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General and systemic pathology I > 02 - Acute and chronic inflammation > Flashcards

02 - Acute and chronic inflammation Flashcards

1
Q

Main characteristics of acute inflammation

A

Main characteristics of acute inflammation are EXUDATION of plasma fluid and proteins, and aggregation of leukocytes, predominantly NEUTROPHILS.

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2
Q

Stimuli for acute inflammation (triggers)

A
  1. Infections – among the most common triggers
  2. Physical injury – trauma and other physical and chemical agents
  3. Tissue necrosis
  4. Foreign bodies
  5. Immune reactions
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3
Q

Major components of acute inflammation

A
  1. Vascular changes – mainly vasodilation and increased vascular permeability
    a. Lead to an increase in blood flow to site of injury.
    b. Allow for delivery of plasma mediators and leukocytes to site of injury.
  2. Vascular changes can be characterized by two major categories of events.
    a. Changes in vascular flow and caliber
    b. Increased vascular permeability (vascular leakage)
  3. Cellular events – mainly recruitment and activation of leukocytes at the site of injury
    a. Provide for neutralization of the assault.
    b. Provide for clean-up of dead cells and debris.
  4. An essential function of inflammation is the recruitment of leukocytes to the site of injury. Activated leukocytes kill bacteria and other microbes and degrade necrotic tissue and foreign antigens.
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4
Q

List the steps in the changes in vascular flow and caliber in acute inflammation

A 
P1 (caliber)
1 Vasoconstriction (minor, if at all)
2 VASODILATION (starts in arterioles)
3 Microvascular bed opens
4 Increased local blood flow = Hyperemia (Hallmark, calor + rubor)
P2 (permeability)
5 INCREASED PERMEABILITY of microvasculature
6 EXUDATION into extravascular tissue
7 Concentration of RBCs in small vessels
8 Increased blood viscosity
9 Slowing of circulation = STASIS
P3 (Intravascular cellular events)
10 Margination of leukocytes
11 Emigration of leukocytes > EXTRAVASCULAR EVENTS
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5
Q

List the steps involved in EXUDATION

A

1 Vasodilation + inc blood flow
2 Inc hydrostatic pressure
3 Increased filtration of fluid from capillaries > Transudation = Pure edema fluid, escape due to changes in hydrostatic + osmotic pressures. Non-inflammatory fluid
4 Inc permeability of vessel wall
5 Escape of protein-rich plasma fluid > Exudation. Exudate = inflammatory fluid
6 Decreased intravascular osmotic pressure
7 Increased osmotic pressure of interstitial tissue
8 Marked outflow of plasma fluid and accumulation in interstitial tissue (EDEMA)

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6
Q

Serous exudate

A

H2O + e- + small plasma proteins

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7
Q

Fibrinous exudate

A
  • H2O + e- + small & larger plasma proteins

* contains fibrinogen, a large plasma protein

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8
Q

Purulent exudate

A

Pus

H2O + e- + s/l plasma proteins + WBCs

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9
Q

Serosanguineous exudate

A

H2O + e- + plasma proteins + RBCs

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10
Q

Increased vascular permeability (mechanisms)

A

a. Gaps due to endothelial cell contraction
b. Direct endothelial injury, resulting in endothelial cell necrosis and detachment
c. Leukocyte-dependent endothelial injury
d. Increased transcytosis
e. Leakage from new blood vessels

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11
Q

What is the sequence of cellular events in acute inflammation?

A

a. Margination and rolling
b. Adhesion and transmigration
c. Chemotaxis and activation of leukocytes
d. Phagocytosis

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12
Q

Margination and rolling

A

a. Sequence of Events
1) Blood flow slows.
2) White blood cells tumble out of central column of flow, move toward periphery (margination) and roll along endothelium.
3) Endothelium becomes lined by leukocytes which are at first loosely adherent.
b. Rolling and loose adhesion require cell activation and expression of selectins. Binding to complementary adhesion molecules occurs between leukocytes and endothelial cells.
2) Expression of selectins can be upregulated by exposure to certain inflammatory mediators.
Selectin Upregulated by
P-selectin Histamine, thrombin, platelet-activating factor (PAF)
E-selectin Il-1 and tumor necrosis factor (TNF)

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13
Q

Adhesion and transmigration

A

1) Firm adhesion is largely mediated by endothelial cell adhesion molecules of the immunoglobulin super family which bind to integrins expressed on leukocytes.
2) Expression of these adhesion molecules are upregulated by certain cytokines, specifically TNF and Il-1.

3) Transmigration consists of the firmly adherent leukocyte traversing the blood vessel wall.
a) The leukocyte crawls between the loosened endothelial cells and then secretes collagenases, allowing it to pass through the basement membrane.
b) This process of “walking through” is also referred to as diapedesis.
c) PECAM-1 (CD31) is the main mediator of diapedesis.

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14
Q

Chemotactic factors

A

1) Bacterial products – particularly peptides with N-formyl-methionine termini
2) Cytokines of the chemokine family, such as Il-8
3) Components of the complement system – particularly C5a
4) Products of arachidonic acid (AA) metabolism – particularly Leukotriene B4

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15
Q

Phagocytosis

A

a. Major functions of recruited leukocytes at the site of inflammation are phagocytosis (“cell eating”) and killing and degradation. These are the means by which invading organisms, cellular debris and foreign material are isolated and eliminated.

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16
Q

Cells capable of phagocytosis

A

1) Neutrophils (PMN)
2) Macrophages
3) Eosinophils (PMN, generally not recruited in acute inflammation)

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17
Q

Substances that act as opsonins

A

1) C3b
2) IgG (Fc fragment)
3) Collectins

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18
Q

Cardinal signs of acute inflammation

A
  1. Heat (calor)
  2. Redness (rubor)
  3. Swelling (tumor)
  4. Pain (dolor)
  5. Loss of function (functio laesa)
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19
Q

Histamine

A

a. Sources
1) Major source – mast cells
2) Other sources – basophils and platelets
b. Stimuli Leading to Degranulation of Mast Cells
1) Physical injury – such as trauma or heat
2) Immune reactions involving binding of antibodies to mast cells
3) Fractions of complement called anaphylatoxins – C3a and C5a
4) Cationic lysosomal proteins derived from neutrophils
5) Neuropeptides
c. Actions of Histamine
1) Vasodilation of arterioles
2) Increased vascular permeability of venules
3) Specifically chemotactic for eosinophils
d. Inactivation is rapidly achieved by histaminase.
e. Histamine is the principal mediator of the immediate phase of increased vascular permeability in the acute inflammatory response.

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20
Q

Serotonin

A

a. Serotonin is released from stimulated platelets during platelet aggregation.
b. Serotonin produces effects similar to histamine.

21
Q

What initiates the plasma protease system?

A

Activation of Hageman Factor (Factor XII)

Activation is initiated by exposure to collagen, basement membrane or activated platelets.

22
Q

What are the components of the plasma protease system?

A

1) The kinin system
2) The clotting system
3) The fibrinolytic system
4) The complement system

23
Q

Kinin system

A

a. Activation of the kinin system leads to the formation of bradykinin.

b. Source and Activation of Bradykinin
1) Bradykinin is a nonapeptide derived from its plasma precursor high-molecular-weight kininogen (HMWK).
2) HMWK is cleaved (activated) by the proteolytic enzyme kallikrein.

c. Actions of Bradykinin
1) Arteriolar vasodilation
2) Increased permeability of venules
3) Pain

d. Bradykinin is inactivated by kininase present in plasma and tissues.
e. Role of bradykinin is limited to the early phase of increased vascular permeability.

24
Q

Clotting system

A

a. The clotting system is activated to ultimately PRODUCE FIBRIN, part of a stable blood clot.
b. Intermediate products of the clotting system act as mediators of acute inflammation.

1) Factor Xa
a) Causes increased vascular permeability.
b) Mediates leukocyte transmigration.

2) Thrombin
a) Causes increased leukocyte adhesion.
b) Generates the fibrinopeptides.

3) Fibrinopeptides
a) Cause increased vascular permeability.
b) Chemotactic for leukocytes

25
Q

Fibrinolytic system

A

From FIBRIN itself. Generated by fibrin molecules

a. PLASMIN (breaks down fibrin)
1) Activates Hageman factor (amplifying effect)
2) Cleaves C3  C3a  increased vascular permeability
3) Degrades fibrin to form fibrin-degradation products

b. Fibrin-degradation products – produce increased vascular permeability

26
Q

Complement system

A

a. The complement system plays an important role in both immunity and inflammation. It serves primarily in the defense against microbes. The end product of complement activation is cell lysis.

27
Q

Pathways of AA metabolism

A

a. The cyclooxygenase pathway produces the prostaglandins and thromboxane – principally PGI2, PGE2 and PGD2.
b. Lipoxygenase pathway produces the leukotrienes and lipoxins – principally LTB4, LTC4, LTD4 and LTE4.

Corticosteroids are powerful anti-inflammatory agents. They act in part by blocking both pathways of AA metabolism.

Leukotrienes and (especially) PROSTAGLANDINS are the most important mediators of the later, sustained phase of acute inflammation.

28
Q

Actions of prostaglandins

A

Produced by cyclooxygenase pathway
1) Vasodilation – PGI2 (endothelial cells) , PGE2, PGE1 and PGD2 (mast cells)
2) Pain – PGE2
3) Fever – PGE2
Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) inhibit prostaglandin synthesis by inhibiting cyclooxygenase. The lipoxygenase pathway is not affected by these agents.

29
Q

Actions of the Leukotrienes

A

Produced by the lipoxygenase pathway

1) Increased vascular permeability (1,000 x potency of histamine) – LTC4, LTD4 and LTE4 (all primarily from mast cells)
2) Chemotaxis and leukocyte adhesion – LTB4 (neutrophils, some macrophages)

30
Q

Platelet activating factor (PAF)

A
  1. It is derived from phospholipid and can be elaborated from basophils, neutrophils, monocytes, and endothelium.
  2. Actions of PAF
    a. Platelet aggregation and release of platelet contents (mediators)
    b. Vasodilation and increased vascular permeability (100-10,000 x potency of histamine)
    c. Leukocyte aggregation and adhesion via the integrins
    d. Chemotaxis
    e. Leukocyte degranulation and the oxidative burst
    f. Also stimulates synthesis of other mediators, especially synthesis of prostaglandins and leukotrienes by leukocytes. (amplifying factors)
31
Q

What are cytokines and how are they produced? Which ones are implicated as mediators of acute inflammation?

A
  1. Cytokines are polypeptides produced by many cell types (principally activated lymphocytes and macrophages). Their major role is in cellular immune responses.
  2. Cytokines that may serve as Mediators of Acute Inflammation
    a. Interleukin-1 (Il-1)
    b. Tumor necrosis factor (TNF)
    c. Interferon-γ (INF-γ)
    d. Chemokines such as Interleukin-8 (Il-8)
32
Q

Il-1 and TNF

A

1) Systemic acute phase reactions – especially fever
2) Local effects – leukocyte adhesion, aggregation and activation of neutrophils (TNF), stimulation of production/release of other mediators (amplifying effects)
3) Effects on fibroblasts (growth factor)
b. INF-γ is a potent ACTIVATOR OF MACROPHAGES AND NEUTROPHILS.
1) Upregulates enzymes which produce the oxidative burst.
2) Stimulates synthesis of NO synthase.
c. Il-8 is a powerful CHEMOATTRACTANT AND ACTIVATOR OF NEUTROPHILS

33
Q

Nitric oxide

A
  1. NO is a short-acting, soluble free radical gas with half-life measured in seconds.
  2. Effects during inflammation include:
    a. Vasodilation via smooth muscle relaxation of the blood vessel wall
    b. Antagonism to adhesion effects, aggregation effects and degranulation effects produced by platelet activation
    c. Microcidal agent in activated macrophages
34
Q

Lysosomal constituents

A
  1. Lysosomes of neutrophils and macrophages contain agents which may mediate the acute inflammatory response.
  2. Acid Proteases – active in phagolysosomes
  3. Neutral proteases (elastase, collagenase, etc.) – active in extracellular matrix
    a. Cause tissue injury by degrading elastin, collagen, basement membrane, matrix proteins
    b. Generate the anaphylatoxins – C3a and C5a.
    c. Generate bradykinin-like peptide from kininogen.
35
Q

Morphological characteristics of chronic inflammation

A
  1. Infiltration with mononuclear leukocytes – macrophages, lymphocytes and plasma cells
  2. Tissue destruction
  3. Repair involving fibrosis and proliferation of new vessels (angiogenesis)
36
Q

When is chronic inflammation most likely to arise?

A
  1. Persistent microbial infections – such as mycobacteria, and some viruses and fungi
  2. Immune-mediated inflammatory diseases – hypersensitivity reactions and autoimmune dz
  3. Prolonged exposure to potentially toxic agents
37
Q

Which cells are involved in chronic inflammation?

A

Macrophages
Lymphocytes
Plasma cells
Eosinophils (sometimes, not major)

38
Q

Macrophages

A

a. Macrophages are members of the mononuclear phagocyte system (MPS) and play a vital role in both acute and chronic inflammation. They are important in mediating the tissue destruction, angiogenesis, and fibrosis characteristic of chronic inflammation.
c. In chronic inflammation, the most important chemotactic factors for macrophages are lymphocyte-derived.
d. Macrophages can be induced by IL-4 or INF-γ to fuse into large, multinucleated cells called GIANT CELLS

39
Q

Activation of The Complement Cascade + summary

A

1) The critical step is activation (cleavage) of C3, after which the common final pathway involves C5 through C9.
2) The alternate pathway is the most important pathway in acute inflammation where cleavage of C3 is triggered by non-immunologic factors, such as bacterial endotoxins and polysaccharides.
3) C3 and C5 can also be directly activated by several proteolytic enzymes found in inflammatory exudates (amplifies reaction).

c. Summary of Actions of Complement in Acute Inflammation
1) Vascular effects – vasodilation and increased vascular permeability
2) White cells effects – leukocyte activation, adhesion, chemotaxis and phagocytosis

40
Q

C3a

A

a) Causes increased vascular permeability by stimulating histamine release by mast cells and platelets.
b) Called an anaphylatoxin because of this role in immediate hypersensitivity reactions.

41
Q

C5a

A

a) Causes increased vascular permeability by stimulating mast cells and platelets to release histamine. Also called an anaphylatoxin.
b) Increases adhesion between WBCs and endothelial cells by increasing affinity of the integrins.
c) Highly chemotactic for granulocytes and monocytes.
d) Activates the lipoxygenase pathway of AA metabolism in neutrophils and macrophages, thus triggering the synthesis of additional potent chemical mediators (the leukotrienes).

42
Q

C3b, C3bi

A

acts as opsonin for bacteria favoring phagocytosis by neutrophils and monocytes which have specific receptors for C3b.

43
Q

Oxygen-derived free radicals

A

Oxygen-Derived Free Radicals have a variety of effects in acute inflammation:

a. Endothelial cell damage with resultant increased vascular permeability and thrombosis
b. Activation of proteinases and inactivation of antiproteases leading to increased breakdown of extracellular matrix
c. Direct injury to other cell types

44
Q

Macrophages (secretions)

A

b. Following activation, macrophages secrete a wide variety of biologically active products.
1) Acid and neutral proteases
a) Elastase and collagenase mediate tissue damage.
b) Plasminogen activator triggers the production of plasmin and greatly amplifies the generation of pro-inflammatory substances.
c) Phosphatases and lipases also mediate tissue damage.
2) Reactive oxygen species and nitric oxide
3) Arachidonic acid metabolites
4) Cytokines
a) Il-1 and TNF
b) Platelet-derived growth factor (PDGF)
c) Epidermal growth factor (EGF)
d) Fibroblast growth factor (FGF)
5) Complement proteins and coagulation factors
a) C1 to C5
b) Coagulation Factors V, VIII and tissue factor

45
Q

Serous Inflammation

A
  1. Characterized by exudation of thin, watery (serous) fluid.
  2. Example: Skin blister following a minor burn
46
Q

Fibrinous Inflammation

A
  1. Seen in more severe injuries where there is greater vascular permeability and exudation of larger molecules.
  2. Characterized by fibrinous exudation, often into body cavities.
  3. If the fibrin is not resolved by macrophages, it may stimulate ingrowth by fibroblasts (organization) and result in scarring.
  4. Example: Acute rheumatic carditis with its characteristic fibrinous pericarditis
47
Q

Suppurative (Purulent) Inflammation

A
  1. Characterized by production of large amounts of pus or purulent exudate.
  2. Abscesses are localized collections of pus.
    a. Caused by pyogenic bacteria such as Staphylococci
    b. Examples: Folliculitis, furuncles (boils), carbuncles, etc.
  3. Cellulitis is spreading edematous and purulent inflammation.
    a. Classically caused by β-hemolytic strep., Lancefield group A.
    b. Infection spreads rapidly through lateral tissue planes with the aid of hyaluronidase, fibrinolysin and other proteases produced by the microorganism
48
Q

Ulcer

A
  1. An ulcer is a local defect of the surface of an organ or tissue that is produced by sloughing of necrotic surface skin/mucosa/serosa along with the associated inflammatory response.
  2. Histologic Characteristics of an Ulcer
    a. Surface has no epithelium (or mesothelium) but instead is covered by fibrinopurulent exudate.
    b. Superficial zone features intense acute inflammation.
    c. Deeper zone may feature chronic inflammation and scarring in chronic ulcers
49
Q

Granulomatous Inflammation

A
  1. This is a distinctive pattern of chronic inflammation which is characterized by the presence of granulomas. Granulomas are inflammatory aggregates formed of activated macrophages which show a characteristic “epithelioid” appearance, lymphocytes, plasma cells and multinucleated giant cells.
  2. Granulomatous inflammation is evoked in only a few pathologic states which involve T cell-mediated immune responses to organisms or indigestible particles.
    a. Tuberculosis
    b. Inflammatory response to foreign bodies  foreign body granulomas
    NOT ACUTE!!!

General and systemic pathology I (13 decks)

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