Rr 02 Inflammation And Repair Part 2

Front 1

Describe the factors involved in tissue repair

Back 1

1. Parenchymal cell regeneration
2. Repair by connective tissue (fibrosis)

Front 2

Describe the sequence of formation of a tuberculous granuloma

Back 2

1. The tubercle bacillus Mycobacterium tuberculosis undergoes phagocytosis by alveolar macrophages (processing of bacterial antigen)
2. Macrophages present antigen to CD4 T cells in association with class II antigen sites
3. Macrophages release IL12 (stimulates naïve Th cells to produce Th1 class memory cells) and IL1 (causes fever, activates Th1 cells)
4. Th1 cells release IL2 (stimulates Th1 proliferation), gamma-interferon (activates macrophages to kill tubercle bacillus; epithelioid cells), and migration inhibitory factor (causes macrophages to accumulate)
5. Lipids from killed tubercle bacillus lead to caseous necrosis
6. Activated macrophages fuse and become multinucleated giant cells

Front 3

Describe parenchymal cell regeneration

Back 3

1. Depends on the ability of cells regeneration
a. Labile cells (eg stem cells in epidermis) and stable cells (eg fibroblasts) can replicate
b. Permanent cells cannot replicate
-Cardiac and striated muscle are replaced by scar tissue (fibrosis)
2. Depends on factors that stimulate parenchymal cell division and migration
-Stimulatory factor include loss of tissue and production of growth factors
3. Cell cycle
4. Restoration to normal

Front 4

Describe the phases of the cell cycle

Back 4

1. G0 phase: Resting phase of stable parenchymal cells
2. G1 phase: Synthesis of RNA, protein, organelles, and cyclin D
3. S (synthesis) phase: Synthesis of DNA, RNA, protein
4. G2 phase: Synthesis of tubulin, which is necessary for formation of the mitotic spindle
5. M (mitotic) phase: Two daughter cells are produced

Front 5

Describe the regulation of the G1 checkpoint (G1 to S phase)

Back 5

1. Most critical phase of the cell cycle
2. Control proteins include cyclin-dependent kinase 4 (Cdk4) and cyclin D
a. Growth factors activate nuclear transcribing proto-oncogenes to produce cyclin D and Cdk4
b. Cyclin D binds to Cdk4, forming a complex causing the cell to enter the S phase
3. RB (retinoblastoma) suppressor gene
a. RB protein product arrests the cell in the G1 phase
b. Cdk4 phosphorylates the RB protein causing the cell to enter the S phase
4. TP53 suppressor gene
a. TP53 protein product arrests the cell in the G1 phase by inhibiting Cdk4
-Prevents RB protein phosphorylation and, if necessary, provides time for repair of DNA in the cell
b. In the event that there is excessive DNA damage, the BAX gene is activated
-BAX genes inhibits the BCL2 antiapoptosis gene causing release of cytochrome c from the mitochondria and apoptosis of the cell

Front 6

Describe the restoration to normal in parenchymal cell restoration

Back 6

1. Requires preservation of the basement membrane
2. Requires a relatively intact ECM (ie collagen, adhesive proteins)
-Laminin , the key adhesion protein in the basement membrane, interacts with type IV collagen, cell surface receptors, and components in the ECM

Front 7

Describe the function of vascular endothelial cell growth factor (VEGF)

Back 7

Stimulates angiogenesis

Front 8

Describe the function of basic fibroblast growth factor (BFGF)

Back 8

Stimulates angiogenesis

Front 9

Describe the function of epidermal growth factor (EGF)

Back 9

-Stimulates keratinocyte migration
-Stimulates granulation tissue formation

Front 10

Describe the function of transforming growth factor beta (TGF-beta)

Back 10

Chemotactic for macrophages, lymphocytes, fibroblasts

Front 11

Describe the function of insulin growth factor-1 (IGF1)

Back 11

-Stimulates synthesis of collagen
-Promotes keratinocyte migration

Front 12

Describe the function of IL1

Back 12

-Chemotactic for neutrophils
-Stimulates synthesis for metalloproteinases (ie, trace metal containing enzymes)
-Stimulates synthesis and release of acute phase reactants from the liver

Front 13

Describe repair by connective tissue (fibrosis)

Back 13

Occurs when injury is severe or persistent
-Tissue in a third-degree burn cannot be restored to normal owing to loss of skin, basement membrane, and connective tissue infrastructure

Front 14

Describe the steps in repair by connective tissue (fibrosis)

Back 14

1. Requires neutrophil transmigration to liquefy injured tissue and then macrophage transmigration to remove the debris
2. Required formation of granulation tissue
-Accumulates in the ECM and eventually produced dense fibrotic tissue
3. Required the initial production of type III collagen
4.Dense scar tissue produced from granulation tissue must be remodeled

Front 15

Describe remodeling at the end of repair by connective tissue

Back 15

1. Remodeling increases the tensile strength of scar tissue
2. Metalloproteinases (collagenases) replace type III collagen with type I collagen, increasing the tensile strength to approximately 80% of the original

Front 16

Describe Days 1-4 of healing by primary intention

Back 16

Day 1: Fibrin clot (hematoma) develops. Neutrophils infiltrate the wound margins. There is increased mitotic activity of basal cells of squamous epithelium in the apposing wound margins.

Day 2: Squamous cells from apposing basal cell layers migrate under the fibrin clot and seal off the wound after 48 hours. Macrophages emigrate into the wound.

Day 3: Granulation tissue begins to form. Initial deposition of type III collagen begins but does not bridge the incision site. Macrophages replace neutrophils

Days 4-6: Granulation tissue formation peaks, and collagen bridges the incision site

Front 17

Describe Days 4-end of healing by primary intention

Back 17

Days 4-6: Granulation tissue formation peaks, and collagen bridges the incision site

Week 2: Collagen compresses blood vessels in fibrous tissue, resulting in reduced blood flow. Tensile strength is ~10%

Month 1: Collagenase remodeling of the wound occurs (breaks peptide bonds), with replacement of type III collagen by type I collagen. Tensile strength increases, reaching ~80% within 3 months. Scar tissue is devoid of adnexal structures (eg hair, sweat glands) and inflammatory cells.

Front 18

Describe healing by primary intention

Back 18

1. Approximation of wound edges by sutures
2. Used for clean surgical wounds

Front 19

Describe healing by secondary intention

Back 19

1. Wound remains open
2. Used for gaping or infected wounds

Front 20

Describe what occurs in healing by secondary intention

Back 20

Typically, these wounds heal differently from primary intention:
1. Most intense inflammatory reaction than primary healing
2. Increased amount of granulation tissue formation than in primary healing
3. Wound contraction caused by increased numbers of myofibroblasts

Front 21

Describe the factors that impair wound healing

Back 21

1. Persistent infection
2. Metabolic disorders
3. Nutritional deficiencies
4. Glucocorticoids

Front 22

Describe the persistent infections that impair wound healing

Back 22

1. Most common cause of impaired wound healing
2. S. aureus is the most common pathogen
3. Nosocomial and community-acquired methicillin-resistant S. aureus wound infections are increased
a. Vancomycin is used for treating nosocomial infections
b. Trimethoprim-sulfamethoxazole is used for treating community acquired infections

Front 23

Give some an example of how metabolic disorders can impair wound healing

Back 23

Diabetes mellitus increases susceptibility to infection by decreasing blood flow to tissue and increasing tissue levels of glucose

Front 24

Describe nutritional deficiencies that impair wound healing

Back 24

1. Decreased protein (eg malnutrition)
2. Vitamin C deficiency
3. Trace metal deficiency
a. Copper deficiency leads to decreased cross-linking in collagen (also in elastic tissue)
b. Zinc deficiency leads to defects in removal of type III collagen in wound remodeling.
-Type III collagen has decreased tensile strength, which impairs wound healing

Front 25

Describe how copper deficiency affects wound healing

Back 25

Copper deficiency leads to decreased cross-linking in collagen (also in elastic tissue)

Front 26

Describe how zinc deficiency affects wound healing

Back 26

Zinc deficiency leads to defects in removal of type III collagen in wound remodeling.
-Type III collagen has decreased tensile strength, which impairs wound healing

Front 27

Describe how glucocorticoids affect wound healing

Back 27

1. Interfere with collagen formation and decrease tensile strength
2. Useful clinically in preventing excessive scar formation
-Example: Dexamethasone is used along with antibiotics to prevent scar formation in bacterial meningitis

Front 28

Describe keloids

Back 28

-Raised scars caused by excessive synthesis of type III collagen
-Common in blacks
-May occur as the result of third degree burns
-Microscopically, keloids appear as irregular, thick collagen bundles that extend beyond the confines of the original injury

Front 29

Describe repair in liver injury

Back 29

1. Mild injury (eg hep A)
a. Regeneration of hepatocytes
b. Restoration to normal is possible if cytoarchtecture is intact
2. Severe or persistent injury (eg hep C)
a. Regenerative nodules develop that lack sinusoids and portal triads
b. Increased fibrosis occurs around regenerative nodules
-Potential for cirrhosis

Front 30

Describe repair of lung injury

Back 30

1. Type II pneumocytes are the key repair cells of the lung
2. They replace damaged type I and type II pneumocytes
3. They synthesize surfactant

Front 31

Describe repair of brain injury

Back 31

1. Astrocytes proliferate in response to an injury (eg brain infection)
-This is called gliosis
2. Microglial cells (macrophages) are scavenger cells that remove debris (eg myelin)

Front 32

Describe repair in peripheral nerve transaction

Back 32

1. Distal degeneration of axon (Wallerian degeneration) and myelin sheath
2. Proximal axonal degeneration up to the next node of Ranvier
3. Macrophages and Schwann cells phagocytose axonal/myelin debris
4. Muscle undergoes atrophy in ~15 days
5. Nerve cell body undergoes central chromatolysis
6. Schwann cells proliferate in the distal stump
7. Axonal sprouts develop in the proximal stump and extend distally using Schwann cells for guidance
8. Regenerated axon grows 2-3 mm/day
9. Axon becomes remyelinated
10. Muscle is eventually reinnervated

Front 33

Describe what occurs when a nerve cell body undergoes chromatolysis

Back 33

1. Nerve cell body wells
2. Nissl bodies (composed of RER and free ribosomes) disappear centrally
3. Nucleus is peripheralized

Front 34

How fast to axons regenerate?

Back 34

2-3 mm/day

Front 35

Describe the leukocyte findings in acute inflammation

Back 35

1. Absolute neutrophilic leukocytosis
2. Left shift
3. Toxic granulation
4. Increase in serum IgM

Front 36

Describe the absolute neurophilic leukocytosis of acute inflammation

Back 36

1. Accelerated release of neutrophils from the bone marrow
2. Mediated by IL-1 and TNF

Front 37

Describe the left shift that occurs in acute inflammation

Back 37

Defined as greater than 10% band (stab) neutrophil or the presence of earlier precursors (eg metamelocytes)

Front 38

Describe the toxic granulation in acute inflammation

Back 38

Prominence of azurophilic granules (primary lyosomes) in neutrophils

Front 39

Describe the increase in serum IgM that occurs in acute inflammation

Back 39

1. Peaks 7-10 days
2. Isotype switching (mu heavy chain replaced by gamma heavy chain) in plasma cells to produce IgG peaks in 12-14 days

Front 40

Describe the leukocyte findings in chronic inflammation

Back 40

1. Absolute monocytosis
2. Increase in serum IgG

Front 41

Describe the characteristics of neutrophils

Back 41

1. Key cell in acute inflammation
2. Receptors for IgG and C3b: important in phagocytosis of opsonized bacteria
3. There are Bone marrow neutrophil pools
4. There are peripheral blood neutrophil pools

Front 42

Describe bone marrow neutrophil pools

Back 42

-Mitotic pool: myeloblasts, promyelocytes, myelocytes
-Post-mitotic pool: Metamyelocyes, band neutrophils (stabs), segmented neutrophils

Front 43

Describe peripheral blood neutrophil pools

Back 43

-Marginating pool: adherent to the endothelium; account for ~50% of peripheral blood pool
-Circulating pool: measured in complete blood cell count (CBC); account for ~50% of peripheral blood pool

Front 44

Describe the causes of neutrophilic leukocytosis

Back 44

-Infections (eg acute appendicitis)
-Sterile inflammation with necrosis (eg acute MI)
-Drugs inhibiting neutrophil adhesion molecules: corticosteroids, catecholamines, lithium

Front 45

Describe monocytes and macrophages

Back 45

-Key cells in chronic inflammation
-Receptors for IgG and C3b
-Monocytes become macrophages: fixed (eg, macrophages in red pulp), wandering (eg alveolar macrophages)

Front 46

Describe the functions of monocytes and macrophages

Back 46

-Phagocytosis
-Process antigen
-Enhance host immunologic response (secrete cytokines like IL1, TNF)

Front 47

Describe the causes of monocytosis

Back 47

-Chronic inflammation
-Autoimmune disease
-Malignancy

Front 48

Describe B and T cells

Back 48

-Peripheral blood lymphocyte count: T cells 60-70%, B cells 10-20% of the total
-B cell function: Become plasma cells when antigenically stimulated
-T cell functions: Cellular immunity (type IV HSR), cytokines regulate B cells, defense against intracellular pathogens (eg tuberculosis)

Front 49

Describe the causes of B and T lymphocytosis

Back 49

Viral infections

Front 50

Describe Plasma cells

Back 50

-Antibody producing cells derived from B cells
-Morphology: well-developing RER. Bright blue cytoplasmic staining with Wright-Giemsa. Nucleus eccentrically located and has perinuclear clearing

Front 51

Describe mast cells and basophils

Back 51

-Release mediators in acute inflammation and allergic reactions (type I HSR)
-Receptors for IgE

Front 52

Describe the early release reaction of mast cells and basophils

Back 52

Release of preformed mediators (ie, histamine, chemotactic factors, proteases)

Front 53

Describe the late release reaction of mast cells and basophils

Back 53

New synthesis and release of PGs and LTs, which enhance and prolong the acute inflammatory process

Front 54

Describe eosinophils

Back 54

-Receptors for IgE
-Red granules contain crystalline material; Become Charcot-Leyden crystals in the sputum of asthmatics
-Preformed chemical mediators in granules

Front 55

Describe the preformed chemical mediators in the granules of eosinophils

Back 55

1. Major basic protein (MBP) kills invasive helminthes
2. Histamine neutralizes histamine
3. Arylsulfatase neutralizes leukotrienes

Front 56

Describe the functions of eosinophils

Back 56

1. Modulate type I HSR by neutralizing histamine and leukotrienes
2. Destruction of invasive helminthes: IgE receptors interact with IgE coating the surface of invasive helminthes-> antibody dependent cytotoxicity reaction (type II HSR) causes the release of MBP-> kills helminth

Front 57

Describe the cause of eosinophilia

Back 57

-Type I HSR: allergic rhinitis, bronchial asthma
-Invasive helminthic infection excluding pinworks and adult worms in ascariasis, which are not invasive

Front 58

Describe the peripheral blood effects of corticosteroid therapy

Back 58

1. Absolute neutrophilic leukocytosis
-Inhibits activation of neutrophil adhesion molecules
2. Lymphopenia
a. Sequesters B and T lymphocytes in lymph nodes
b. Signal for apoptosis of lymphocytes
3. Eosinopenia
-Sequesters eosinophils in lymph nodes

Front 59

Describe the erythrocyte sedimentation rate (ESR)

Back 59

-ESR is the rate (mm/hour) of settling of RBCs in a vertical tube
1. ESR is increased in acute and chronic inflammation
2. Plasma factor or RBC factors that promote rouleaux formation increase the ESR
a. Increase in fibrinogen (Acute-phase reactant) in plasma decreases negative charge in RBCs, promoting rouleaux formation
b. Anemia promotes rouleaux formation
-Abnormally shaped RBCs (eg sickle cells) do not produce rouleaux

Front 60

Describe how proteins separate in serum protein electrophoresis

Back 60

From anode (+) pole (most negatively charged protein) to cathode(-) pole
-Albumin
-alpha1-globulin
-alpha2-globulin
-beta-globulin
-gamma-globulin
-IgG
-IgA
-IgM
-(IgD and IgE are in very low concentrations)

Front 61

What is the major fibrous component of connective tissue?

Back 61

Collagen

Front 62

Describe Tropocollagen, the structural unite of collagen

Back 62

-A triple helix of alpha chains
1. Undergoes extensive posttranslational modification
2. Hydroxylation reactions in the RER convert proline to hydroxyproline and lysine to hydroxylysine
-Ascorbic acid is required in these hydroxylation reactions
3. Hydroxyproline residues produce bonds that stabilize the triple helix in the tropocollagen molecule
4. Hydroxylysine residues are oxidized to form and aldehyde residue that produces covalent cross-links at staggered intervals between adjacent tropocollagen molecules
-Lysyl oxidase is a MMP enzyme containing copper

Front 63

Describe cross-linking of collagen

Back 63

1. Cross-linking increases the overall tensile strength of collagen (also elastic tissue)
-Type I collagen in skin, bone and tendons has the greatest tensile strength
2. Cross-linking increases with age
-This leads to decreases elasticity of skin, joints, and blood vessels
3. Decreased cross-linking (eg vit C deficiency) reduces the tensile strength of collagen
-In vitamin C deficiency, the structurally weakened collagen in responsible for a bleeding diathesis (eg bleeding into skin and joints) and poor wound healing

Front 64

Describe Ehlers-Danlos syndrome

Back 64

-Consists of a group of mendelial disorders characterized by defect of type I and type III collagen synthesis and structure
-Clinical findings include hypermobile joints, aortic dissection (most common cause of death), bleeding into the skin(ecchymoses), rupture of the bowel, and poor wound healing

Front 65

Describe C-reactive protein

Back 65

1. Acute-phase reactant
2. Clinical usefulness
a. Sensitive indicator of necrosis associated with acute inflammation
-CRP is increased in inflammatory (disrupted) atherosclerotic plaques and bacterial infections
b. Excellent monitor of disease activity (eg rheumatoidarthritis)

Front 66

Describe serum protein electrophoresis (SPE) in acute inflammation

Back 66

1. Slight decrease in serum albumin
a. Catabolic effect of inflammation
b. Amino acids are used by the liver to synthesize acute phase reactants
2. Normal gamma-globulin peak
-Serum IgM is increased in acute inflammation; however, it does not alter the configuration of the gamma-globulin peak

Front 67

Describe serum protein electrophoresis (SPE) in chronic inflammation

Back 67

1. Greater decrease in serum albumin than in acute inflammation
2. Increased in gamma-globulins due to increase in IgG
-Diffuse increase in gamma-globulin peak is due to many clones of benign plasma cells producing IgG (polyclonal gammopathy)