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DD & BL Unit 1 > Tissue Injury, Inflammation, and Repair > Flashcards

Tissue Injury, Inflammation, and Repair Flashcards

1
Q

Exudate

A

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

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2
Q

Transudate

A

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

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3
Q

Increased vessel permeability

A

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

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4
Q

Pus

A

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

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5
Q

Leukocyte adhesion

A

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

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6
Q

Diapedesis

A

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

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7
Q

Role of Neutrophils in acute inflammation

A

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

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8
Q

How do neutrophils recognize microbes?

A

Mannose receptors - recognize molecules found on microbial cell walls

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

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9
Q

How to neutrophils kill microbes?

A

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

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10
Q

Histamine

A

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

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11
Q

Serotonin

A

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

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12
Q

Termination of the acute inflammatory response

A

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

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13
Q

Prostaglandins (PGs)

A

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

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14
Q

Production of Prostaglandins & Leukotrienes

A

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

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15
Q

Thromboxane (TxA2)

A

A prostaglandin produced by thromboxane synthetase in platelets

Effects: Increases platelet aggregation and vasconstriction

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16
Q

Leukotrienes

A

Lipid class; Produced by lipoxygenase enzymes from arachidonic acid

Mainly secreted by macrophages & leukocytes

Increase vascular permeability and chemotactic for WBCs

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17
Q

Prostacyclin

A

A prostaglandin produced by prostacyclin synthetase in vascular endothelium

Effects: Increases vasodilation and vascular permeability, decreases platelet aggregation

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18
Q

Platelet Activating Factor (PAF)

A

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

Effects: Platelet aggregation, vasoconstriction

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19
Q

Lipoxins

A

Generated from arachidonic acid by the lypoxygenase pathway

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

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20
Q

Nitric Oxide (NO)

A

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

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

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21
Q

Reactive Oxygen Species (ROS)

A

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

Effects: destroy phagocytosed microbes

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22
Q

TNF and IL-1

A

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

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23
Q

Chemokines

A

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

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24
Q

Neutrophil granule contents

A

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

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25
Q

Cytokines

A

Newly synthesized by lymphocytes, macrophages, and endothelial cells

Ex: TNF and IL-1 in acute inflammation, IFN-y in chronic inflammation

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26
Q

Substance P

A

Neuropeptide secreted by sensory nerves, especially in the lung and GI tract;

Effects: Transmission of pain signals, regulation of blood pressure, increased vascular permeability

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27
Q

Role of C3a and C5a in inflammation

A

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

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28
Q

Mechanism of the intrinsic clotting pathway

A

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

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29
Q

Kinin Pathway

A

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

30
Q

Fibrinolytic System

A

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

31
Q

Role of C3b in inflammation

A

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

32
Q

Role of mast cells in chronic inflammation

A

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

33
Q

Migration and activation of macrophages in chronic inflammation

A

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

34
Q

Role of eosinophils in chronic inflammation

A

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

35
Q

Acute Phase Response - Components

A 
Fever
Leukocytosis 
Increased pulse
Increased BP
Shivering
Chills
Anorexia 
Malaise
36
Q

Fever - Mechanism

A

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

37
Q

Leukocytosis

A

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

38
Q

Formation of blood clot

A

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

39
Q

Formation of Granulation Tissue

A

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

40
Q

Scar formation, Wound Contraction, and Recovery of Tensile Strength

A

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

41
Q

Systemic factors affecting wound repair

A

Nutrition - protein and Vitamin C deficiencies

Metabolic Status - Diabetes Mellitus

Circulatory status - arteriosclerosis, venous stasis

Hormones - glucocorticoids

42
Q

Local factors that affect wound healing

A

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

43
Q

Hypertrophic and Keloid Scar Formation

A

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

44
Q

Fibrosis

A

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

45
Q

Coagulative (Ischemic) Necrosis

A

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

46
Q

Liquefactive Necrosis

A

Dead cell dissolves away as lysosomal hydrolases digest cellular components

Commonly seen in the brain and spleen, and with acute infection

47
Q

Caseous Necrosis

A

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

48
Q

Fat Necrosis

A

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

49
Q

Burns - Partial vs. Total Thickness

A

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

50
Q

Hyperthermia - Exertional vs. Classic

A

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

51
Q

How does the body neutralize ROS?

A

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

52
Q

Early changes seen in injured cells

A
  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
53
Q

Classic Pathway of Necrosis

A

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

54
Q

IFN-y

A

Produced by Th1 and Th17 cells; activates M1 macrophages

55
Q

IL-17

A

Produced by Th17 cells; recruits neutrophils and monocytes

56
Q

Critical Features of Acute Inflammation

A

Vasodilation - causes erythema (redness) and warmth

Increased vascular permeability - causes swelling

Inflammatory cell infiltrate - neutrophils predominate

57
Q

Abscess

A

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

58
Q

Empyema

A

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

59
Q

Cellulitis

A

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”

60
Q

Granuloma

A

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

61
Q

Functions of Macrophages - Key Processes & Chemical Mediators

A
  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
62
Q

Chemical mediators of vasodilation

A

Prostaglandins
NO
Histamine

63
Q

Chemical Mediators of Vascular Permeability

A 
Histamine and Serotonin
C3a and C5a via their actions as anaphylatoxins
Bradykinin
Leukotrienes
PAF 
Substance B
64
Q

Chemical Mediators of Fever

A

IL-1, TNF

Prostaglandins

65
Q

Chemical Mediators of Pain

A

Prostaglandins
Bradykinin
Substance B

66
Q

Chemical Mediators of Tissue Damage & Microbicide

A

ROS

Lysosomal enzymes of leukocytes

67
Q

C3a and C5a

A

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

68
Q

Bradykinin

A

Plasma protein derived from proteolysis of kininogens by Kallikrein proteases

Functions: Vasodilation, increased vascular permeability, pain

Inactivation: Kininases

69
Q

Hereditary Angioedema

A

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

70
Q

Histologic changes seen with acute MI

A

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

71
Q

What are the histologic criteria for the diagnosis of cirrhosis?

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

DD & BL Unit 1 (6 decks)

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