration….
Chronic inflammation is characterized by
1) Infiltration of mononuclear cells including dominantly ____, along with ___ and ___
2) ___ destruction
3) Attempts at healing by ___ tissue replacement of damaged tissues accomplished by proliferation of small blood vessels called ___ and in particular, fibrosis
Neutrophils
1) Macrophages, plasma and lymphocytes
2) Tissue
3) Connective, angiogenesis
Macrophages are tissue derived from Progenitor cells in the yolk sac and fetal liver during early development, where they most likely populate the tissues as resident macrophages where they stay for long periods in the steady state. As development continues and during times where injury occurs, hematopoietic stem cells in the bone marrow can give rise to monocytes that go to their respected tissues and turn into macrophages
They have different names depending on where in the body they are found
1) Circulating in the blood = ___
2) Liver macrophages = ___
3) In the spleen and lymph nodes = ___
4) In the CNS = ___
There are two types of macrophages, M1 and M2
M1 is stimulated by microbes and ___ mainly and is most likely the macrophage activated in innate and adaptive immunity to kill the microbes via ROS, NO, and Lysosomal enzymes… Along with its role in inflammation via IL-1, IL-12, IL-23, Chemokines, etc.
M2 is activated via ___ and ___ mainly and secretes ___ and growth factors for tissue repair and fibrosis, along with secreting ___ and ___ for anti-inflammatory effects
1) Monocytes
2) Kupffer cells
3) Sinus histiocytes
4) Microglial cells
IFN-Gamma
IL-13 and IL-4, TGF-Beta, TGF-Beta and IL-10
CD4+ T cells have an important role in amplifying the immune response along with their role in humoral immunity and cellular immunity
For this chapter, we need to recognize that ____ induces TH1 cells, which produce they cytokine ___, which activates more macrophages via the classical pathway
TH2 secrete ___, ___, and ___, which recruits eoinophils, plays a role in asthma responses, and activates M2s
^** Therefore this is important for defense against helminthic parasites in allergic reactions
Th17 produce IL-17 in order to induce secretion of chemokines for recruiting neutrophils and monocytes into the reaction
*** So realize that activated T cells can recruit macrophages via IL-17, TNF, chemokines, etc… AND also activate them via IFN-Gamma
IL-12, IFN-Gamma
IL-4, IL-5, and IL-13
___ cells are important for defense against intracellular microbes
____ cells are important for defense against helminthic parasites
____ cells are important for defense against Extracellular bacteria and fungi
Th1
Th2
Th17
Eosinophils are abundant in immune reactions mediated by ___ and in ___ infections
^** Contains eosinophilic granules with major basic protein inside
IgE, parasitic
___ inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis and they form due to a cellular attempt to contain an offending agent that is difficult to eradicate
^In granulomas, ___ cells (macrophages that developed abundant cytoplasm and begin to resemble epithelial cells) along with ___ (fused, multinucleated macrophages) are present**
Also note there are two types of granulomas, ___ granulomas (which are not associated with T-cell mediated immune responses) and occur from sutures, talc aka a type of intravenous drug abuse, or other large fibers.
The other granuloma is a ___ granuloma, which is an immune response most often from an agent that is difficult to eradicate like a persistent microbe or a self antigen
Granulomatous
Epithelioid cells, giant cells
Foreign body
Immune
******Activate macrophages in granulomas will have a pink granular cytoplasm with indistinct cell boundaries, called ____ because they resemble the epithelia
These epithelioid cells (macrophage aggregates) are surrounded by ___
Often, the fusion of multiple activated macrophages result in multinucleated ___ cells are also found in granulmoas and are called ___ giant cells ****
Epithelioid
Lymphocytes
Giant, Langhans
******In granulomas associated with certain infectious organisms, such as Myobacterium Tuberculosis, a combination of hypoxia and ROS injury leads to ____ necrosis (shown as a cheesy like appearance grossly and an amorphous, structureless, eosinophilic, and complete loss of cellular details microscopically) *****
Some diseases with granulomas like Crohns, Sarcidosis, and foreign body reactions do not have necrotic centers and are therefore called _____ granulomas
SO IF YOU SEE CASEOUS NECROSIS, YOU THINK GRANULOMA, AND THEN YOU THINK CHRONIC INFLAMMATION
Caseous
Noncaseating
Name the type of necrosis that would be seen
1) Tuberculosis
2) Brain infract (Due to ischemia)
3) Infract (due to ischemia) in any tissue except brain
4) Acute pancreatitis
5) Immune reaction in vessels
6) Entire loss of blood to lower limbs
7) Loss of blood supply to lower limbs due to coagulative necrosis
8) Loss of blood supply to lower limbs due to bacterial infection (resulting in liquefactive necrosis)
9) Firm tissue and microscopically cells have their outlines preserved (looks gohstly) and everything else looks red
10) Pus due to lost of neutrophils are seen
11) Chalky-white areas
12) Garnulomas are seen in this type of necrosis and is indicative of a ___ inflammatory response
13) Vessel walls are thickened and pinkish-red
14) A granuloma is observed, with no necrotic center
^** See in Chron’s disease, sarcoidosis, and foreign body reactions
1) Caseous
2) Coagulative
3) Liquefactive
4) Fat
5) Fibrinlid
6) Gangrenous
7) Dry Gangrene
8) Wet gangrene
9) Coagulative
10) Liquefactive
11) Fat
12) Caseous, chronic
13) Fibrinoid
14) Noncaseating
Both acute and chronic inflammation is associated with cytokine-induced systemic reactions that are collectively called the ____ repsonse/reaction
The cytokines ___, ___, and ___ are important mediators of this acute-phase reaction along with some type 1 interferous
Acute-phase
TNF, IL-1, and IL-6
Three major things happen in the systemic response to inflammation
1) A prominent manifestation like LPS an exogenous pyrogen which can stimualte leukocytes to secreted IL-1, IL-6 and TNF which are endogenous pyrogens, gets relayed to the hypothalamus, where ___ is increased and therefore arachidonic acid is cleaved and ___ are created to cause a FEVER
2) Acute phase proteins are another systemic effect and activated via mainly ___, although IL-1 and TNF can have some influence.
These proteins are mainly produced in the ___ and include ___, ____, ____, and ___ and these can bind to the microbial cell wall and act as opsonins to fix complement
3) Accelerated release of cells from the bone marrow postmitotic reserve pool can lead to ___ and occurs from colony-stimulating factors
1) COX, PGE2
2) IL-6
Liver, CRP (C-reactive protein)/fibrinogen/SAA (Serum Amyloid Assocaited protein)/Hepcidin
3) Leukocytosis
The clinically important acute-phase proteins have beneficial effects during acute inflammation, but prolonged production in states of chronic inflammation can be harmful
1) Elevated CRP can put one at risk for ___
2) Elevated fibrinogen can cause ____ formation by binding to RVS and cause them to form stacks (rouleaux) that sediment more rapidly and therefore can be used to measure the ___ as a simple test for an inflammatory response caused by any stimulus
3) ** Elevated SAA can cause ____
4) Elevated hepcidin can cause ___ due to the fact that it reduces the availability of iron
1) MI (myocardial infract)
2) Rouleaux, ESR (Erythrocyte sedimentation rate)
3) Secondary amyloidosis
4) Anemia
For leukocytosis, if the number of WBCs reaches 40k-100k it can actually look like leukemia and is called a ___ reaction and therefore they must be distinguished
A rise in the number of more immature neutrophils in the blood is referred to as a ___ shift
*** 1) If the infection is a bacterial infection, ___ can occur
2) If the infection is a viral infection, ____ can occur
3) If the infection is a allergy or parasite infection, ____ can occur
^** Decreased white cells is called leukopenia
leukemoid
Left
1) Neutrophilia
2) Lymphocytosis
3) Eosinophilia
Intravascular coagulation, hypotensive shock, and Insluin resistance/hyperglycemia is the triad known as ___ and occurs due to severe ___ infections that cause IL-1 and TNF to be produced in large quantities
^** Will be discussed in more details later
Sepsis, Bacterial
Tissue repair can occur via two mechanisms
1) ___ via the proliferation of cells that survive the injury and retain the capacity to proliferate or tissue stem cells can mature to regenerate the tissue
^So as we just said, the regeneration of injured tissues and cells involves proliferation and this is driven by ___ and is critically dependent on the integrity of the ___ and stem cell maturation… It also involves the cell cycle*
2) The formation of a ___ occurs in tissues that are not capable of dividing aka they can’t proliferate and therefore regenerate (like in the brain or heart)
^** Occurs via laying down connective tissue (fibrous tissue)
1) Regeneration
Growth factors, ECM
2) Scar
The ability of tissues to repair themselves is determined by their intrinsic proliferative capacity and there are three groups for this
1) ___ tissues are continuously dividing tissues and include ___ stem cells in the bone marrow and the majority of ____ cells (such as those found in the skin/oral cavity/vagina/cervix = stratified squamous, GI tract/uterus/fallopian tubes = Columnar, Salivary glands/pancreas/biliary tract = Cuboidal, and Bladder/urinary tract = Transitional)
2) __ tissues are quiescent aka in the G0 stage of the cell cycle and can respond to injury or loss of tissue mass. They are located in the ___ of most solid tissues including the liver, kidney, and pancreas; along with endothelial cells, fibroblasts, and smooth muscle cells
3) ___ tissues have their repair dominated by scar formation since these cells are considered to be terminally differentiated and nonproliferative in postnatal life
^** Include the majority of ___ muscle cells and ___
1) Labial, Hematopoietic, surface epithelial
2) Stable, parenchyma (aka the functional parts of an organ)
3) Permanent
Cardiac, neurons (aka the brain and heart)
If one were to undergo a hepatectomy due to a liver tumor or liver transplant, there are two mechanisms that will allow the liver to regenerate
1) ___ of the residual hepatocytes
^** For hepatocyte proliferation, polypeptide growth factors and cytokines trigger the events (the exact mechanism is discussed in another card)
2) Or if the proliferative capacity is lost such as in chronic liver injury or inflammation, liver regeneration from ___ cells (can come from canals of hering)
1) Proliferation
2) Progenitor
** For the proliferation of the liver, there are multiple steps
1) First is the ___ phase, where TNF activates ___ cells to release ___ that acts on the hepatocytes to make these cells able to respond to growth factor signals
2) In the second, aka ___ phase, growth factors like ___ and ___ that are produced via various cells act on the primed hepatocytes to stimulate cell metabolism and the entry of the cells into the cell cycle (Quiescent hepatocytes in the G0 phase go to-> G1 -> S phase of DNA replication)
^** The wave of hepatocyte replication is followed by nonparenchymal cell replication (like kupffer, endothelial, stellate cells, etc) along with various activation of genes needed for a functional liver
3) The final stage is the ___ phase, where the hepatocytes return to their original quiescent state and the antiproliferative cytokine TGF-Beta is most likely involved
1) Priming, Kuppfer (the macrophages of the liver), IL-6
2) Growth factor, HGF and TGF-Alpha
3) Termination
The process of angiogenesis is as follows
1) First, NO promotes vasodilation and ___ produces increased vascular permeability
2) Next, the ___ separate from the abluminal surface and the breakdown of the basement membrane and ECM via ___ allows the formation of a vessel to sprout
3) Next VEGF and FGFs (Fibroblast growth factors) stimulate the migration and proliferation of ___ cells and its leading “tip” and also Notch signaling helps guide the “tip” and endothelial cells behind it to have proper spacing etc.
4) Next, pericytes for small vessels and smooth muscle cells for larger vessels are recruited to the elongating vascular stalk for the synthesis of the ECM via various factors like Angiopoietins (ANG1 and ANG2), PDGF, etc
5) Suppression of the endothelial proliferation and migration and the continued synthesis of the ECM occurs via ___ and the deposition of the basement membrane
1) VEGF (Vascular endothelial growth factor)
2) Pericytes, Metalloproteinase (MMPs)
3) Endothelial
5) TGF-Beta
For the steps in scar formation, first ____ aka the formation of new blood vessels occurs to supply nutrients and oxygen to support the repair process…
^** Newly formed vessels are leaky due to incomplete interendothelial junctions and VEGF increasing vascular permeability and this can be a reason for edema even after the acute inflammatory response has subsided
2) The formation of ___ tissue occurs, which consists of the migration and proliferation of ___, deposition of ___ tissue (aka ___ is the most common), along with the newly formed vessels and some leukocytes
3) ___ of the connective tissue produces a stable fibrous scar
1) Angiogenesis
2) Granulation, fibroblasts, loose connective, collagen
3) Remodeling
The most important cytokine for synthesis and deposition of connective tissue proteins is ___ and it stimulates ___ migration and proliferation (remember, it inhibits endothelial cell migration and proliferation), increases the synthesis of collagen and fibronectin, and decreases the degredation of the ECM by inhibiting ___ (which is called a TIMP)
^** It also has antiinflammatory properties
TGF-Beta, Fibroblast, MMP (Metalloproteinases)
For the skin, when the wound only involves the ___ layer it is called healing by first intention and involves epithelial regeneration
First, the wound causes a clot, which serves to stop the bleeding and act as a scaffold for migrating cells. This clot contains ___, which acts as a glue to bind platelets to each other and form the clot
Then inflammation occurs and within 24 hours, lots of ___ are seen migrating towards the fibrin clot to phagocytose and release proteolytic enzymes to clear the debris.. Basal cells also show increased mitotic activity to close off the wound
By day 3 and until around day 7, most of the neutrophils have been replaced by ___ and the proliferation phase is well underway, causing angiogenesis, ECM deposition via collagen and fibronectin excreted by ___, granulation tissue formation, and continues epithelialization
^** Migration of fibroblasts to the incision site is driven by chemokines, TNF, TGF-Beta, FGF and PDGF and the fibroblasts are activated by growth factors like PDGF, EGF, TGF-Beta, IL-1, TNF, etc.
Finally, maturation and remodeling occurs
Epithelial
Fibrin
Neutrophils
Macrophages, fibroblasts
Healing by second intention occurs when the cell or tissue loss is more extensive like large wounds, abscesses, ulceration, ischemic necrosis in parenchymal organs, etc… and involves regeneration and scarring
Unlike primary healing, secondary healing is a ___ (more or less?) intense inflammation response, ___ (larger or smaller?) amounts of granulation tissue is formed, a provisional matrix that contains fibrin, plasma, fibronectin, and type 3 collagen at first but then replaced in 2 weeks by mainly ___ collagen, and ** wound _____ occurs *** in which the initial steps of wound contraction involve the formation of a network of ____ with many features in common with contractile smooth muscle cells
^** So note that large amounts of granulation tissue, more extensive scarring, and wound contraction are indicative of healing by second intention*****
More, larger, Type 1, wound contraction, myofibroblasts
The accumulation of excess collagen (aka excessive production of the ECM) can give rise to a raised scare called a ___ scar
And if the scar grows beyond the boundaries of the original wound, it is called a ___
Also, ___ granulation occurs when excess granulation tissue is formed and this can block reepithelialization
Hypertrophic
Keloid
Exuberant
