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Colin MOD > Ch. 3 - Inflammation and Repair > Flashcards

Ch. 3 - Inflammation and Repair Flashcards

1
Q

What are the 5 cardinal clinical signs of inflammation?

A

Calor

Rubor

Tumor

Dolor

Functio Laesa

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2
Q

What is calor?

A

Heat

Warmth is brought to an inflammed area due to vasodilation

Brings warm blood to region

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3
Q

What is Rubor?

A

Redness

Occurs as a result of vasodilation, bringing blood to target region

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4
Q

What is tumor?

A

Swelling

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5
Q

What is Dolor?

A

Pain

Increased nerve ending sensitvity

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6
Q

What is Functio Laesa

A

Loss of Function

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7
Q

What are the 5 Steps/R’s for typical inflammatory reaction?

A
  1. Recognition
    - Offending agent, located in extravascular tissue, is RECOGNIZED by cells and molecules
  2. Recruitment
    - Leukocytes and Plasma proteins are RECRUITED from circulation to site where offending agent is located
  3. Remove
    - Leukocytes and plasma proteins are activated and work together to destroy and eliminate (REMOVE) the offending substance
  4. Regulated
    - The reaction is controlled (REGULATED) and terminated
  5. Repaired
    - The damaged tissue is REPAIRED
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8
Q

What is the time-frame for the onset of acute inflammation?

A

Fast

Minutes to hours

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9
Q

What is the time-frame for the onset of chronic inflammation?

A

Slow

Days

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10
Q

What types of cells infiltrate extravascular tissue in acute inflammation?

A

Mainly neutrophils

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11
Q

What types of cells infiltrate extravascular tissue in chronic inflammation?

A

Monocytes/Macrophages

Lymphocytes (T cells)

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12
Q

What is the tissue injury/fibrosis like in acute inflammation?

A

Usually mild and self-limited

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13
Q

What is the tissue injury/fibrosis like in chronic inflammation?

A

Often severe and progressive

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14
Q

What are the local and systemic signs like in acute inflammation?

A

Prominent

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15
Q

What are the local and systemic signs like in chronic inflammation?

A

Less

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16
Q

What are the stimuli that trigger inflammatory reactions?

A

Infections

Tissue Necrosis

Foreign Bodies

Immune Reactions (hypersensitivity)

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17
Q

What are the three major components of acute inflammation?

A

Vasodilation

Increased Permeability

Emigration of leukocytes

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18
Q

Describe the vasodilation seen in acute inflammation

A

Dilation of small vessels leading to an increase in blood flow

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19
Q

Describe the increase in permeability seen in acute inflammation

A

Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation

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20
Q

Describe leukocyte emigration in acute inflammation

A

Emigration of leukocytes from the microcirculation

Leukocytes then accumulate in the focus of injury, and their activation to eliminate the offending agent

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21
Q

What is exudate?

A

Exudate is an extravascular fluid that has a high protein concentration and contains cellular debris

Exudate is formed in inflammation because:

  • Vascular permeability increases
  • Increased interendothelial spaces
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22
Q

What is transudate?

A

Transudate is a fluid with:

  • Low protein content
  • Little or no cellular debris
  • Low specific gravity

Essentially an ultrafiltrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability

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23
Q

What is edema?

A

Edema denotes an excess of fluid in the interstitial tissue or serous cavities

Can either be either an exudate or a trnsudate

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24
Q

What is pus?

A

Purulent exudate

Inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells, and (in many cases) microbes

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25
Q

What is Leukocyte margination?

A

Normal blood flow confines RBCs to the central axial column

This displaces leukocytes toward the wall of the vessel

When blood flow slows in the event of inflammation, hemodynamic conditions change

This change causes more white cells to assume a peripheral position along the endothelial surface

It is important that WBCs travel along the walls of the vessel so they are in position to exit the vessel when responding to inflammation signals

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26
Q

What is leukocyte rolling?

A

Leukocytes roll along the walls of blood vessels to slow their momentum in order to be able to exit the blood vessel

The initial rolling interactions are mediated by SELECTINS

  • L-selectin (leukocyte)
  • E-selectin (endothelium)
  • P-selectin (platelets)

Expression selectins and their ligands is regulated by cytokines produces in response to infection and injury

TNF and IL-1 act on the endothelial cells of POSTCAPILLARY VENULES adjacent to infection and induce coordinate expression of numerous adhesion molecules

Within 1-2 hours the endothelial cells begin to express E-selectin and the ligands for L-Selectin

The interaction of Selectins between the endothelium and leukocyte cause rolling to occur

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27
Q

What is endothelial adhesion of leukocytes?

A

Firm adhesion is mediated by a family of Heterodimeric Leukocyte Surface Proteins called INTEGRINS

TNF and IL-1 induce endothelial epxression of ligands for integrins, mainly vascular cell adhesion molecule (VCAM-1)

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28
Q

What is CD31?

A

Member of Immunoglobulin (Ig) superfamily

It is an adhesion molecule present in the intercellular junctions between endothelial cells and is involved in the migration of leukocytes

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29
Q

How does leukocyte trans endothelial migration work?

A

Several adhesion molecuels present in the intercellular junctions between endothelial cells are involved in the migration of leukocytes

Including CD31 (or PECAM-1; platelet endothelial cell adhesion molecule)

After traversing endothelium, leukocytes pierce the basement membrane, probably by secreting COLLAGENASES, and enter the extravascular tissue

The cells then migrate toward the chemotactic gradient created bychemokines and other chemoattractants

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30
Q

What is chemotaxis?

A

Leukocytes move in the tissues toward a site of injury via a process called chemotaxis

Chemotaxis is defined as locomotion along a chemical gradient

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31
Q

What are leukocyte chemoattractants?

A

Molecuels responsible for chemotaxis

Bacterial products

  • Peptides that possess an N-formylmethionine terminal amino acid
  • Some lipids

Cytokines
- Particulary of the chemokine family (e.g., IL-8)

Components of Complement System
- Particularly C5a

Arachidonic acid (AA) metabolites
- Mainly Leukotriene B4 (LTB4)
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32
Q

What is the mechanism responsible for chemotaxis?

A

Chemoattractants bind to specific GPCRs on surface fo leukocyte

Transduction signals result in activation of secondary messengers that increase cytosolic Ca2+, thus activating small GTPases of the Rac/Rho/CD24 family and other kinases

These signals induce polymerization of actin at the leading edge of the cell

Leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension (toward source of chemoattractants)

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33
Q

What is the lifespan like for a leukocyte?

A

In most forms of acute inflammation, neutrophils predominate during the first 6-24 hours and replaced by macrophages in 24-48 hours

After entering the tissues, neutrophils are short-lived

They undergo apoptosis and disappear within 24-48 hours

Macrophages not only survive longer, but may also proliferate in the tissues

Thus they become the dominant population in prolonged inflammatory reactions

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34
Q

Why are neutrophils so early to respond to inflammatory signals?

A

They are more numerous in the blood than other leukocytes

They respond more rapidly to chemokines

They may attach more firmly to adhesion molecules

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35
Q

List the steps of leukocyte activation

A
  1. Recognition of the offending agent by TLRs (toll-like receptors) and other receptors
  2. Receptors deliver signals that activate leukocytes to phagocytose and destroy the offending agents
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36
Q

What are the different phagocytic receptors?

A

Mannose Receptors, Scavenger Receptors, and Receptors for various opsonins bind and ingest microbes

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37
Q

What are mannose receptors?

A

Macrophage receptor. It is a lectin that binds TERMINAL MANNOSE AND FUCOSE residues of glycoproteins and glycolipids

Typically part of microbial cell walls

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38
Q

What are scavenger receptors?

A

Bind a variety of microbes in addition to modified LDL particles

Macrophage Integrins, notably Mac-1 (CD11b/CD18) may also bind microbes for phagocytosis

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39
Q

How does opsonization affect phagocytosis?

A

Opsonization is when microbes are targeted by phagocytes when bound with opsonin proteins

Opsonization greatly enhances phagocytosis

The major opsonins are IgG antibodies

IgG is the breakdown product of C3 of the complement system as well as plasma lectins (notably mannose-binding lectin)

Phagocytes express high-affinity receptors for opsonins

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40
Q

How do phagocytes engulf their targets?

A

Once a particle is bound to the phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle.

Phagosome then fuses with a Lysosomal granule, resulting in discharge of the granules contents into the phagolysosome

Phagocytosis is dependent on polymerization of actin filaments

Similar process to chemotaxis

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41
Q

How do leukocytes destroy microbes and debris?

A

Leukocytes use ROS, reactive nitrogen species (derive from NO), and lysosomal enzymes to destroy phagocytosed debris

Most phagocytosed material are brought to the lysosome, segregating potentially harmful substances from the cells cytoplasm and nucleus

Avoids damage to the phagocyte

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42
Q

How are ROS produced and utilized in phagocytes?

A

ROS are prouced in the lysosomes of neutrophils

An enzymatic reaction creates H2O2 (hydrogen peroxide) in the phagolysosome

H2O2 cannot kill microbes

Azurophilic granules of neutrophils contain MYLOPEROXIDASE (MPO)
- Converts H2O2 into HClO (ClO-; hypochlorite; aka bleach)

H2O2-MPO-halide system is most efficient bactericidal system of neutrophils

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43
Q

How are reactive nitrogen species produced and utilized in leukocytes?

A

iNOS = Inducibe NO Species
- kill microbes

Production of iNOS is induced in phagocytes when they are activated by the cytokines (e.g., IFN-gamma) or microbial products

In macrophages:
- NO reacts with superoxide (O2-) to generate the highly reactive free radical PEROXYNITRITE (ONOO-)

Similar to ROS, iNOS attack and damage the lipids, proteins, and nucleic acids of microbes and host cells

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44
Q

How do phagocytes utilize lysosomes?

A

Lysosomes contain proteases that, when released, start breaking down various parts of both bacterial and host cells

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45
Q

What are NETs?

A

Neutrophil Extracellular Traps

They are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of microbes by trapping them in fibrils

Basically a literal net

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46
Q

How are NETs formed?

A

Extracellular traps consist of a viscous meshwork of NUCLEAR CHROMATIN that binds and concentrates granule proteins such as antimicrobial peptides and enzymes

In the process of NET formation, the nuclei of the neutrophils are lost, leading to death of the cells

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47
Q

How does normal leukocyte response become associated with tissue injury?

A

Once leukocytes become activated, their effector mechanisms do not distinguish between offender and host.

The microbical substances that leukocytes produce within the phagolysosome (ROS, NO, lysosomal enzymes) are also released into the extracellular space,

This causes dmage to normal cells and vascular endothelium

The leukocyte response may amplify effects of the initial injurious agent

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48
Q

What are the mechanisms associate with termination of the acute inflammatory response?

A

Inflammation declines after the offending agents are removed
- Mediators of inflammation are no longer present

Neutrophils also have short half lives in tissues
- Die by apoptosis within hours after leaving the blood

Inflammation process itself triggers a variety of stop signals that actively terminate the reaction

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49
Q

What are the sources of histamine?

A

Mast cells
- Normally present in the connective tissue adjacent to blood vessels

Blood Basophils

Platelets

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50
Q

What are the major physiologic actions of Histamine?

A

Histamine causes vasodilations of arterioles

Histamine causes increased permeability in Post-capillary Venules

Histamine causes contraction of some smooth muscles

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51
Q

What are the sources of prostaglandins?

A

Every tissue

Lipid modulators prostaglandins and leukotrienes are PRODUCED FROM ARACHIDONIC ACID (AA)

AA is present in membrane phospholipids

Mechanical, chemical, and physical stimuli or other mediators (C5a) release AA from membrane phospholipids through the action of cellular phospholipases

Mainly phospholipase A 2

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52
Q

What are the physiological actions/systemic effects of Prostacyclin?

A

Prostacyclin is a VASODILATOR and a potent INHIBITOR of PLATELET AGGREGATION

It also potentiates the permeability-increasing and chemotactic effects of other mediators

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53
Q

What are the physiological actions/systemic effects of PGD2

A

Prostaglandin D2 i made by mast cells along with PGE2

PGD2 causes VASODILATION and INCREASES PERMEABILITY of postcapillary venules

Potentiates edema

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54
Q

What are the physiological actions/systemic effects of PGE2?

A

Prostaglandin E2 is a HYPERALGESIC

Means that is makes the skin hypersensitive to painful stimuli such as intradermal injections

It is involved in cytokine-induced FEVER during infections

pgEEEE2

FEEEEver

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55
Q

What are the physiological actions/systemic effects of Thromboxane A2?

A

Platelets contain the enzyme Thromboxane Synthase

Thus, Thromboxane A2 (TxA2) is the major product in these cells

TxA2 is a potent Platelet-Aggregatig Agent and VASOCONSTRICTOR

It is very unstable and rapdily converts to its inactive form TxB2

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56
Q

What are some pharmacological implications of Prostaglandins?

A

Cyclooxygenase Inhibitors

  • Aspirin
  • NSAIDs (ibuprofen)

They inhibit both COX-1 and COX-2

Thus they inhibit Prostaglandin synthesis

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57
Q

What are the sources of leukotrienes?

A

Leukotrienes are produced by Leukocytes and Mast Cells by the action of Lipoxygenase

They are involved in vascular and smooth muscle reactions and leukocyte recruitment

58
Q

What are the physiological actions of LTB4?

A

Leukotriene B4 is a potent chemotactic agent and activator of neutrophils

Causes aggregation and adhesion of the cells to venular endothelium

Causes generation of ROS

Causes release of Lysosomal Enzymes

59
Q

What are the physiological actions of LTC4, LTD4, and LTE4?

A

Leukotrienes C4, D4, and E4 are cysteinyl-containing leukotrienes

They cause intense

  • Vasoconstriction
  • Bronchospasms
  • Increase permeability

Leukotrienes are more potent than is Histamine in increasing vascular permeability and causing Bronchospasms

60
Q

What are the pharmacological implications of Leukotrienes?

A

Lipoxygenase inhibitors:

  • 5-lipoxygenase is not affected by NSAIDs

Pharmacological agents Zileuton or Montelukast inhibit leukotriene synthesis

Useful for treating asthma

61
Q

What is the role of TNF/IL-1?

A

TNF (tissue necrosis factor) and IL-1 (interleukin-1) are CYTOKINES that serve critical roles in Leukocyte Recruitment

Promote adhesion of leukocytes to endothelium and their migration

These cytokines are produced by macrophages and Dendritic Cells

TNF Augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates microbicidal activity of macrophages
- Induces production of NO

IL-1 activates fibroblasts to syntehsize collagen and stimulates proliferation of synovial and other mesechymal cells

IL-1 stimulates TH17 responses, which induce acute inflammation

IL-1 and TNF (plus IL-6) induce systemic acute-phase responses associated with infection or injury, INCLUDING FEVER

TNF suppresses appetite, contributing to cachexia (muscle wasting)

62
Q

What is the role of IL-6 in acute inflammation?

A

Implicated in the syndrome of sepsis, along with IL-1 and TNF

Come from macrophages

63
Q

What is the role of IL-17 in acute/chronic inflammation?

A

IL-17 specifically comes from T cells

Serves in recruitment of neutrophils and monocytes/macrophages

64
Q

What is the role of IFN-gamma in chronic inflammation?

A

IFN-gamma comes from T cells and NK (natural Killer) cells

Helps in the activation of macrophages (increasing its ability to kill microbes and tumor cells)

65
Q

What is the source of complement components?

A

Complement proteins come from the liver

They circulate in the plasma in their inactive form

66
Q

What is the C3 CLASSICAL cleavage pathway?

A

Triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen

GM makes CLASSIC cars

67
Q

What is the C3 ALTERNATIVE cleavage pathway?

A

Triggered by:

  • Microbial surface molecules (e.g., endotoxin, or LPS)
  • Complex polysaccharides
  • Cobra venom
  • Other substances in the absence of antibody
68
Q

What is the C3 LECTIN cleavage pathway?

A

Plasma Mannose-Binding LECTIN binds to carbohydrates on microbes

Directly activating C1

69
Q

What mechanism do all three C3 cleavage pathways follow?

A

All 3 pathaways cause the formation of C3 Convertase

C3 convertase splits C3 into C3a and C3b

C3a is relased, while C3b binds to the cell which complement is being activated

More C3b binds to previously generated fragments to form C5 Convertase

C5 convertase splits C5 into C5a and C5b

C5a is released while C5b attaches to cell surface

C5b binds to late components (C6-C9) culimating in the formation of the Membrane Attack Complex (MAC, composed of multiple C9 molecules)

70
Q

What are the functions of the complement system?

A

Inflammation

Opsonization and Phagocytosis

Cell Lysis

71
Q

How does the complement system cause inflammation?

A

C3a, C5a, and C4a are cleavage products of the corresponding complement components

They stimulate histamine release from mast cells

Histamine causes increased vacular permeability and causes vasodilation

C5a is also chemotactic (attractant) for neutrophils, monocytes/macrophages, eosinophils, and basophils

C5a also activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes, causing further release of inflammatory mediators (leukotrienes)

72
Q

How does the complement system cause opsonization and phagocytosis

A

C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins

Opsonins promote phgocytosis by neutrophils and macrophages

73
Q

How does the complement system cause cell lysis?

A

The deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis)

Important for killing microbes with thin cell walls

74
Q

What does a C1 inhibitor do?

A

C1 inhibitor (C1 INH) blocks the activation of C1, the first protein in the CLASSICAL PATHWAY

Inherited deficiency of this inhibitor is the cause of hereditary angioedema

75
Q

What is the Decay Accelerating Factor?

A

Decay Accelerating Factor prevents formation of C3 convertases

CD59 inhibits formation of the MAC

Acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells

Disease called Paroxysmal Nocturnal Hemoglobinuria (PNH)

76
Q

What are the morphologic patterns of acute inflammation?

A

Serous Inflammation

Fibrinous Inflammation

Purulent (suppurative) inflammation/abcess

Ulcer

77
Q

What is serous inflammation in regard to acute inflammation?

A

Serous inflammation is marked by exudation of Cell-Poor Fluid into spaces created by cell injury or into body cavities lined by peritoneum, pleura or pericardium

EFFUSION

78
Q

What is Fibrinous Inflammation in regard to acute inflammation?

A

Fibrinous exudate develops when vascular permeability allows LARGE molecules such as FIBRIN to pass out of the blood

OR there is local procoagulant stimulus (malignant cells)

Fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as meninges, pericardium, and pleura

79
Q

What is Purulent (suppurative) Inflammation/abcess?

A

Purulent inflammation is characterized by production of pus
- Exudate consisting of neutrophils, liquefied debris of necrotic cells, and edema fluid

Most often caused by infection with bacteria taht cause liquefactive necrosis

80
Q

What is an ulcer?

A

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue

81
Q

What are the 3 Possible outcomes of acute inflammatory reactions?

A

Resolution

Fibrosis

Chronic Inflammation

82
Q

What happens to acute inflammation as it resovles?

A

Resolution invovles:

  • Clearance of injurous stimuli
  • Clerance of mediators and acute inflammatory cells
  • Replacement of injured cells
  • Normal function
83
Q

What happens to acute inflammation as it progresses to Fibrosis?

A

Two paths can occur

Either the acute inflammation causes the formation of an abcess (pus formation) and then heals to become fibrotic

OR

Acute inflammation heals and directly becomes fibrotic

Fibrosis - Scar formation LOSS OF FUNCTION

84
Q

Chronic inflammation occur?

A

Either it is directly stimulated through:

  • Viral infection
  • Chronic Infections
  • Persistent Injury
  • Autoimmune Disease

OR

It progresses from an acute inflammation that began as:

  • Infarction
  • Bacterial infections
  • Toxins
  • Trauma
85
Q

What are the settings/causes associated with the development of chronic inflammation?

A

Persistent Infections

  • Microorganisms that are difficult to eradicate
  • Myobacteria
  • Viruses
  • Fungi
  • Parasites

Hypersensitivity Diseases
- Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system

Prolonged exposure to potentially toxic agents

  • Exogenous
  • Or endogenous
86
Q

What are the morphologic features associated with Chronic Inflammation?

A

Acute inflammation is manifested by vascular changes, edema, and predominantly neutrophilic,

CHRONIC INFLAMMATION is characterized by:

  • Infiltration of Mononuclear Cells (macrophages, lymphocytes, and plasma cells)
  • Tissue destruction, induced by persistent offending agent or by the inflammatory cells
  • Attempts at healing by connective tissue replacement of damaged tissue
  • Acomplished by angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis -SCARRING
87
Q

What are the different terminology of Macrophages?

A

Liver = Kupffer cells

Spleen and lymph nodes = Sinus Histiocytes

Central nervous System = Microglial Cells

Lungs = Alveolar Macrophages/dust cells

Skin = Langerhans Cells

Monocytess = Blood

88
Q

What are the two pathways of Macrophage Activation?

A

M1 / Classical Pathawy

M2 / Alternative Pathway

89
Q

What is the Classical Activation Pathway?

A

May be induced by Microbial Products (endotoxin)

Microbial products engage TLRs and other sensors

T-cell derived signals, importantly the cytokine IFN-gamma, in immune responses; or by foreign substances (crystals and particulate matter)

90
Q

What is the Alternative Activation Pathway?

A

Induced by cytokines other than IFN-gamma, such as IL-4 and IL-13, produced by T-lymphocytes and other cells

91
Q

What is the function of Classically Activated Macrophages?

A

Classically activated Macrophages (aka M1 Macrophages) produce NO and ROS and up-regulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms and secrete cytokines that stimulate inflammation.

These macrophages are important in host defense against microbes and in many inflammatory reactions

92
Q

What is the function of Alternatively Activated Macrophages?

A

Alternatively Activated Macrophages (aka M2 Macrophages) are not actively microbicidal and the cytokines may actaully inhibit the classical activation pathway

Instead the principal function of M2 macrophages is in the TISSUE REPAIR

They Secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.

93
Q

What negative outcomes occur with macrophage activation?

A

Classically Activated macrophages (M1) are capable of injuring normal tissues

Alternatively Activated Macrophages DO NOT injure tissues

94
Q

What is the role of Eosinophils in chronic inflammtion?

A

Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections

Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells.

Eosinophils have granules that contain major basic protein
- highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells

95
Q

What is the role of Mast Cells in chronic inflammation?

A

Mast cells are also present in chronic inflammatory reactions.

Because they secrete a plethora of cytokines, they may promote inflammatory reactions in different situations

96
Q

What is the role of Neutrophils in chronic inflammation?

A

Although neutrophils are characteristic of acute inflammation, many forms of chronic, lasting months, continue o show large numbers of neutrophils, induced by persistent microbes or by mediators produced by activated macrophages and T lymphocytes

This pattern of inflammation has been called acute or chronic

97
Q

What is the role of T Lymphocytes in chronic inflammation?

A

Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation

Macrophages:

  • Display antigens to T cells
  • Express membrane molecules (costimulators)
  • Produced Cytokines (IL-12 and others) that stimulate T cell responses
  • IL-12 increases IFN-gamma production

Activated T cells, in turn, produce cytokines which recruit and activate macrophages, promoting more antigen presentation and cytokine secretion

The result is a cycle of cellular reactions that fuel and sustain chronic inflammation

98
Q

What is granulomatous inflammation?

A

Granulomatous Inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis

99
Q

What are the two types of Granuloma?

A

Foreign Body Granuloma

Immune Granuloma

100
Q

What is Foreign Body Granuloma?

A

A type of granuloma incited by relatively inert foreign bodies, in the absence of T-cell-mediated immune responses.

Typically, foreign body granulomas form around materials such as Talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to prevent phagocytosis by a macrophage and do not incite any specific inflammatory or immune response

101
Q

What is an Immune Granuloma?

A

Type of granuloma caused by a variety of agents that are capable of inducing a persistent T-cell-mediated immune response

This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self antigen

102
Q

What is the morphology of granulomas?

A

In H/E staining, activated macrophages in granulomas have pink granular cytoplasm with distinct cell boundaries and are called epitheloid cells (due to similarity to epithelial cells)

Aggregates of epitheloid macrophages are surrounded by a collar of lymphocytes

Older granulomas may have a rim of fibroblasts and connective tissue

Frequently but not invariably, multinucleated giant cells 40 to 50 micrometers in diameter, are found in granulomas; these are called Langhans giant cells

They consist of a large mass of cytoplasm and many nuceli, they derive from the fusion of multiple activated macrophages

In granulomas associated with certain infectious organisms (myobacterium tuberculosis) a combination of hypoxia and free radical-mediated injury leads to a central zone of necrosis

Grossly this has a granular, cheesy appearance, and is therefore called Caseous Necrosis (seen in tuberculosis)

103
Q

What are diseases associated with granulomas?

A
  • Tuberculosis
  • Leprosy
  • Syphilis
  • Cat-scratch Disease
  • Sarcoidosis
  • Crohn’s Disease (inflammatory bowel disease)
104
Q

What is the Cause and Tissue reaction of TB?

A

Mycobacterium Tuberculosis

Caseating granuloma (tubercle): focus of activated macrophages (epitheloid cells), rimmed by fibroblasts, lymphocytes, histiocytes, ocasional Lnaghans giant cells

Central necrosis with shape-less granular debris.

Acid-fast bacilli

105
Q

What is the cause and tissue reaction of Leprosy?

A

Mycobacterium leprae

Acid-fast bacilli in macrophages

Noncaseating Granulomas

106
Q

What is the cause and tissue reaction of Syphilis?

A

Treponema Pallidum

Gumma: type of granuloma. Microscopic grossly visible lesion, enclosing wall of histiocytes, plasma cell infiltrate

CEntral cells are necrotic without loss of cellular outline

107
Q

What is the cause and tissue reaction of Cat-scratch disease?

A

Gram-negative bacillus

Rounded or stellate granuloma containing central granular debris and recognizable neutrophils

Giant cells uncommon

108
Q

What is the cause and tissue reaction of Sarcoidosis?

A

Unknown cause

Noncaseating granulomas with abundant activated macrophages

109
Q

What is the cause and tissue reaction of Crohn disease (inflammatory bowel disease)?

A

Caused by immune rection against intestinal bacteria, possibly self antigens

Occasional noncaseating granulomas in the wall of the intestine with dense chronic inflammatory infiltrate

110
Q

What is the acute phase response?

A

Inflammation, even if localized, is associated with cytokine-induced systemic reactions that are collectively called the ACUTE-PHASE RESPONSE

Cytokines TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction

Other cytokines, notably Type I Interferons, also contribute to the reaction

111
Q

How does the acute phase response relate to fever?

A

Fever = elevation of body temp by 1-4 degrees C.

More prominent of the manifestations of acute phase response

Especially when inflammation is associated with infection

Increase in body temp caused by prostaglandins that are produced in the vascular and perivascular cells of the HYPOTHALAMUS

Prostaglandins, especially PGE2 (Eeee2; feeever) in the Hypothalamus stimulates the production of neurotransmitters that reset the temperature set point at a higher level

NSAIDs, including aspiring, reduce fever by inhibiting prostaglandin synthesis

112
Q

Endogenous and Exogenous Pyrogens and Fever

A

Exogenous Pyrogens - Bacterial products, such as LPS, stimulate leukocytes to release cytokines such as IL-1 and TNF (Endogenous Pyrogens)

Endogenous pyrogens increase the enzymes (cyclooxygenases) that convert Arachadonic Acid (AA) into prostaglandins

Acute Phase Proteins have beneficial effects during acute inflammation, but prolonged production of these proteins (especially SAA) in states of chronic inflammation causes secondary amyloidosis

113
Q

What are acute phase reactants?

A

Acute phase proteins are plasma proteins mostly synthesized in the LIVER, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli

Three of the best known of those proteins are

  • C-reactive Protein (CRP)
  • Fibrinogen
  • Serum Amyloid A (SAA) protein
114
Q

How do C-reactive protein and Serum Amyloid A contribute to the Acute Phase Response?

A

Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement

They also bind chromatin, possibly aiding in clearing necrotic cell nuclei

Serum amyloid is associated with secondary amyloidosis

Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease

115
Q

How does Fibrinogen contribute to the Acute Phase Response?

A

Fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual red cells

This is the basis for measuring the erythrocyte sedimentation rate as a simple test for an inflammatory response caused by any stimulus

116
Q

How does Hepcidin contribute to the Acute Phase Response?

A

Another Peptide whose production increases in the acute phase response is the Iron-regulated peptide hepcidin

Chronically elevated plsama concentrations of hepcidin reduce the availability of iron and are responsible for anemia associated with chronic inflammation

117
Q

How is leukocytosis related to the Acute Phase Response?

A

Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections

The leukocyte count usually climbs to 15,000 or 20,000 cells/ml

But sometimes it may reach extraordinarily high levels of 40k to 100k cells/ml

These extreme elevations are referred to as leukemoid reactions, because they are similar to the white cell counts observed in leukemia and have to be distinguished from leukemia

The leukocytosis occurs iniitally because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood referred to as a Left Shift

118
Q

What are the additional systemic manifestations of Acute Phase Response?

A

Other manifestations of the Acute phase Response include:

  • Increased pulse and blood pressure
  • Decreased sweating (because of redirection of blood flow from cutaneous to deep vascular beds; minimize heat loss through the skin
  • Rigors (shivering)
  • Chills (search for warmth)
  • Anorexia
  • Sleepiness
  • Malaise (feeling sick)
119
Q

How is septic shock related to Acute Phase response?

A

High blood Levels of cytokines (TNF and IL-1) cause various widespread clinical manifestations such as
- DISSEMINATED INTRAVASCULAR COAGULATION

  • HYPOTENSIVE SHOCK
  • METABOLIC DISTURBANCES (including insulin resistance and hyperglycemia)

This clinical triad is known as SEPTIC SHOCK

120
Q

What are the two phases/reactions associated with tissue repair?

A

Regeneration

Connective Tissue Deposition

121
Q

What is the regeneration phase of tissue repair?

A

Some tissues are able to replace damaged components and essentially return to a normal state

This process if called regeneration

Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate

Ex: Rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver

In other cases, tissue stem cells may contribute to the restoration of damaged tissue

122
Q

What is connective tissue deposition phase of tissue repair?

A

AKA scar formation

If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of CONNECTIVE (FIBROUS) TISSUE

A process that may result in scar formation

Although the fibrous scar is not normal, it provides enough structural stability that the injured tissue is usually able to function

123
Q

What is Labile tissue and how is it related to tissue repair?

A

Labile = continuously dividing tissues

Cells of these tissues are continuously being lost and replaced by maturation from tissue stem cells and by proliferation of mature cells

Labile cells include:

  • Hematopoietic Cells in bone marrow
  • Majority of surface epithelia (skin, oral cavity, vagina, and cervix, ducts draining exocrine organs, Gi tract, uterus, fallopian tubes, transitional epithelia of the urinary tract)

These tissues readily regenerate after injury as long as the pool of stem cells is preserved

124
Q

What are stable cells and how are they related to tisue repair?

A

Cells fo this tissue are quiescent (in G0 stage) and have only minimal proliferative activity in their normal state

However, these cells are capable of dividing in response to injury or loss of tissue mass

Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney , pancreas

They also include endothelia, fibroblasts, and smooth muscle

Proliferation of these cells is particularly important in wound healing

With the exception of liver, stable tissues have a limited capacity to regenerate after injury

125
Q

What are permanent tissues and how are they related to tissue repair?

A

The cells of permanent tissues are considered terminally differentiated and nomproliferative in postnatal life

The majority of neurons and cardiac muscle cells belong to this category

Skeletal muscle is usually classified as a permanent tissue

But satelite cells attached to the endomysial sheath provide some regenerative capacity for muscle

In permanent tissues, repair is typically dominated by scar formation

126
Q

What is the role of the macrophage in tissue repair/scar formation?

A

macrophages play a central role in repair by CLEARING offending agents and dead tissue

They provide GROWTH FACTORS for theprolfieration of various cells

They secrete CYTOKINES that stimulate fibroblasts proliferation and connective tissue synthesis and deposition

The macrophages that are involved in repair are mostly of the alternatively activated (M2) type

127
Q

What is the role of angiogenesis in tissue repair/scar formation?

A

Vascular Endothelial Growth Factors (VEGFs) mainly VEGF-A, simtulates both migration and proliferation of endothelial cells

Thus initiating the process of capillary sprouting in angiogenesis

NOTCH SIGNALING
- Through cross-talk with VEGF, the Notch Signaling pathway regulates the sprouting and branching of new vessels and thus ensures that new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood

ECM PROTEINS
- Participate in the process of vessel sprouting in the angiogenesis, largely through interactions with integrin receptors in endothelial cells and by providing the scaffold for vessels growth

ENZYMES IN THE ECM
- Notably the matrix metalloproteinase (MMPs) degrade the ECM to permit remodeling and extension of the vascular tube

128
Q

What is the role of TGF-beta in tissue repair/scar formation?

A

Transforming Growth Factor - Beta

Is the most important cytokine for the synthesis and deposition of connective tissue proteins

It is prouced by most of the cells in granulation tissue, including alternatively activated macrophages (M2)

TGF-Beta stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of metalloproteinase

TGF-Beta is involved in not only scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation

TGF-Beta is also an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses

It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes

129
Q

What is the role of matrix metalloproteinases in tissue repair/scar formation?

A

After deposition, the connective tissue in the scar continues to be modified and remodeled

The DEGRADATION OF COLLAGEN and other ECM components is accomplished by a family of MATRIX METALLOPROTEINASES (MMPs) so called because they are dependent on metal ions (e.g., zinc) for their activity

130
Q

What factors alter/influence tissue repair?

A

Infection

Diabetes

Nutritional Status

Glucocorticoids

Mechanical Factors

Poor perfusion

Foreign Bodies

Type and Extent of Tissue Injury

Location of Injury

131
Q

What is healing by first intention?

A

When an injury invovles only the EPITHELIAL LAYER, the principal mechanism of repair is Epithelial Regeneration

Also called Primary Union

Also called Healing by First Intention

132
Q

What is healing by second intention?

A

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring

133
Q

How does first intention healing work?

A

First intention healing occurs for an injury that involves only the epithelial layer

The principal mechanism of repair is epithelial regeneration (First Intention Healing)

Wound causes the rapid activation of coagulation pathways, which results in the formation of a blood clot on the wound surface

As dehydration occurs at the external surface of the clot a scab covering the wound is formed

Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot

They release proteolytic enzymes that begin to clear the debris

Basal cells at the cut edge of the epidermis begin to show increased mitotic activity

  • Within 24-48 hours, epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane components as they progress. The cells meet in the midline beneath the surface of the scab, yielding a thin but continuous epithelial layer that closes the wound

Macrophages are key cellular constituents of tissue repair, clearing extracellular debris, fibrin, and other foreign material, and promoting angiogenesis and ECM deposition

Collagen fibers are now evident at the incision margins

By day 5, neovascularization reaches its peak

Migration of fibroblasts to the site of injury is driven by chemiokines, TNF, PDGF, TGF-beta, and FGF

Their subsequent proliferation is triggered by multiple growth factors, including PDGF, EGF, TGF-beta and FGF and the Cytokines IL-1 and TNF

134
Q

How does second intention healing work?

A

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring

In wounds causing large tissue deficits, the fibrin clot is large, and there is more exudate and necrotic debris in the wounded area

Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed

Much larger amounts of granulation tissue are formed

Larger defects require greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium

A greater volume of granulation tissue generally results in a greater mass of scar tissue

At first a provisional matrix containing fibrin. plasma fibronectin, and Type III Collagen is formed

But in 2 weeks, this is replaced by a matrix composed of primarily of Type I Collagen

Ultimately, the original granulation tissue scaffold is converted into a pale, avascular scar, composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components

The dermal appendages that have been destroyed in the line of the incision are permanently lost.

The epidermis recovers its normal thickness and architecture

By the end of the first month, the scar is made up of acellular connective tissue devoid of inflammatory infiltrate, covered by intact epidermis

135
Q

What is the mechanism involved in tissue fibrosis?

A

Persistent tissue injury leads to chronic inflammation and loss of tissue Architecture

Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other extracellular matrix proteins

The net results is replacement of normal tissue by fibrosis

The major cytokine involved in Fibrosis is TGF-Beta

136
Q

What are the two types of complication that stem from inadequate formation o granulation tissue or formation of a scar?

A

Dehiscence (rupture of wound)

Ulceration

137
Q

What is Dehiscence?

A

Rupture of a wound

Although not comon, occurs most frequently after abdominal surgery and is due to increased abdominal pressure

Vomiting, coughing, or ileus can generate mechanical stress on theabdominal wound

138
Q

What is Ulceration?

A

Wounds can Ulcerate because of inadequte vascularization during healing

For example:
- Lower extremity wounds in the individuals with atherosclerotic peripheral vascular disease typically ulcerate

Non healing wounds also form in areas devoid of sensation

These neuropathic ulcers are occasionally seen in patients with Diabetic Peripheral Neuropathy

139
Q

What are Keloids?

A

Excessive formation of the components of repair process can give rise to hypertrophic scars and KELOIDS

The accumulation of excessive amounts of COLLAGEN may give rise to a raised scar known as a hypertrophic scar

If the scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a KELOID

140
Q

What is Exuberant Granulation?

A

Exuberant Granulation is another deviation in wound healing consisting of the excessive amounts of GRANULATION TISSUE, which protrudes above the level of the surrounding skin and blocks reepithelialization (this process has been called, more literary fervor, PROUD FLESH

Excessive granulation must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium.

Fortunately rarely, incisional scars or traumatic injuries may be followed by exuberant proliferation of firoblasts and other connective tissue elements that may in fact recur after excision

Called DESMOIDS or Aggressive Fibromatoses
- these neoplasms lie in the interface between benign and malignant (though low-grade) tumors

Colin MOD (5 decks)

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