Robbins - Chapter 3

Question 1

Differentiate between the different components of Acute and Chronic Inflammation responses.

Which diseases are caused in both?

Answer 1

Table 3-2; Pg. 71

Table 3-1; Pg. 71

Question 2

List some causes of inflammation.

Answer 2

1. Infections
2. Tissue necrosis
3. Foreign Bodies
4. Immune Reactions

Question 3

List some pathways in which cells can recognize microbes and damaged cells.

Answer 3

1. Cellular receptors for Microbes –> TLRs
2. Sensors of Cell Damage –> Cytosolic receptors activate the Inflammasome which will release IL-1; Molecules that bind to the Cytosolic receptors are: 1. Uric acid (product of DNA breakdown), 2. ATP (Mitochondria Breakdown), 3. Reduced Intracellular K+ (plasma membrane malfunction), 4. DNA; Gain-of-Function mutations involving the Inflammasome are deemed AUTOINFLAMMATORY SYNDROMES
3. Other Cellular Receptors –> Fc receptors for complement
4. Circulating Proteins –> Mannose-Binding Lectin and Collectins

Question 4

List the three major components of Acute Inflammation.

Answer 4

1. Dilation of Small Blood Vessels (leads to an increase in blood flow) happens in the ARTERY
2. Increased Permeability of the microvasculature (enabling plasma proteins and leukocytes to leave the circulation) happens in the POSTCAPILLARY VENULUES
3. Emigration of leukocytes from the microcirculation

(Figure 3-1; Pg. 70)

Question 5

Differentiate between:

1. Exudation
2. Transudation
3. Edema
4. Pus

Answer 5

1. Exudate –> Extravascular Fluid that has a high protein concentration and contrails cellular debris
2. Transudate –> Low protein content, little or no cellular material and low specific gravity
3. Edema –> Accumulation of fluid in the interstitial tissues
4. Pus –> Purulent exudate rich in leukocytes (mainly neutrophils)

Figure 3-2; Pg. 73

Question 6

What is the main mediator of vasodilation that acts on the vascular smooth muscle?

Answer 6

Histamine

Question 7

Define Stasis.

Answer 7

Loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels and increased viscosity of the blood –> this results in Stasis (vascular congestion and localized redness of the involved tissue)

Question 8

How do you get increased vascular permeability associated with Acute Inflammatory Reactions?

Answer 8

1. Contraction of Endothelial cells –> Results in INCREASED interendothelial spaces (most common!); Mediated by Leukotrienes, histamine and bradykinins; Can happen immediately and last for 15-30 minutes; Delayed Prolonged Leakage can begin 2-12 hours after the damage and last for hours or days! (I.e. Late-Appearing Sun Burn)
2. Endothelial Injury –> Leads to endothelial necrosis and detachment; Rapid onset of Neutrophils binding to the endothelial cells and can last for hours to days
3. Transcytosis –> Vascular Endothelial Growth Factor (VEGF) can promote vascular leakage

Figure 3-3; Pg. 74

Question 9

What does the presence of red streaks near a skin wound tell us?

Answer 9

Telltale sign of an infection in the wound!

Red streak follows the course of the lymphatic channels and is diagnostic of lymphangitis (Inflammation of SECONDARY lymph nodes) and it may be accompanied by Lymphadenitis (Inflammation of PRIMARY lymph nodes)

Question 10

Describe the process of leukocyte rolling, adhesion, transmigration and chemotaxis into the extracellular matrix.

Answer 10

Figure 3-4; Pg. 75

ROLLING –> SELECTINS: Three types 1. L-Selectin (on leukocytes), 2. E-selectin (endothelium), 3. P-selectin (Platelets and on endothelium)

• • TNF and IL-1: Act on the E-SELECTIN @ postcapillary venules
• • Histamine and Thrombin: Bring P-selectin to the cell surface (via WEBIEL-PALADE bodies)
• • Ligands: Sialyated Oligosaccharides bound to glycoproteins

LEUKOCYTE ADHESION –> INTEGRINS

• • TNF and IL-1: Induce expression of VCAM-1 (Ligand for B1 integrin VLA-4) and ICAM-1 (Ligand for the B2 integrin LFA-1 and Mac-1)
• • Leukocytes normally express integrins in a LOW AFFINITY state
• • Chemokines that bind to the leukocytes are going to change the integrins into a HIGH AFFINITY state

LEUKOCYTE TRANSMIGRATION –> Occurs mainly in POSTCAPILLARY VENULES
– CD31 or PECAM-1 are involved in the migration of leukocytes

CHEMOTAXIS OF LEUKOCYTES –> Can be Endogenous to Exogenous structures that will bind to specific 7-transmembrane GPCRs on the surface of leukocytes; Chemokines are going to increase Intracellular Ca2+ and that will activate RAC and RHO ATPases to polymerize actin

Question 11

Describe the different cells that are present in different times during inflammatory reactions.

Answer 11

Initially –> EDEMA

6-24 Hours –> Neutrophils (attach more firmly to adhesion molecules and will respond faster to chemokines); Once they enter the tissues, they will undergo Apoptosis within 24-48 hours

24-48 Hours –> Monocytes (proliferate in the tissues)

Figure 3-6; Pg. 78

Question 12

Describe the various pathways for activation of Leukocytes.

Answer 12

Figure 3-7; Pg. 79

Question 13

Describe the process of Phagocytosis.

Answer 13

Three sequential steps:

1. Recognition and Attachment of the particle to be ingested by the leukocyte
2. Engulfment and formation of a phagocytic vacuole
3. Killing or degradation of the ingested material

Receptors –> Mannose, Scavenger and other receptors; Bacteria have Terminal Mannose and Fucose residues (mammillian cells have terminal sailing acid or N-acetylgalactosamine); Scavenger Receptors are used to Recognize LDL particles that no longer work; Recognition is MORE EFFECTIVE if the particle has opsonins (IgG, C3b, MBL) attached to it

Engulfment –> Plasma membrane pinches off and forms a phagosome which will fuse with a lysosome to degrade the materials inside

Killing of microbes –> ROS, NOS, and lysosomal enzymes

• • ROS: Produced by oxidizing NADPH and reducing O2 to the Superoxide anion (enzyme: Phagocyte Oxidase); Called RESPIRATORY BURST; ROS are produced in the Phagolysosome and then converted to H2O2 which will combine with MYELOPEROXIDASE (MPO) and will produce HPOYCHLORITE (active ingredient in bleach) which will disrupt various functions in the bacteria via Halogenation or Lipid Peroxidation (More common in NEUTROPHILS)
• • NITRIC OXIDE: Gas produced from Arginine by Nitric Oxide Synthase (NOS); Three forms: 1. eNOS (endothelial), 2. nNOS (neuronal), 3. iNOS (Inducible); iNOS is the major form that is involved in Microbial Killing and that is induced by IFN-GAMMA! NO reacts with superoxide to generate peroxynitrite (ONOO-)(iNOS is more commonly seen in Macrophages)
• • Lysosomal Enzymes: Have two different granules (Look @ pg. 80); Acidic Proteases, Neutral Proteases, Neutrophil elastase (inhibited by alpha1-antitrypsin), Defensins, Cathelicidins, Lysozyme

Question 14

Describe the Neutrophil Extracellular Traps.

Answer 14

CHROMATIN from the fibrillar network of fibers produced by neutrophils in response to infectious pathogens

*** Neutrophil will die in the mission to kill the pathogens

Figure 3-9; Pg. 81

Question 15

What are you going to be more susceptible to if you lack TH17?

Answer 15

Fungal and Bacterial Infections

*** You will have Cold Abscesses that are lacking the classic features of acute inflammation (i.e. Warmth and Redness)

Question 16

List some of the components that are involved in the termination of the Acute Inflammatory Response.

Answer 16

1. TGF-Beta and IL-10
2. Removal of the leukocytes (neutrophils die quickly)
3. Cholinergic Discharge from neurons (inhibits the Release of TNF in Macrophages)

Question 17

Have an understanding about the principle mediators of inflammation.

Answer 17

Table 3-4; Pg. 83

Question 18

Which stimuli are going to cause degranulation and the release of Vascactive Amines (Histamine and Serotonin).

Once released, what are some of their respective actions?

Answer 18

1. Histamine –> Richest source is in MAST cells; Released by: Physical trauma, Antibodies (IgE), Complement (C5a and C3a), Neuropeptides (Substance P) and Cytokines (IL-1 and IL-18)
   - - Function: Causes DILATION of arterioles and INCREASES the permeability of venules; Binds to H1 Receptors on the Endothelium and will produce Interendothelial gaps
2. Serotonin –> Mainly in the GI and not present in human Mast Cells!

Question 19

Discuss the formation and Actions of the Arachidonic Acid Metabolites in Inflammation.

Answer 19

Figure 3-10 and Table 3-5; Pg. 84

1. Prostaglandins –> Involved in Vascular AND Systemic reactions of inflammation; Vascular endothelium LACKS thromboxane synthase but possesses Prostacyclin Synthase (Formation of PGI2); TXA2 (promotes Platelet Aggregation) and PGI2 (INHIBITS platelet aggregation) imbalances here are involved with the early event of thrombus formation in Coronary and Cerebral Blood Vessels. “Nephroxin” will inhibit COX.
2. Leukotrienes –> Chemotaxic for Neutrophils; Formed by 5-Lipoxygenase and inhibitors of this molecule is going to be used to treat ASTHMA!
3. Lipoxins –> Suppress Inflammation by INHIBITING the RECRUITMENT of Leukocytes; Formed by 12-Lipoxygenase

Question 20

Discuss the Pharmacological Inhibitors of Prostaglandins and Leukotrienes:

1. COX Inhibitors
2. Lipoxygenase Inhibitors
3. Corticosteroids
4. Leukotriene Receptor Antagonists

Answer 20

1. COX Inhibitors –> NSAIDs (Aspirin and Ibuprofen) inhibit BOTH COX-1 and COX-2 which will inhibit Prostaglandin Synthesis; Irreversibly Acetylating and Inactivating COX (Aspirin); Selective COX-2 inhibitors are becoming more popular because COX-2 is involved in almost ONLY inflammatory processes. The only drawback is that it is going to tip the Prostacyclin (PGI2) < Thromboxane (TXA2) ratio because it inhibits the production of Prostacyclin
2. Lipoxygenase Inhibitors –> 5-Lipoxygenase is NOT affected by NSAIDs. Useful in treating Asthma
3. Corticosteroids –> Broad Antiinflammatory Agents that reduce the transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines (TNF and IL-1) and iNOS
4. Leukotriene Receptor Antagonists –> Block leukotriene receptors and are useful in treating Asthma

Question 21

Be able to differentiate the use of various cytokines in Acute and Chronic Inflammatory Processes.

Answer 21

Table 3-6; Pg. 87

IL-1 –> Need the INFLAMMASOME!!!! FEVER!!!!

Question 22

Describe the Major Roles of the various cytokines involved in Acute Inflammation.

Answer 22

Figure 3-11; Pg. 87

Question 23

Describe the different groups of Chemokines:

1. C-X-C
2. C-C
3. C
4. CX3C

Describe the main functions of chemokines

Answer 23

1. C-X-C –> Have one Amino Acid residue that separates 2 of the 4 cysteines from each other; IL-8 is part of this group (recruits neutrophils)
2. C-C –> MCP-1; Generally attract Monocytes, Eosinophils, and NOT as potent for Neutrophils; Eotaxin selectively recruits Eosinophils
3. C –> Lack the First and Third of the four conserved cysteines; Lymphotactin
4. CX3C –> Contains three amino acids between the two cysteines; FRACTALKINE is only known and has two forms: Cell Surface-Bound protein induced on endothelial cells and a Soluble Form

Main Functions:
1. In Acute Inflammation –> “Inflammatory Chemokines” Production is induced by microbes and other stimuli; Stimulate Chemotaxis of Leukocytes in tissues to the site of infection or tissue damage

2. Maintenance of tissue architecture –> “Homeostatic Chemokines” Production is constant in tissue

Question 24

Be able to describe the Complement System.

Answer 24

Figure 3-12; Pg. 88

*** Most critical step in the Complement Cascade is the CLEAVAGE of C3

Three main Functions:

1. Inflammation (C3a and C5a) - Anaphylatoxins
2. Opsonization and Phagocytosis (C3b)
3. Cell Lysis (MAC) - Kills Neisseria Bacteria and if you are missing the MAC complex you are going to be more susceptible to these types of Bacteria

Question 25

Describe the various proteins that are responsible for regulating the complement activation:

1. C1 Inhibitor (C1 INH)
2. Decay Accelerating Factor
3. CD59

Answer 25

1. C1 Inhibitor –> Blocks Classical Pathway activation (deficiency causes Hereditary ANGIOEDEMA)
2. Decay Accelerating Factor (DAF) –> Linked to Plasma Membrane by a GPI-anchor and INHIBITS formation of C3 Convertases
3. CD59 –> Also uses the GPI-anchor and INHIBITS formation of MAC

Question 26

Describe the various functions of:

1. Platelet-Activating Factor (PAF)
2. Kinins
3. Neuropeptides

Answer 26

1. PAF –> Can cause Platelet Aggregation
2. Kinins –> Peptides derived from Kininogens and cleaved by KALLIKREINS to produce BRADYKININ (Increases vasculature permeability and causes contraction of smooth muscle, dilation of blood vessels and pain when injected into skin)
3. Neuropeptides –> Substance P

Table 3-7; Pg. 90

Question 27

List the TWO morphological hallmarks of Acute Inflammatory Reactions.

Answer 27

1. Dilation of Small Blood Vessels

2. Accumulation of Leukocytes and fluid in the extravascular tissue

Question 28

Be able to identify and describe the cause for the following morphological patterns involved in Acute Inflammation:

1. Serous Inflammation
2. Fibrinous Inflammation
3. Purulent (Suppurative) Inflammation
4. Ulcers

Answer 28

1. Serous Inflammation –> Exudation of cell-poor fluid into spaces created by cell injury or into body cavities (i.e. Skin Blisters)
2. Fibrinous Inflammation –> Fibrinous Exudate will develop when the vascular leaks are Large of there is a local Procoagulant Stimulus; Characterized as typically lining the Body Cavities (i.e. Meninges, Pericardium, Pleura of Lungs)
3. Purulent (Suppurative) Inflammation –> Characterized by the Accumulation of PUS which is an Exudate of Neutrophils, Liquefied Debris of necrotic cells, and edema fluid; Most Common cause is the infection with Bacteria that causes liquefactive tissue necrosis (i.e. Staphylococci); Good example is ACUTE APPENDICITIS; Abcesses have a central region that appears as a mass of necrotic leukocytes and tissue cells
4. Ulcers –> Local defect of the surface of an organ or tissue that is produced by the shedding of inflamed necrotic tissue; Can ONLY OCCUR when tissue necrosis and resultant inflammation exist on or near a surface

Figures are found on Pgs. 90-92

Question 29

Describe the THREE outcomes of Acute Inflammation.

Answer 29

Figure 3-17; Pg. 92

1. Complete Resolution
2. Healing by Connective Tissue Replacement
3. Progression to Chronic Inflammation

Question 30

List the morphological changes that are predominately associated with Chronic Inflammation.

Answer 30

1. Infiltration with mononuclear cells (Macrophages, Lymphocytes, and Plasma Cells) (Figure 3-18; Pg. 94)
2. Tissue Destruction
3. Attempts at healing

Question 31

List the different names for Macrophages if they are found in the:

1. Liver
2. Spleen and Lymph Nodes
3. Central Nervous System
4. Lungs

Answer 31

1. Liver –> KUPPFER cells
2. Spleen and Lymph Nodes –> Histiocytes
3. Central Nervous System –> Microglial Cells
4. Lungs –> Alveolar Macrophages

Question 32

Describe the Maturation of Mononuclear Phagocytes.

Answer 32

Figure 3-19; Pg. 95

Question 33

Differentiate between Classical and Alternative Macrophage Activation.

Answer 33

1. Classical Macrophage Activation (M1) –> “Pro-Inflammatory”, Activated by IFN-gamma and Microbes; Induce NO and ROS which will increase the capacity to kill microbes and release more cytokines to stimulate inflammation
2. Alternative Macrophage Activation (M2) –> “Anti-Inflammatory”, Activated by IL-13 and IL-4; Principal function is going to be in Tissue Repair - Secrete Growth Factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis; Cause the release of TGF-Beta and IL-10

(Figure 3-20; Pg. 95)

Question 34

Differentiate between the various types of T Lymphocytes:

1. TH1 Cells
2. TH2 Cells
3. TH17 Cells

Explain the Relationship between Macrophages and T Lymphocytes.

Answer 34

1. TH1 Cells –> Produces IFN-gamma which is going to activate macrophages (Bacteria and Virus Defense)
2. TH2 Cells –> Secrete IL-4, IL-5, and IL-13 which will recruit and activate eosinophils and activate the alternative macrophages (Helminthic Parasite and allergic inflammation defense)
3. TH17 Cells –> Secrete IL-17 which will induce the secretion of chemokines responsible for recruiting neutrophils (and monocytes) into the reaction (Bacteria and Virus Defense)

Relationship –> Figure 3-21; Pg. 97

Question 35

Describe the role of B Lymphocytes in Chronic Inflammation.

Answer 35

Plasma Cells cluster together in some inflammatory reactions and form Tertiary Lymphoid Organs as seen in RHEUMATOID ARTHRITIS and HASHIMOTOS THYROIDITIS

Question 36

Describe the role of the various cells in chronic inflammation:

1. Eosinophils
2. Mast Cells
3. Neutrophils

Answer 36

1. Eosinophils –> Abundant in infections mediated by IgE and parasitic infections; Contain granules with MAJOR BASIC PROTEIN (highly cationic protein that is toxic to parasites, BUT also causes lysis of mammalian epithelial cells)
2. Mast Cells –> Express the receptor FceRI which will bind to the Fc portion of IgE antibodies
3. Neutrophils –> Usually just for Acute Inflammation but can be activated and recruited during chronic inflammatory reactions (i.e. Smoking); Called “Acute on Chronic”

Question 37

Describe what a granulomatous inflammation pattern is and what the TWO main types are.

Answer 37

Form of Chronic inflammation characterized by collections of activated macrophages, often with T Cells and sometimes associated with Central Necrosis.

*** Will have the presence of GIANT cells

1. Foreign Body Granulomas –> IV use and sutures
2. Immune Granulomas –> Produces granulomas when the inciting agent is difficult to eradicate; Macrophages will activate T-Cells and T-Cells will keep activating the Macrophages

Question 38

Describe the morphology of Granulomas.

Answer 38

1. Activated macrophages have a Pink Granular Cytoplasm with distinct cell boundaries and are called EPITHELIOID CELLS
2. Multinucleated GIANT CELLS
3. Crossly it is Casseous Necrosis

Figure 3-23; Pg. 98

Question 39

List some diseases that are involved with Granulomatous Inflammation.

Answer 39

Table 3-8; Pg. 98

Question 40

Describe the various clinical manifestations that are involved in the acute-phase response:

1. Fever
2. Acute-Phase Proteins
3. Leukocytosis

Answer 40

1. Fever –> Elevation of body temperature by 1-4 Degrees; PYROGENS (substances that induce fever): Exogenous Pyrogens (Bacterial Products - LPS) causes Leukocytes to release Endogenous Pyrogens (IL-1 and TNF) which will increase COX enzymes to convert AA to Prostaglandins. PGE2 is the main prostaglandin that is going to cause the Hypothalamus to raise the set point temperature (NSAIDs will lower fever by inhibiting prostaglandin synthesis)
2. Acute-Phase Proteins –> IL-6 (C-Reactive Protein & Fibrinogen) and IL-1 or TNF (Serum Amyloid A protein); Proteins bind to microbial cell walls and may act as opsonins; Fibrinogen will bind to RBCs and form stacks which will cause them to settle more rapidly than normal RBCs in regards to their Erythrocyte Sedimentation Rates; Elevated CRP is a marker for increased risk of MI in patients with CAD. Inflammation involving atherosclerotic plaque in the Coronary arteries may predispose one to THROMBIS; HEPCIDIN is also increased and if it remains high for long periods of time you can get ANEMIA
3. Leukocytes is –> Leukemoid Reactions (40,000 to 100,000 cells/mL); LEFT SHIFT - Rise in the number of more immature neutrophils in the blood due to an infection; Neutrophilia (most bacterial infections cause an increase in neutrophil count); Lymphocytosis (Viral Infections cause an increase in the TOTAL amount of lymphocytes); Eosinophilia (Allergies and Parasitic infections cause an increase in the number of Eosinophils); Leukopenia (DECREASE in the number of circulating white blood cells)

*** Also includes Increased Pulse and BP, Decreased sweating, shivering, chills, etc.

*** Sepsis –> Causes enormous quantities of TNF and IL-1 to be released

Question 41

Describe the two types of repair of damaged tissues:

1. Regeneration
2. Scar Formation

Answer 41

1. Regeneration –> Occurs by proliferation of cells that have survived the injury and retain the capacity to proliferate
2. Scar Formation –> Damage is too great for complete restoration; Fibrous tissue is used to repair the damage; FIBROSIS occurs when you have a lot of Collagen deposited around organs (lungs, liver, kidney); ORGANIZATION (If fibrosis develops in a tissue space occupied by an inflammatory exudate; i.e. Organizing pneumonia affecting the lung)

Figure 3-24; Pg. 100

Question 42

Describe the various types of tissues that are based on their proliferative capacities:

1. Labile Tissues
2. Stable Tissues
3. Permanent Tissues

Answer 42

1. Labile Tissues –> Continuously being lost and replaced! Tissues can readily regenerate after injury if them pool of stem cells is in tact
2. Stable Tissues –> Cells of tissues that are quiescent (in the G0 stage of cell division) and have MINIMAL proliferative activity in their normal state but can help contribute to regeneration in the case of injury
3. Permanent Tissues –> Terminally differentiated; Neurons and Cardiac cells will present with a scar after injury

Question 43

What is the most important source for Growth factors?

Answer 43

MACROPHAGES that are located near the site of cell damage and activated by the tissue injury (Epithelial and Stromal Cells also produce these factors)

Question 44

After blood loss, what is the growth factor called that will drive the regeneration of new RBCs?

Answer 44

Colony-Stimulating Factors (CSFs)

Question 45

Describe the process of Liver Regeneration.

Answer 45

1. Proliferation of hepatocytes –> About 90% of the liver can be regenerated in this fashion; Process occurs in Distinct Stages
   - - Priming Phase: IL-6 (Produced by Kupffer Cells) act on hepatocytes to make the parenchymal cells able to respond to growth factor signals
   - - Cell Proliferation Phase: Controlled by growth factors; HGF (Binds to MET) and EGF/TGF-alpha (Bind to EGFR)

Figure 3-25; Pg. 102

2. Liver Regeneration from Progenitor Cells –> Reside in Canals of Herring (bile canaliculi connect with larger bile ducts) and can drive the proliferation of progenitor cells and their differentiation to mature hepatocytes

Question 46

Describe the various steps in Scar Formation:

1. Angiogenesis
2. Formation of Granulation Tissue
3. Remodeling of Connective Tissue

Answer 46

1. Angiogenesis –> VEGF (drives angiogenesis and Vascular Permeability); This “leakiness” is going to account for the edema that may persist in healing wounds after the acute inflammatory response has resolved; NOTCH signaling is involved in sprouting of new vessels
2. Formation of Granulation Tissue –> Depends on the size of the tissue deficit and the intensity of inflammation
3. Remodeling of Connective Tissue –> Amount of connective tissue will increase in the Granulation Tissues, resulting in a scar;

Figures 3-26 & 3-27; Pg. 103

Question 47

Describe the role of Macrophages in tissue repair.

Answer 47

Clear Debris from dead cells, Provide Growth Factors, and secrete cytokines

*** Alternatively Activated (M2) Type is most often seen in Tissue Repair

Question 48

Describe the Mechanism of Angiogenesis that is involved in Tissue Repair.

Answer 48

Steps:

1. Vasodilation response by NO and INCREASED vascular Permeability by VEGF (Vascular Endothelial Growth Factor)
2. Separation of Pericles from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel
3. Migration of endothelial cells toward the area of tissue injury
4. Proliferation of endothelial cells just behind the leading fron of migrating cells
5. Remodeling the capillary beds
6. Recruitment of Periendothelial cells to form the mature vessels
7. Suppression of endothelial proliferation and migration and deposition of the basement membrane

Figure 3-28; Pg. 104

Question 49

Describe the various signaling pathways involved in Angiogenesis:

1. Growth Factors
2. Notch Signaling
3. ECM proteins
4. Enzymes

Answer 49

1. Growth Factors –> VEGF-A (Stimulates migration and proliferation of endothelial cells; Promotes Vasodilation by stimulating the production of NO); Fibroblast Growth Factors (Mainly FGF-2; Stimulates proliferation of endothelial cells; Promotes the migration of macrophages and fibroblasts to the damaged area); Angiopoietins 1 and 2 (Ang 1 and Ang 2; Play a role in the Maturation of new blood vessels. Ang 1 interacted with Tyrosine kinase receptor on endothelial cells (called Tie2); PDGF (Recruits smooth muscle); TGF-Beta (suppresses endothelial proliferation and migration, and enhances the production of ECM proteins)
2. Notch Signaling –> Works with VEGF in order to ensure that the SPROUTING of blood vessels have enough room to proliferate and grow
3. ECM Proteins –> Provides the scaffolding for Vessel Growth
4. Enzymes –> Matrix Metalloporteinase (MMPs) degrade the ECM to permit remodeling and extension of the vascular tube

Question 50

What is the MOST IMPORTANT cytokine for synthesis and deposition of connective tissue proteins?

Why?

Answer 50

TGF-Beta

*** Functions: Stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of Metalloproteinases.

*** Antiinflammatory Agent by terminating the inflammatory responses and inhibiting lymphocyte proliferation and the activity of other Leukocytes

Question 51

What are myofibroblasts?

Answer 51

Fibroblasts that have smooth muscle cells and the presence of actin filaments

*** Contribute to the contraction of the scar overtime

Question 52

Describe the process of remodeling the connective tissue in a scar.

Answer 52

Matrix Metalloproteinases –> DEGRADATION of ECM and include many different proteinases

• • Interstitial Collagenases (Cleave Fibrillar Collagen; MMP-1, -2, -3)
• • Gelatinases (Degrad amorphous collagen and Fibronectin; MMP-2 and -9)
• • Stromelysins (MMP-3, -10, and -11; Degrad Proteoglycans, Laminin, Fibronectin, and Amorphous Collagen)

*** Produced as inactive Zymogens (activated by Proteases - i.e. Plasmin)

TISSUE INHIBITORS OF METALLPOPROTEINASES (TIMPs) –> Shut down the function of MMPs

A Disintegrin and Metalloproteinase (ADAMs) –> Anchored to the Plasma Membrane and will Cleave and Release TNF, TGF-Beta and members of the EGF Family

Question 53

Differentiate between Resolution and Organization in regards to an exudate located in the interstitial space.

Answer 53

1. Resolution –> Repair occurs by digestion of the exudate initiated by the proteolytic enzymes of leukocytes and resorption of the liquefied exudate
2. Organization –> Granulation tissue grow into the exudate and a fibrous scar forms

Question 54

Differentiate between the two types of healing of skin wounds:

1. Healing by First Intention
2. Healing by Second Intention

Answer 54

1. Healing by First Intention –> Good example is healing of a surgical incision approximated by sutures; Consists of Three Steps: 1. Inflammation, 2. Proliferation of epithelial and other cells, 3. Maturation of the connective tissue scar
   - - Wounding causes rapid activation of the coagulation pathway and you will have a scab form on the outside of the wound
   - - Within 24 hours, Neutrophils will have shown up to the wound and release proteolytic enzymes to clear the debris
   - - By Day 3, Neutrophils have largely been replaced by macrophages, and granulation tissue is going to invade the space
   - -By Day 5, new vessels are reaching their peak numbers as the granulation tissue fills in the space of the wound; Macrophages are the main source for all of the growth factors that are responsible for the migration and proliferation of Fibroblasts; Fibroblasts produce collagen fibers and ECM proteins to bridge the incision;
   - - During the Second Week, Continued collagen accumulation and fibroblast proliferation; Process of “Blanching” begins by increasing collagen deposition within the scar and the regression of vascular channels
   - - By the end of the first month, the scar will have no more inflammatory cells and is covered by an essentially normal epidermis
2. Healing by Second Intention –> Used when the cell or tissue loss is more extensive; At first you will use a Provisional Matrix (Fibrin, Plasma Fibronectin, and Type III Collagen) and in 2 weeks is replaced with a matrix composed primarily of Type I Collagen; Wound Contracture is going to use the help of MYOFIBROBLASTS and will reduce the size of the wound to 5-10% of their original size by 6 weeks

Figure 3-29; Pg. 107 and Figure 3-30; Pg. 108

Question 55

How does wound Strength increase?

Answer 55

Carefully sutured wounds are going to be 70% of the strength that is present in normal skin

*** When the sutures are removed, you are going to lose 10% of that strength. The tensile strength is regained when you have an excess of collagen synthesis over collagen degradation during the first 2 months of healing (Wound strength will reach a maximum of 70-80% of the normal tissue after 3 MONTHS)

Question 56

Describe the mechanism of Fibrosis in Parenchymal Organs.

Answer 56

Figure 3-31; Pg. 109

Major Cytokine involved in Fibrosis is: TGF-Beta

Question 57

Describe some complications that will lead to Abnormalities in Tissue Repair.

Answer 57

1. Inadequate formation of granulation tissue or formation of a scar can lead to two types of complications: 1. WOUND DEHISCENCE (Rupture of wound. Occurs most frequently after abdominal surgery with increase abdominal pressure), 2. ULCERATION (Due to inadequate vascularization during healing; Patients with lower extremity wounds that have atherosclerosis tend to ulcerated because not enough blood is getting to the wound)
2. Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids –> Accumulation of excessive amounts of collagen; If the scar grows beyond the boundary of the original wound it is called a KELOID (More common in African Americans); HYPERTROPHIC scars generally develop after an injury that involved the deep layers of the dermis

Figure 3-32; Pg. 110

3. Exuberant Granulation –> Formation of excessive amounts of granulation tissue which protrudes above the level of the surrounding skin and blocks reepithelialization (aka “Pround Flesh”); Excessive granulation must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium; Desmond’s or Aggressive Fibromatoses will lie in the interface between Beningn and Malignant tumors
4. Contraction of the size of a wound –> More prone to develop of the palms, the soles, and the anterior aspect of the thorax. Commonly seen after serious BURNS and can compromise the movement of joints.