Inflammation & Repair Flashcards
(100 cards)
1
Q
What enzyme is deficient in Gaucher disease, and what is the resulting protein accumulation?
A
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.
2
Q
What are the two main hemoglobin derived pigments? Where are each derived from? What can be the cause of their accumulations?
A
-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)
3
Q
What is hemochromatosis?
A
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.
4
Q
This endogenous pigment is evidence of lipid peroxidation of polyunsaturated lipids and residual from partially degraded cell membrane lipids.
A
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.
5
Q
Describe the pathogenesis of dystrophic calcification. Compare dystrophic calcification to metastatic calcification in terms of calcium and phosphate levels in the body.
A
- 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.
6
Q
Differentiate between metastatic and dystrophic calcification:
A
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.
7
Q
What is the definition of hyaline change?
A
Any change that results in a glossy, pink homogenous staining of the tissue.
8
Q
When does physiological decline with aging begin?
A
Begins in the 4th decade
9
Q
What is the protein that aggregates in the following pathologies: - AAT - Creutzfeld-Jakob disease - Parkinson’s disease - Systemic AL amyloidosis - Alzheimer disease
A
- 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.
10
Q
Explain the effects of ROS on cellular aging:
A
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.
11
Q
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?
A
No. This process only occurs in somatic cells.
12
Q
What is the enzyme responsible for lengthening telomeres by adding on repeating sequences of DNA?
A
Telomerase. In its absence, repeat sequences are progressively lost with each cell division. Embryonic and malignant cells exhibit greater telomere length.
13
Q
What is a telomere?
A
A repeating DNA sequence
14
Q
Caloric restriction is believed to increase longevity by reducing the signaling of the IGF-1 pathway (mimics the effect of insulin). Describe this effect:
A
- 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.
15
Q
T or F: Inflammation is due to injury of vascularized tissue?
A
True
16
Q
List the five cardinal signs of inflammation. List the most common factors that lead to them.
A
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
17
Q
How do the starling forces help to maintain fluid homeostasis?
A
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)
18
Q
What is a notable difference between transudate and exudate?
A
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.
19
Q
Describe the function of PAMPS and PRR:
A
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.
20
Q
What transcription factor is activated by receptor stimulation?
A
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.)
21
Q
What is the function of bradykinin?
A
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.
22
Q
What is the function of complement C3a?
A
Increases vascular permeability by releasing histamine from mast cells; mediator of inflammation.
23
Q
What is the function of histamine?
A
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.
24
Q
T or F: Neutrophils are most numerous within the initial 48 hours after infarction, but are not numerous after the first week.
A
True
25
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.
26
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.
27
What are the major cytokines that produce fever?
TNF, IL-1 - produced by macrophages and other cell types
28
What role does leukotriene B4 play?
Leukotriene B4, generated in the lipoxygenase pathway of arachidonic acid metabolism, is a potent neutrophil chemotactic factor.
29
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)
30
Describe the mechanism of ROS formation by neutrophils during inflammation:
NADPH oxidase generates superoxide ions during oxygen-dependent killing by neutrophils
31
What are two hallmark signs for acute inflammation?
Edema (exudate) & neutrophils
32
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.**
33
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.
34
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
35
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
36
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.
37
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.
38
What three cells make up the macrophages?
- Neutrophils - Macrophages - Dendritic cells (the important in mediating specificity)
39
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
40
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.
41
Contrast acute and chronic inflammation:
Acute: - rapid and short duration -edema (exudation) - migration of leukocytes (predominantly neutrophils) Chronic: - slow onset, longer duration - lymphocytes , plasma cells, macrophages - may see scar tissue
42
Explain how congestive heart failure and venous obstruction leads to transudate:
Both can increase intravascular hydrostatic pressure (starling forces) leading to transudate edema.
43
Explain how hypoalbuminemia (from liver, kidney disease or malnutrition) can lead to transudate:
Loss of proteins disrupts and decreases intravascular oncotic pressure
44
List some of the mechanisms that cause increased vascular permeability:
- Adherent leukocytes can release toxins and cause endothelial cell injury - Endothelial cell contraction - Endothelial injury - leakage from new blood vessels that develop during the repair process
45
What antibody is highly expressed as a receptor on mast cells, and when activated, allows for the degranulation of histamine and other chemotactic factors important in signaling eosinophils and neutrophils?
IgE (Ab-IgE Ab complexes)
46
What specific leukocyte plays a role in the pathogenesis of hypersensitivity runs such as asthma, hay fever, and anaphylaxis? What granules are found in this leukocyte?
**Eosinohphils** (major role in destruction of parasitic organisms)
Granules contain enzymes such as: -histaminase - collagenase- responsible for lysing BM - major basic protein (which binds to the surface of a parasite and causes membrane damage)
47
What structure is similar to smooth muscle and will allow contraction during wound healing?
Myofibroblasts
48
What structure is vital in the repair process and manufactures collagen, eventually forming scar tissue?
Fibroblasts
49
The principal adhesion molecules are selectins and integrins. What are their roles?
**Selectins**- leukocyte *_rolling_* along endothelium
**Integrins**- firm *_adhesion_* to endothelium
50
What are the two most important mediators of leukocyte adhesion and increased binding affinity for their ligands?
**IL-1, TNF**
51
At what timing will neutrophils and macrophages peak during inflammation?
Neutrophils- ~**6-8 hours**
Macrophages- ~**24 hours**
52
Chemotaxis involves cell migration along concentration gradient of an inflammatory mediator. What are some common chemotactants for neutrophils, and what is the mechanism of action?
-bacterial products - endogenous mediators (C5a, LTB4, chemokine with chemotactic activity like IL-8)
Gq mechanism- PIP2/DAG \> **increased cytosolic Ca \> assembly of cytoskeletal contractile elements for cell motility**.
53
What is responsible for increasing the effectiveness of phagocytosis?
Oposins through oposonization to "label" substances for phagocytosis
54
Give an example of three oposins:
- Fc IgG
- C3b
- mannose binding protein
55
Defects in leukocyte adhesion can result in...
- recurrent bacterial infections - impaired wound healing
56
Infections due to S. aureus and E coli can cause a defect in genes coding for **NAPDH oxidase.** what is the likely result of this defect?
**Decreased** oxidative burst; NADPH oxidase produces ROS (oxygen \> superoxide anion)
57
Describe the pathogenies of Chediak-Higashi syndrome:
There is a defect in the docking and fusion capabilities of organelles and thus, a decreased formation of the **phagolysosome**. Increased occurrence of **pyogenic infections.**
58
Explain which arachidonic acid metabolites are functions of the innate immune system:
AA is released from the phospholipid cell membrane by phospholipase A2. It can then either be enacted upon by 5-lipooxygenase (produces leukotrienes) or by cyclooxygenase (produces prostaglandins)\>
PG: PGI2, PGD2, PGE2- responsible for vasodilation, vascular permeability, pain and fever (mainly PGE2 for pain and fever)
Leukotrienes attract and activates neutrophils:
LTB4- attracts and activates neutrophils
LTC4, LTD4, LTE4- substances of anaphylaxis; mediates vasoconstriction, bronchospasm, and increase vascular permeability.
59
Two of the five signs of inflammation are **redness (rubor) and warmth (calor)**. Describe the facotrs affecting this phenomenon and list three key mediators of these signs:
Due to **vasodilation** and increased blood flow.
Key mediators are **bradykinin, prostaglandin, and histamine**
60
Swelling (tumor) is a key feature of inflammation. Describe the pathologenesis of this feature and its mediators:
Swelling is due to increased vascular permeability. The *main mediators are:*
## Footnote
**1. Tissue Damage = endothelial cell damage**
**2. Histamine = Endothelial cell contraction**
61
Pain (dolor) is a key sign of inflammation. Describe the mediators and pathogenesis of this occurence.
**PGE2 and Bradykinin** sensitizes sensory nerve endings.
62
What substance is responsible for raising the temperature set point in the body? Also, fever is a sign of inflammation. Describe th emediators and pathogenesis of this feature:
**PGE2** acts to increase the body set temperature by acting on perivascualr cells of the **hypothalamus**. This is due to **pyrogens (ex, LPS from bacteria)** which causes **macrophages** to release **IL-1 and TNF, which will increase the activity of cyclooxygenase in perivascular cells of the hypothalamus.**
63
The seven steps involved in diapedesis includes:
1. MArgination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the **first** step, list the important steps that occur along with mediators:
Margination- due to **vasodilation**
Recall, the three main mediators of vasodilation are: **histamine, prostaglandins, and bradykinin.**
These mediators are important for slowing the blood, which allows for cells to marginate from the center of flow to the periphery.
64
The seven steps involved in diapedesis includes:
1. Marrgination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the second step, list the important steps that occur along with mediators:
Rolling: due to **selectins (P and E selectins)**
## Footnote
**P-selectins: derived from Weibel-Palade bodies and is mediated by _histamine_**
**_E-_selectins: induced by IL-1 and TNF**
**Selectins bind _sialyl Lewis X_ on leukocytes**
65
The seven steps involved in diapedesis includes:
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the third step, list the important steps that occur along with mediators:
Adhesion:
Mediators: **ICAM/VCAM on endothelial wall**
**Integrins on leukocytes**
**TNF/IL-1** mediates upregulation of ICAM/VCAM on endothelium while **C5a and LTB4** mediate upregulation of integrins on leukocytes.
66
LAD (leukocyte adhesion disease) causes an increase in bacterial and fungal infections. Describe the pathogenesis.
LAD occurs usually due to a mutation in the integrin genes on leukocytes. Thus, leukocytes cannot migrate from out of the vascular system and into tissues to fight infection. **This means that no pus is form in LAD!**
67
The seven steps involved in diapedesis includes:
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the fourth step, list the important steps that occur along with mediators:
Transmigration and Chemotaxis:
Leukocytes transmigrate across the endothelium of *postcapillary venules* and move toward chemical attractants (chemotaxis).
**Neutrophils** are attracted by bacterial products including **IL-8, C5a, LTB4**
68
The seven steps involved in diapedesis includes:
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the fifth step, list the important steps that occur along with mediators:
Phagocytosis:
Enhanced by opsonins **C3b, IgG**
Clinical correlation: **Chediak-Higashi: impaired phagolysosome formation \>**
**- increased pyogenic infections**
**- neutropenia (due to intramedullary death of neutrophils)**
69
The seven steps involved in diapedesis includes:
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the sixth step, list the important steps that occur along with mediators:
Destruction of phagocytized material:
- **O2 dependent killing is the most effective mechanism, the oxidative burst destroys phagocytized material.**
70
Describe what occurs in the oxidative burst:
Oxygen is oxidized by **NADPH oxidase** to form superoxide anion.
*\* note that persons with G6PD deficiency experience heomlytic anemia. G6PD is the R.L. enzynme in the pentose phosphate pathway and produces NADPH and pentose sugars. NADPH is normally oxidized to form reduced glutathione, which is necessary to convert ROS to water. Thus, no NADPH = no reduced glutathione = oxidative stress*
Superoxide anion is oxidized to H2O2 by **superoxide dismutase**
H2O2 is oxidized to wter **by glutathione peroxidase**
OH- is oxidized to water by **catalase**
71
Oxygen-independent killing is less effective than oxygen-dependent killing. Describe two examples of substances that cause oxygen-independent killing of organisms:
**lysozymes in _macrophages_**
**major basic protein in _eosinophils_**
Both are found in leukocyte secondary granules
72
The seven steps involved in diapedesis includes:
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytized material
7. Resolution
For the seventh step, list the important steps that occur along with mediators:
Resolution:
Neutrophils undergo apoptosis and disappear within **24 hours** after resoltuion of the inflammatory stimulus.
73
Describe the mechanism of action used by macrophages to destroy material:
Phagocytize material and participate in oxygen-independent killing through lysozymes in secondary granules
74
Explain mechanism of action for macrophages in terms of their ability to produce abscesses and mediate chronic inflammation.
MAcrophages appear **_~2-3 days after inflammation begins_**. If inflammatory stimulus is destroyed, macrophages can produce **anti-inflammatory cytokines (_IL-10, TGF-b_) to begin resolution and healing.**
**An abscess can be formed by macrophages, which includes acute inflammation surrounded by fibrosis. Macrophages mediate fibrosis via fibrogenic growth factors and cytokines.**
**MAcrophages can also act as APC to CD4+/Helper T cells, which can release cytokines that promote chronic inflammation.**
75
T lymphocytes are components of the adaptive immune response. There are two types of T cells- CD4+ (helper) and CD8+ (cytotoxic). In order for T-lymphocytes to perform their respective actions of killing foreign/dead material, 2 signals must occur. Recall the two different signals that must be present for each type of T cell which will allow them to complete their actions:
**T4+/helper T -cells: secretes cytokines that helps intiatiates inflammation**
**1st signal:** presentation of foreign material on **_MHCII_** complexes
**2nd signal:** B7 on APC binds with **_CD28_** on T cells
**T8+/cytotoxic T-cells**: kills cells through the release of **perforins and granzymes**
**1st signal:** presentation of signals on **_MHC1_** complexes (MDC1 complexes is expressed by ALL nucleated cells and platelets)
**2nd signal: IL-2 from CD4+ T cells provides the secondary activation signal**
76
B lymphocytes are components of the adaptive immune response. There are two types of B cells- helper B cells and Effector (plasma) cells. In order for B-lymphocytes to perform their actions, 2 activation signals must occur. Recall the two different signals that must be present for each type of B cell which will allow them to complete their actions:
Naive B cells express IgM and IgD on their surface. Activation occurs when:
1. APC presents antigen onto MHCII to B-lymphocyte
2. **CD40 on B cell binds to CD40L on T cells (helper T cells/CD4+)**
**The _helper T cell_ then secretes _IL-4, IL-5_ which mediates:**
**1. B-cell isotype switching**
**2. hypermutation**
**3. Maturation of plasma cells**
77
Describe granulatous inflammation and the process for the conversion of macrophages into epithiliod histiocytes:
- subset of **chronic inflammation**
- granuloma: collection of **epithiliod histiocytes within macrophages** and surrounded by **giant cells**.
**Caseating granulomas exhibit central necrosis and are characteristic of _tuberculosis and fungal infections._**
**Process for conversion of macrophages into epithiloid histiocytes:**
Macrophages (an APC) presents antigen to TH4+ cells, secreting IL-12, which allows for TH4 cells to differentiate into Th-1 helper cells. Th-1 cells produce IFN-gamma, which causes the conversion of macrophages into giant cells and epithiliod histiocytes.
78
Regeneration and repair occur simultaneously with inflamamtion. Describe the three categories which seperate tissues based on their regenerative capacity. Give examples of each:
**1. Labile-** Cells constantly divide: **skin, large/small intestine, bone marrow**
## Footnote
**2. Stable- cells enter quiesent stage until they are needed for regeneration; after regeneration requirements have been met, cells return back into quiescent stage: liver regeneration via compensatory hyperplasia**
**3. Permanent- cells have limited regernation ability:skeletal muscle, cardiac muscle, neurons**
79
Explain the repair process, wherein damaged tissue is replaced by fibrous tissue, forming a scar.
When a tissue has limited regenration ability, or when extensive damage is done to a tissue that has regenerative abilities (destruction of the basement membrane of the skin- where stem cells are found), fibrous tissue will form.
Granulation tissue is the inital state of repair. **Fibriblasts are important for laying down Type III collagen, which is later replaced to Type I collagen (a more tensile collagen found in bones, skin and tendons) by collagenase (note that collagenase requires _zinc_ as a cofactor.) Angiogenesis (stimulated largely by VEGF) causes the formation of new blood vessels to provide. nutrition to site of damage and myofibroblasts, thich allow wound contraction.**
80
Explain how a scar is formed in second intention healing:
Edges of the wound are NOT brought together, resulting in formation of granulation tissue. **Myofibroblasts will then contract the wound, resulting in a scar.**
81
Explain how a copper deficiency can disrupts wound healing:
Copper is a required cofacter for **lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen.**
82
Explain how a zinc deficiency disrupts wound healing:
Zinc is a required cofactor for **the enzyme collagnase, which transforms Type III collagen into more stable/tensile Type I collagen.**
83
Explain how a Vitamin C deficiency disrupts wound healing:
Vitamin C is required **for the hydroxylation of proline and lysine procollagen residues to allow for cross-linking of collagen.**
84
Describe the primary difference between a keloid and hypertrophic scar:
A keloid is growth of tissue outside a defined boundary to the wound, while a hypertrophic scar is localized to the wound. Also, keloids are characterized by excess Type III collagen.
85
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.
86
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.
1. Inflammatory signals/cytokines (**IL-1, TNF)** activate phospholipase A2 in lymphocytes.
2. Phospholipase A2 breaks down the phospholipids found in the PM, forming **free AA.**
3. 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.**
4. COX-1 (found in most cells) and COX-2 (upregulared in inflammatory processes) will produce **prostaglandins, prostacyclins, and thromboxanes.**
5. 5-lipoxygenase will produce **leukotrienes.**
87
Differentiate between the products released by cyclooxygenase enzymes acting on free AA.
**Prostacyclin- vasoconstriction; inhibits platelet activation**
**Prostaglandin- vasodilation, pain, fever**
**Thromboxane- vasodilation; promotes platelet aggregation**
88
Free AA will undergo activation by cyclooxygenase or lipoxygenase enzymes depending on tissue type. Differentiate between the actions of leukotrienes and lipoxins, which re both products of the lipoxygenase pathway.
Leukotrienes: **vasodilation, chemotaxis = increased vasscular adhesion/diapedesis**
Lipoxins: **actually *inhibits LT synthesis* and has a role in _resolution_ of inflammation; inhibits neutrophil chemotaxis, adhesion to endothelium**
89
Detail which AA metabolites cause vasoconstriction, vasodilation, increased vascular permeability, chemotaxis, and leukocyte adhesion.
90
How do corticosteroids act as broad spectrum anti-inflammatory agents?
Corticosteroids inhibits phospholipases. Phospholipases are critical in the production of free AA from phospholipids. AA metabolites are important mediators of inflammation, including leukotrienes, prostaglandins, prostacyclins, thromboxanes, and lipoxins (i.e. LXA4, LXB4).
91
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**
92
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
93
Note the effects of cytokines on:
- local inflammation
- systemic protective effects
- systemic pathological effects
94
Note the acute phase response:
Note effects on ***neuroendocrine, metabolis, heamtologic and biochemical***
95
When exposed to HIV, a patient may be protected if they are lacking what normally expressed receptor?
Certain **_chemokine receptors act aas co-receptors_** for HIV and are involved in viral entry into cells.
96
What are the 3 major classes of chemokines, differentiated based on the arrangment of *cystein residues in proteins?*
**C-X-C chemokines act mainly on _neutrophils_**
**C-C chemokines act mainly on _monocytes_**
**C chemokines are relatively specific for _lymphocyte_ recruitment**
97
Explain how activation of Hageman factor (XII) can lead to the activation of several additional plasma proteases including the:
## Footnote
**- Kinin cascade**
**- Clotting cascade**
**- Fibrinolytic system**
**- Complement cascade**
98
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
99
What are four examples of antioxidants that protects against potentially harmful effects?
**Ceruloplasmin, superoxide dismutase, catalase, glutathione peroxidase**
100
Explain how activated macrophages can be involved in both inflammation and tissue injury and repair:
