Tissue Injury, Inflammation, and Repair

Question 1

Exudate

Answer 1

Extravascular fluid with high protein and cellular content, released from the vascular system into the interstitial tissue as a result of increased vessel permeability

Question 2

Transudate

Answer 2

Extravascular fluid with low protein and cellular content; released from vessels as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability

Question 3

Increased vessel permeability

Answer 3

Occurs as a result of the contraction of endothelial cells, signaled by histamine, bradykinin, leukotrienes, PAF, and substance P

Question 4

Pus

Answer 4

Purulent exudate rich in leukocyte (mostly neutrophils), cellular debris, and often microbes

Question 5

Leukocyte adhesion

Answer 5

Occurs as a result of TNF and IL-1 release from M1 macrophages; adhesion molecules on leukocytes (L-selectin) and on endothelium (E-selectin) are expressed; low-affinity reactions between adhesion molecules lead to “rolling” of leukocytes along the endothelial wall

Question 6

Diapedesis

Answer 6

TNF and IL-1 released by M1 macrophages activate endothelial cells in the post-capillary venules to express E-selectin; E-selectin interacts with L-selectin on the surface of neutrophils; neutrophils adhere to the endothelial wall and can slip through gaps in the “leaky” endothelium to enter the underlying connective tissue

Question 7

Role of Neutrophils in acute inflammation

Answer 7

Neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours; they appear early because they are numerous in the blood, respond rapidly to chemokines, and attach firmly to endothelial adhesion molecules

Neutrophils phagocytose bacteria and tissue debris; they release ROS and proteolytic enzymes

Question 8

How do neutrophils recognize microbes?

Answer 8

Mannose receptors - recognize molecules found on microbial cell walls

Opsonin receptors - recognize IgG antibodies, C3b component of complement, and other opsonins

Question 9

How to neutrophils kill microbes?

Answer 9

Neutrophils generate reactive oxygen species (ROS) within their lysosomes, where the phagocytosed materials are segregated; phagocyte oxidase oxidizes NADPH and reduces O2 to the superoxide anion O2-, which is convered into hydrogen peroxide, H2O2, which is converted into hypochloride (OCl-), a potent antimicrobial agent

Question 10

Histamine

Answer 10

Amine class; Stored as pre-formed molecules within mast cells located in connective tissue adjacent to blood vessels

Release stimulated by cellular trauma, binding of antibodies to mast cells, recognition of anaphylatoxins C3a and C5a, substance P, IL-1

Effects: Vasodilation, increased vascular permeability

Inactivation: Hisaminase

Question 11

Serotonin

Answer 11

Amine class; Stored as a pre-formed molecule within platelets

Release stimulated when platelets aggregate after contact with collagen

Effects: Increases vascular permeability

Serotonin mediates the linkage between clotting and inflammation

Question 12

Termination of the acute inflammatory response

Answer 12

Degradation of inflammatory mediators
Neutrophil apoptosis within hours after leaving the blood
Release of anti-inflammatory cytokines (TGF-B and IL-10) from macrophages

Question 13

Prostaglandins (PGs)

Answer 13

Lipid class; Produced by mast cells, macrophages, endothelial cells, etc. via the action of COX1 and COX2 on arachidonic acid; different prostaglandins are made in the tissues by tissue-speciic enzymes and function in vasodilation, fever, and pain

Question 14

Production of Prostaglandins & Leukotrienes

Answer 14

Phospholipase A2 enzyme cleaves membrane Arachidonic Acid; arachidonic acid is cleaved by COX1 and COX2 to make Prostaglandins or by 5-lipoxygenase to produce leukotrienes

Question 15

Thromboxane (TxA2)

Answer 15

A prostaglandin produced by thromboxane synthetase in platelets

Effects: Increases platelet aggregation and vasconstriction

Question 16

Leukotrienes

Answer 16

Lipid class; Produced by lipoxygenase enzymes from arachidonic acid

Mainly secreted by macrophages & leukocytes

Increase vascular permeability and chemotactic for WBCs

Question 17

Prostacyclin

Answer 17

A prostaglandin produced by prostacyclin synthetase in vascular endothelium

Effects: Increases vasodilation and vascular permeability, decreases platelet aggregation

Question 18

Platelet Activating Factor (PAF)

Answer 18

Lipid class; Newly synthesized by platelets as well as all leukocytes and endothelial cells

Effects: Platelet aggregation, vasoconstriction

Question 19

Lipoxins

Answer 19

Generated from arachidonic acid by the lypoxygenase pathway

Effects: Inhibit leukocyte recruitment, inhibit neutrophil recruitment, negatively regulate leukotrienes

Question 20

Nitric Oxide (NO)

Answer 20

Newly synthesized from L-arginine by the enzyme nitric oxide synthase (NOS) in macrophages

Effects: Vasodilation, relaxation of smooth muscle, reduced platelet adhesion

Question 21

Reactive Oxygen Species (ROS)

Answer 21

Newly synthesized by macrophages and neutrophils; major species are superoxide anion O2-, hydrogen peroxide H2O2, and hydroxyl radical OH-

Effects: destroy phagocytosed microbes

Question 22

TNF and IL-1

Answer 22

Major cytokines of acute inflammation, produced by M1 activated macrophages

Effects: Endothelial activation, including induction of endothelial adhesion molecules and activation of acute-phase response; fever production; WBC chemotaxis

Question 23

Chemokines

Answer 23

Small proteins that act as chemoattractants for leukocytes into areas of inflammation

Question 24

Neutrophil granule contents

Answer 24

Primary and secondary granules contain a wide variety of enzymes

Acid hydrolases degrade bacteria and debris within the phagolysosomes, in which acid pH is maintained; neutral proteases degrade extracellular components (i.e. collagen, basement membrane, etc.) resulting in collateral tissue damage

Question 25

Cytokines

Answer 25

Newly synthesized by lymphocytes, macrophages, and endothelial cells Ex: TNF and IL-1 in acute inflammation, IFN-y in chronic inflammation

Question 26

Substance P

Answer 26

Neuropeptide secreted by sensory nerves, especially in the lung and GI tract; Effects: Transmission of pain signals, regulation of blood pressure, increased vascular permeability

Question 27

Role of C3a and C5a in inflammation

Answer 27

C3a and C5a are anaphylatoxins - they stimulate release of histamine from mast cells, causing increased vascular permeability and vasodilation C5a is also chemotactic for leukocytes

Question 28

Mechanism of the intrinsic clotting pathway

Answer 28

Factor XII is produced by the liver and circulates in an inactive form in the plasma; Factor XII is activated by contact with negatively charged surfaces (i.e. basement membrane, collagen) and becomes factor XIIa; factor XIIa activates the clotting cascade, leading to production of thrombin; thrombin activates the enzymatic conversion of fibrinogen into fibrin and fibrin split products

Question 29

Kinin Pathway

Answer 29

Factor XIIa converts plasma prekallikrein into active enzyme kallikrein, which cleaves kininogens to produce Bradykinin Bradykinin increases vasodilation and vascular permeability, and causes increased transmission of pain Bradykinin is quickly inactivated by the enzyme kininase

Question 30

Fibrinolytic System

Answer 30

The fibrinolytic system counterbalances the clotting cacasde by solubizing clots via cleavage of the plasma protein plasminogen to form plasmin, an active protease Factor XIIa converts plasma prekallikrein to active enzyme kallikrein; kallikrein converts plasminogen to plasmin; plasmin not only solubizes clots by cleaving fibrin to form fibrin split products but also cleaves C3 and C5 of the complement cascade to C3a and C5a, which are anaphylatoxic

Question 31

Role of C3b in inflammation

Answer 31

C3b is an opsonin - it affixes to microbial cell walls and promotes phagocytosis by neutrophils and macrophages which bear cell surface receptors for the complement fragments

Question 32

Role of mast cells in chronic inflammation

Answer 32

Mast cells contain on their surface a receptor that binds to the Fc portion of IgE; in immediate hypersensitivity reactions, IgE bound to mast cells causes degranulation and release of histamine and prostaglandins Mast cells are also activated to release histamine by C3a and C5a components of the complement system

Question 33

Migration and activation of macrophages in chronic inflammation

Answer 33

Monocytes from the blood migrate into extravascular tissue early in acute inflammation and differentiate into phagocytic macrophages Macrophages are activated by the classical pathway via IFN-y secreted by Th1 cells; they phagocytose pathogens and secrete TNF and IL-1 Macrophages can be alternatively activated by IL-4 secreted by Th2 cells; these macrophages secrete TGF-B and participate in tissue remodeling, angiogenesis, and scar formation

Question 34

Role of eosinophils in chronic inflammation

Answer 34

Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections; eosinophils have granules that contain Major Basic Protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells

Question 35

Acute Phase Response - Components

Answer 35

``` Fever Leukocytosis Increased pulse Increased BP Shivering Chills Anorexia Malaise ```

Question 36

Fever - Mechanism

Answer 36

Produced in response to pyrogenic substances that stimulate prostaglandin synthesis in the hypothalamus Pyrogens may be exogenous (i.e. bacterial products) or endogenous (i.e. cytokines such as IL-1 and TNF released from activated leukocytes) Pyrogens increase COX1 and COX2 activity converting arachidonic acid into prostaglandins; in the hypothalamus, prostaglandins stimulate the production of neurotransmitters which re-set the body's thermostat to a higher level

Question 37

Leukocytosis

Answer 37

Occurs as part of the acute phase response Cytokines (TNF and IL-1) stimulate accelerated release of immature leukocytes from the bone marrow Bacterial infections cause neutrophilia Viral infections cause lymphocytosis Asthma, allergy, and parasitic infections cause eosinophilia

Question 38

Formation of blood clot

Answer 38

Wounding causes the rapid activation of coagulation pathways leading to the formation of a clot containing fibrin, fibronectin, and complement components; the clot stops bleeding and serves as a scaffold for migrating cells attracted by local chemokines Within 24 hours, neutrophils appear at the margins of the wound, releasing proteolytic enzymes that clean out debris and bacteria

Question 39

Formation of Granulation Tissue

Answer 39

Fibroblasts and vascular endothelial cells proliferate to form a specialized tissue called granulation tissue, characterized by the processes of angiogenesis and fibroblast proliferation

Question 40

Scar formation, Wound Contraction, and Recovery of Tensile Strength

Answer 40

Granulation tissue scaffolding is converted into avascular scar tissue composed of fibroblasts, collagen, elastin, and other ECM components Wound contraction results from the formation of a network of myofibroblasts at the edges of the wound; these cells have characteristics of smooth muscle and contract int he wound tissue to draw the edges closer together Recovery of tensile strength is mostly due to the accumulation of type I collagen

Question 41

Systemic factors affecting wound repair

Answer 41

Nutrition - protein and Vitamin C deficiencies Metabolic Status - Diabetes Mellitus Circulatory status - arteriosclerosis, venous stasis Hormones - glucocorticoids

Question 42

Local factors that affect wound healing

Answer 42

Infection - persistent tissue injury and inflammation Mechanical stress - may compress blood vessels and seperate the edges of the wound Foreign bodies Size, location, and type of wound

Question 43

Hypertrophic and Keloid Scar Formation

Answer 43

Hypertrophic scar - accumulation of excessive amounts of collagen giving rise to a raised scar Keloid scar - scar tissue grows beyond the boundaries of the original wound and does not regress

Question 44

Fibrosis

Answer 44

Excessive deposition of collagen as a result of chronic inflammation Alternatively activated macrophages produce TGF-B, which causes increased fibroblast migration and proliferation, increased synthesis of collagen, and decreased degradation of ECM components due to inhibition of MMPs

Question 45

Coagulative (Ischemic) Necrosis

Answer 45

The dead cell remains a "ghost-like remnant" of its former self; occurs in stages: Pyknosis - the cell nucleus shrinks and stains darkly Karyorrhexis - fragmentation of the pyknotic nucleus Karyolysis - complete break down and disappearance of the nucleus Classically seen following MI

Question 46

Liquefactive Necrosis

Answer 46

Dead cell dissolves away as lysosomal hydrolases digest cellular components Commonly seen in the brain and spleen, and with acute infection

Question 47

Caseous Necrosis

Answer 47

Seen only in tuberculosis infection; the central portion of an infected lymph node becomes necrotic due to toxic levels of mycobacteria, producing a soft, whitish-grey tissue

Question 48

Fat Necrosis

Answer 48

Leakage of lipases from dead cells attack triglycerides in surrounding adipose cells and generate free fatty acids and calcium soaps with a chalky white appearance Classically seen in the pancreas following acute infection

Question 49

Burns - Partial vs. Total Thickness

Answer 49

Partial Thickness burns affect the epidermis but not the dermis Total thickness burns involve complete destruction of the epidermis and dermis, including dermal appendages (i.e. hair shaft) and the stem cells found in these areas

Question 50

Hyperthermia - Exertional vs. Classic

Answer 50

Exertional Hyperthermia - may lead to rhabdomyolysis (breakdown of skeletal muscle fibers), lactic acidosis, disseminated intravascular coagulation (DIC), and acute tubular necrosis (ATN) Classic heat stroke - typically seen in hot, humid weather affecting young, old, and ill patients; may lead to respiratory alkalosis 2/2 hyperventilation, hypotension, and coma

Question 51

How does the body neutralize ROS?

Answer 51

Superoxide radicals (O2-) are neutralized by the enzyme superoxide dismutase (SOD), which generates H2O2 H2O2 itself is a reactive species that is neutralized by catalase Glutathione Peroxidase neutralizes ROS

Question 52

Early changes seen in injured cells

Answer 52

1. Cell Membrane - Lipid peroxidation, cell swelling 2. Mitochondria - Swelling 3. ER - Swelling, leading to detachment of polyribosomes from rough ER and decreased protein synthesis 4. Nucleus - decreased synthesis of rRNAs in the nucleolus

Question 53

Classic Pathway of Necrosis

Answer 53

Irreversible changes in the cell membrane occur leading to Ca2+ influx across the plasma membrane and from stores in the ER; intracellular Ca2+ activates Ca2+ dependent proteases and lipases; the mitochondrial membrane permeability transition pore (MTP) is opened, with a loss of the ability of the mitochondria to make ATP; the cytoplasm and mitochondria swell and eventually burst, releasing intracellular contents

Question 54

IFN-y

Answer 54

Produced by Th1 and Th17 cells; activates M1 macrophages

Question 55

IL-17

Answer 55

Produced by Th17 cells; recruits neutrophils and monocytes

Question 56

Critical Features of Acute Inflammation

Answer 56

Vasodilation - causes erythema (redness) and warmth Increased vascular permeability - causes swelling Inflammatory cell infiltrate - neutrophils predominate

Question 57

Abscess

Answer 57

An accumulation of inflammatory fluid that develops within a confined space, forming a new cavity; neutrophils predominate

Question 58

Empyema

Answer 58

An accumulation of inflammatory infiltrate located within an anatomic space or cavity (i.e. pleural empyema, subdural empyema); neutrophils predominate early but macrophages & lymphs also seen

Question 59

Cellulitis

Answer 59

An inflammatory infiltrate located in the skin (epidermis, dermis) - usually bacterial (staph or strep) but may be inflammatory Involvement of the deep fascia is called "necrotizing fasciitis"

Question 60

Granuloma

Answer 60

Accumulation of inflammatory infiltrate within the parenchyma (i.e. lung, liver, spleen) forming a rounded, nodular structure; contains macrophages, lymphocytes, and plasma cells Epitheloid / Giant Macrophages predominate May be mineralized and so visible on X ray

Question 61

Functions of Macrophages - Key Processes & Chemical Mediators

Answer 61

1. Removal of injured tissue and debris - phagocytosis, collagenase, elastase 2. Anti-microbial activity - ROS 3. Chemotaxis and proliferation of fibroblasts (repair) - TGF-B 4. Angiogenesis - VEGF 5. Deposition and remodeling of ECM: TGF-B, MMPs

Question 62

Chemical mediators of vasodilation

Answer 62

Prostaglandins NO Histamine

Question 63

Chemical Mediators of Vascular Permeability

Answer 63

``` Histamine and Serotonin C3a and C5a via their actions as anaphylatoxins Bradykinin Leukotrienes PAF Substance B ```

Question 64

Chemical Mediators of Fever

Answer 64

IL-1, TNF | Prostaglandins

Question 65

Chemical Mediators of Pain

Answer 65

Prostaglandins Bradykinin Substance B

Question 66

Chemical Mediators of Tissue Damage & Microbicide

Answer 66

ROS | Lysosomal enzymes of leukocytes

Question 67

C3a and C5a

Answer 67

Complement cascade components produced in the liver Effect: Anaphylatoxic; bind receptors on Mast cells, triggering release of Histamine leading to vasodilation, increased vascular permeability, and WBC chemotaxis

Question 68

Bradykinin

Answer 68

Plasma protein derived from proteolysis of kininogens by Kallikrein proteases Functions: Vasodilation, increased vascular permeability, pain Inactivation: Kininases

Question 69

Hereditary Angioedema

Answer 69

Caused by a deficiency in the C1 esterase inhibitor (C1-INH) enzyme; C1-INH is responsible for down-regulating the complement pathway Characterized by pathologic inflammation/edema

Question 70

Histologic changes seen with acute MI

Answer 70

Injury Phase - Cytoplasmia eosinophilia, loss of myocyte nuclei Acute phase - PMN infiltrate Chronic Phase - Foamy macrophages, increased fibroblasts, neovascularization Repair Phase - Fibroblasts surrounded by lots of collagen fibers, some lymphocytes

Question 71

What are the histologic criteria for the diagnosis of cirrhosis?

Answer 71

1. Fibrosis 2. Regenerative nodules 3. Alteration in architecture / blood flow