Inflammation & Repair Flashcards
What enzyme is deficient in Gaucher disease, and what is the resulting protein accumulation?
Gaucher disease is characterized as a deficiency of glucocerbrosidase, which breaks down glycolipids normally found in the PM > abnormal accumulation in macrophages of spleen, BM, etc.
What are the two main hemoglobin derived pigments? Where are each derived from? What can be the cause of their accumulations?
-Hemosiderin- from heme iron; can accumulate as large aggregates of ferritin. Usually accumulates in tissues following hemorrhage. Systemic deposits (either intra- or extra-) can be due to transfusions, hemolytic anemia, increased dietary absorption, and hemochromatosis. -Bilirubin- derived from the heme porphyrin ring. can accumulate from breakdown (hb>heme>biliverdin>bilirubin) increased levels can cause jaundice (clinical hyperbilirubinemia)
What is hemochromatosis?
Too much iron in the body.
Iron overload is usually caused by an inherited condition called hemochromatosis. Excess iron can poison organs, which can lead to conditions such as cancer, irregular heartbeat, and cirrhosis of the liver. Symptoms are related to conditions that arise from iron overload such as diabetes, darkening of the skin, abnormal heart rhythm, or arthritis. Iron can be dropped to safe levels by regularly removing blood from the body.
This endogenous pigment is evidence of lipid peroxidation of polyunsaturated lipids and residual from partially degraded cell membrane lipids.
Lipofuscin Lipid peroxidation is oxidative damage that affects cellular membranes, lipoproteins, and other molecules that contain lipids in conditions with oxidative stress. … Lipid peroxidation is a chain reaction and is created by free radicals influencing unsaturated fatty acids in cell membranes, leading to their damage.
Describe the pathogenesis of dystrophic calcification. Compare dystrophic calcification to metastatic calcification in terms of calcium and phosphate levels in the body.
- Dystrophic calcification begins due to an increase in cytosolic Ca. This calcium can be due to injurious effects on the ER and mitochondria. - Calcium activates phospholipases, which breaks down phospholipids to FFA. - Calcium binds to FFA, forming calcium soaps. Opposed to metastatic calcification, which involves high levels of calcium, in dystrophic calcification, calcium and phosphate levels are normal.
Differentiate between metastatic and dystrophic calcification:
Dystrophic- - normal levels of calcium - mainly occurs in damaged/dead tissue Metastatic: - has an association to hypercalcemia - deposits occur in uninjured tissues. Therefore, while it looks microscopically similar to dystrophic calcification, the tissues underneath are still viable.
What is the definition of hyaline change?
Any change that results in a glossy, pink homogenous staining of the tissue.
When does physiological decline with aging begin?
Begins in the 4th decade
What is the protein that aggregates in the following pathologies: - AAT - Creutzfeld-Jakob disease - Parkinson’s disease - Systemic AL amyloidosis - Alzheimer disease
- serpins - prion - alpha-synuclein - immunoglobulin light chain - beta amyloid peptide Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction.
Explain the effects of ROS on cellular aging:
Cellular metabolism and repeated environmental exposures can cause a generation of ROS, which can damage other cellular structures. Studies show that species with longer lifespans show higher resistance to cellular oxidative stress and lower ROS production when compared to species with shorter lifespans.
Telomeric sequences shorten with each DNA replication In most somatic cells, eventually leading to cell cycle arrest. Does this process occur in germ and stem cells?
No. This process only occurs in somatic cells.
What is the enzyme responsible for lengthening telomeres by adding on repeating sequences of DNA?
Telomerase. In its absence, repeat sequences are progressively lost with each cell division. Embryonic and malignant cells exhibit greater telomere length.
What is a telomere?
A repeating DNA sequence
Caloric restriction is believed to increase longevity by reducing the signaling of the IGF-1 pathway (mimics the effect of insulin). Describe this effect:
- Caloric restriction retards the aging process by shifting cellular metabolism from growth to maintenance and repair activities. 2. Decreases the accumulation of senescent cells, a key mediator of aging. May increase autophagy and prevent accumulation of senescent cells. 3. Attenuates low-grade inflammatory status.
T or F: Inflammation is due to injury of vascularized tissue?
True
List the five cardinal signs of inflammation. List the most common factors that lead to them.
Redness/Warmth: vasodilation due to histamine, prostaglandins, and bradykinin
Swelling: increased vascular permeability due to histamine (endothelial cell contraction) and endothelial injury
Pain/loss of function: increased inflammatory mediators (PGE2, Bradykinin) acting on sensory nerves
Fever: pyogenic bacteria causes macrophages to produce TNF, IL-1 which increases AA metabolites (cyclooxygenase) and forms PGE2, which raises the set temperature due to interactions in perivascular cells of the hypothalamus
How do the starling forces help to maintain fluid homeostasis?
Intravascular hydrostatic pressure on the arteriolar end of the capillary (fluid out), and plasma oncotic pressure on the venular end of the capillary (fluid in)
What is a notable difference between transudate and exudate?
Transudate is leakage from a vessel due to changes in starling forces and therefore does not involve presence of proteins. Exudate is due to an increase in vascular permeability. Thus, proteins are found in solution.
Describe the function of PAMPS and PRR:
PAMPS- pathogen associated molecular patterns PRR- pattern recognition receptor The initial sensing of infection is mediated by innate PRRs. PRRs recognize molecular patterns that may be present on different pathogens. PRRs also recognize damage signals from apoptotic or necrotic host cells. PRRs are located on most body cells including plasma membrane, endosomal membrane, and cytosol.
What transcription factor is activated by receptor stimulation?
NFkB (NF-kB is a short name of Nuclear Factor kappa-light-chain-enhancer of activated B cells. It is not a single protein, but a small family of inducible transcription factors that play an important role in almost all mammalian cells.)
What is the function of bradykinin?
Promotes vascular permeability, smooth muscle contraction, and pain. Bradykinin, generated from the kinin system on surface contact of Hageman factor (F12) with collagen and basement membrane from vascular injury.
What is the function of complement C3a?
Increases vascular permeability by releasing histamine from mast cells; mediator of inflammation.
What is the function of histamine?
Causes vascular leakage; Histamine is found in abundance in mast cells, which are normally present in connective tissues next to blood vessels beneath mucosal surfaces in airways. Binding of an antigen (allergen) to IgE antibodies that have previously attached to the mast cells by the Fc receptor triggers mast cell degranulation, with release of histamine.
T or F: Neutrophils are most numerous within the initial 48 hours after infarction, but are not numerous after the first week.
True
What is the mechanism of action of acetylsalicylic acid (aspirin)?
Aspirin (acetylsalicylic acid) blocks the cyclooxygenase pathway of arachidonic acid metabolism, which leads to reduced prostaglandin generation. Prostaglandins promote vasodilation at sites of inflammation.
Describe the different types of inflammation: Acute Chronic Serous Granulomatous Fibrinous
One outcome of acute inflammation with ulceration is chronic inflammation. This is particularly true when the inflammatory process continues for weeks to months. Chronic inflammation is characterized by tissue destruction, mononuclear cell infiltration, and repair. In acute inflammation, the healing process of fibrosis and angiogenesis has not begun. Serous inflammation is an inflammatory process involving a mesothelial surface (e.g., lining of the pericardial cavity), with an outpouring of fluid having little protein or cellular content. Granulomatous inflammation is a form of chronic inflammation in which epithelioid macrophages form aggregates. In fibrinous inflammation, typically involving a mesothelial surface, there is an outpouring of protein-rich fluid that results in precipitation of fibrin.
What are the major cytokines that produce fever?
TNF, IL-1 - produced by macrophages and other cell types
What role does leukotriene B4 play?
Leukotriene B4, generated in the lipoxygenase pathway of arachidonic acid metabolism, is a potent neutrophil chemotactic factor.
What are the key cellular events of acute inflammation?
- vasodilation/increased vascular permeability, increases [lymphocytes] - activation of endothelium, allowing for adhesion of lymphocytes (first neutrophils, then macrophages) - activated endothelium allows for adhesion, emigration, phagocytosis, bacterial killing and generation of additional mediators. - chemotaxis follows - injured tissue is removed and healing process beings (regeneration or repair)
Describe the mechanism of ROS formation by neutrophils during inflammation:
NADPH oxidase generates superoxide ions during oxygen-dependent killing by neutrophils
What are two hallmark signs for acute inflammation?
Edema (exudate) & neutrophils
The 5 mediators of acute inflammation are Toll-like receptors, arachidonic acid metabolites, mast cells, complement system, and Hageman factor (F12). Describe the function of toll-like receptors?
TLRs (include PRRs) are located on cells of the innate immune response (macrophages and dendrites) and cells of the adaptive response (lymphocytes). TLRs recognize PAMPs and regulates transcription of immune mediators through NFKb.
CD14 (a co-receptor for TLR4) on macrophages recognizes what structural component of gram-negative bacteria? Describe the mechanism of action that ensues after the TLR recognizes a PAMP?
Lipopolysaccharide. The lipopolysaccharide is a PAMP (pathogen associated molecular pattern) and is recognized by CD14 of TLR4, found on macriphages, and cells of the adaptive immune system, including lymphocytes.
After recognition, the NF-kB signaling path is begun, leading to the transcription of immune mediators.
The 3 mediators of acute inflammation are Toll-like receptors, arachidonic acid metabolites, and mast cells. Describe the function of arachidonic acid (AA) metabolites.
AA is released from the phospholipid by phospholipase A2. Once released, it can go down one of two paths: - activated by cyclooxygenase to produce prostaglandins - activated by 5-lipoxygenase to produce leukotrienes
What are the functions of prostaglandins PGI2, PGD2, PGE2?
PGI2, PGD2, and PGE2 activate vasodilation and increased vascular permeability. PGE2 also mediates pain and fever
What are the functions of leukotrienes LTB4, LTC4, LTD4, LTE4?
LTB4 attracts and activates neutrophils. LTC4, LTD4, LTE4 mediate vasoconstriction, bronchospasm, and increased vascular permeability.
Describe mast cells. Include their initial location and immediate and delayed response:
Mast cells are found in the connective tissue around the site of inflammation. They can be activated by three ways: - tissue trauma - complement C3a and C5a activation - cross-linking of cell surface IgE by antigen. Mast cell exhibits different responses based on time:
- Immediate response*: releases histamine, which mediates vasodilation of arterioles and increased vascular permeability.
- Delayed response*: production of arachidonic acid metabolites, particularly leukotrienes.
If you have an allergy, your immune system overreacts to an allergen by producing antibodies called Immunoglobulin E (IgE). These antibodies travel to cells that release chemicals, causing an allergic reaction. This reaction usually causes symptoms in the nose, lungs, throat, or on the skin.
What three cells make up the macrophages?
- Neutrophils - Macrophages - Dendritic cells (the important in mediating specificity)
What structure, produced by damaged membrane-bound vesicles becomes the nidus for the binding of calcium in dystrophic calcification?
Membrane-bound vesicles nucleate hydroxyapatite crystals containing calcium and inorganic phosphate
Explain the correlation between acute inflammation and the systemic characteristic of decreased serum iron:
Iron can be stored/absorbed into the cells of the body in three main mechanisms: - Intestinal cells of the gut - Macrophage iron recycling - Hepatocyte iron storage Iron can be released into the bloodstream via the transporter ferroportin. Hepcidin, is an enzyme made in the liver and acts to inhibit ferroportin. Hepcidin is enhanced during an inflammatory response. Also note, deficiency in hepcidin is a cause of hereditary hemochromatosis.
List inflammatory mediators based on whether they are preformed mediaots in secretory granules, or newly synthesized. Also mention the source of the mediator.
The only mediators that are presynthesized are histamine, serotonin and lysosomal enzymes.
Lipid mediators (derived from membrane phospholipids) of inflammation includes Arachidonic Acid metabolites. Describe the mechanism of action for these metabolites, including the locations where they can be found.
- Inflammatory signals/cytokines (IL-1, TNF) activate phospholipase A2 in lymphocytes.
- Phospholipase A2 breaks down the phospholipids found in the PM, forming free AA.
- Free AA can go down two different pathways via activation by two types of enzymes: cyclooxygenases and lipoxygenases. The enzyme pathway depends on the type of cells: lipoxygenases are more present in PMNS and cycloxygenases are present in every cell.
- COX-1 (found in most cells) and COX-2 (upregulared in inflammatory processes) will produce prostaglandins, prostacyclins, and thromboxanes.
- 5-lipoxygenase will produce leukotrienes.
Detail which AA metabolites cause vasoconstriction, vasodilation, increased vascular permeability, chemotaxis, and leukocyte adhesion.
Differentiate between the three pathways involved in complement activation: Classical, alternative, and MBL pathways.
Note the initial interactions defining each pathway:
Classical- Antigen/antibody complex
Alternative- microbial interaction
MBL- lectin binding to mannose residue on bacteria
C3b- opsonization, activation of C5 convertase
What are the effector functions of complement activation?
C3a,C5a- anaphylatoxins- releases histamine from mast cells and basophils/inflammation
C3b- opsonization > phagocytosis
MAC- plasma membrane lysis
Note the effects of cytokines on:
- local inflammation
- systemic protective effects
- systemic pathological effects
Note the acute phase response:
Note effects on neuroendocrine, metabolis, heamtologic and biochemical
Explain how activation of Hageman factor (XII) can lead to the activation of several additional plasma proteases including the:
- Kinin cascade
- Clotting cascade
- Fibrinolytic system
- Complement cascade
Describe how thrombin and histamine can be used to increase vascular permeability via leukocyte adhesion molecules.
Thrombinboundtoreceptorson platelets, endothelial and other cells can induce:
– Expression of adhesion molecules
– Production of chemokines
– Production of AA metabolites
Explain how activated macrophages can be involved in both inflammation and tissue injury and repair:
