Inflammation and Repair

Chapter 2 Inflammation and Repair



I. Acute Inflammation (AI)


AI: chemical, vascular, cellular responses



A. Definition

1. Transient and early response to injury

2. Involves release of chemical mediators

3. Leads to stereotypic vessel and leukocyte responses

4. Not a synonym for infection


AI: not synonymous with infection



B. Cardinal signs of inflammation (Fig. 2-1)

1. Rubor (redness) and calor (heat)

• Histamine-mediated vasodilation of arterioles

2. Tumor (swelling)

a. Histamine-mediated increase in permeability of venules

b. Synonymous with edema

• Increased fluid in the interstitial space

image

2-1: Signs of acute inflammation. The patient has erysipelas of the face due to group A streptococcus. Signs of acute inflammation that are present in the photograph include redness (rubor) and swelling (tumor). The infection is associated with warm skin (calor) and pain (dolor).


(From Forbes C, Jackson W: Color Atlas and Text of Clinical Medicine, 2nd ed. St. Louis, Mosby, 2003, p 37, Fig. 1-106.)



Rubor, calor, tumor: histamine-mediated


3. Dolor (pain)

• Prostaglandin (PG) E2 sensitizes specialized nerve endings to the effects of bradykinin and other pain mediators.

4. Functio laesa (loss of function)

C. Stimuli for acute inflammation

1. Infections (e.g., bacterial or viral infection)

2. Immune reactions (e.g., reaction to a bee sting)

3. Other stimuli

• Tissue necrosis (e.g., acute myocardial infarction), trauma, radiation, burns, foreign body (e.g., glass, splinter)

D. Sequential vascular events

1. Vasoconstriction of arterioles

• Neurogenic reflex that lasts only seconds

2. Vasodilation of arterioles

a. Histamine and other vasodilators (e.g., nitric oxide) relax vascular smooth muscle, causing increased blood flow.

b. Increased blood flow increases hydrostatic pressure.


Mast cells: release preformed histamine


3. Increased permeability of venules

a. Histamine and other mediators contract endothelial cells producing endothelial gaps.

• Tight junctions are simpler in venules than arterioles.

b. A transudate (protein and cell-poor fluid) moves into the interstitial tissue.

4. Swelling of tissue (tumor, edema)

• Net outflow of fluid surpasses lymphatic ability to remove fluid.

5. Reduced blood flow

• Decrease in hydrostatic pressure caused by outflow of fluid into the interstitial tissue

E. Sequential cellular events (Fig. 2-2)

• The events described will emphasize neutrophil events in acute inflammation due to a bacterial infection (e.g., Staphylococcus aureus).

image

2-2: Neutrophil events in acute inflammation. See text for discussion.



Neutrophils: primary leukocytes in acute inflammation


1. Neutrophils are the primary leukocytes in acute inflammation (Fig. 2-3).

2. Margination

a. RBCs aggregate into rouleaux (“stacks of coins”) in venules.

b. Neutrophils are pushed from the central axial column to the periphery (margination).

3. Rolling (selectin adhesion molecules)

a. Adhesion of neutrophils to endothelial cell ligands via complementary selectin molecules on these two cells is enhanced by interleukin-1 (IL-1) and tumor necrosis factor (TNF).

image

2-3: Acute inflammation. Histologic section of lung in bronchopneumonia showing sheets of neutrophils with multilobed nuclei.


(From Damjanov I: Pathology for the Health-Related Professions, 2nd ed. Philadelphia, WB Saunders, 2000, p 182, Fig. 8-8.)



Selectins: responsible for “rolling” of neutrophils


b. Neutrophil adhesion is weak and transient causing them to “roll” along the endothelium.

4. Firm adhesion (integrin adhesion molecules)

a. Adhesion molecules firmly bind neutrophils to endothelial cells.

(1) Neutrophils in the peripheral blood are subdivided into a circulating pool and a marginating pool (already attached to endothelial cells).

(2) Normally, ∼︀50% of peripheral blood neutrophils are in the circulating pool and ∼︀50% in the marginating pool.

(3) This distribution can be altered by activating or inactivating neutrophil adhesion molecules (see later).


β2-Integrins: neutrophil/endothelial adhesion molecules; firm adherence


b. β2-Integrin (CD11a:CD18) adhesion molecules

(1) These integrins are located on neutrophils and endothelial cells (serve as ligands).

(2) Neutrophil integrins are activated by C5a and leukotriene B4 (LTB4).


Neutrophil leukocytosis: catecholamines, corticosteroids, lithium


(3) Catecholamines, corticosteroids, and lithium inhibit activation of adhesion molecules.

(a) Peripheral blood neutrophil count (neutrophilic leukocytosis) is increased.

(b) Normal marginating pool is now part of the circulating pool.

(4) Endotoxins enhance activation of adhesion molecules.

(a) Peripheral blood neutrophil count (neutropenia) is decreased.

(b) Normal circulating pool is now part of the marginating pool.


Neutropenia: endotoxins


c. Endothelial cell integrin adhesion molecules (ligands)

(1) Intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) bind to integrins on the surface of activated neutrophils.

(2) ICAM and VCAM activation to a high energy state is mediated by IL-1 and TNF leading to firm adhesion of neutrophils to venular endothelial cells.

d. Leukocyte adhesion deficiency (LAD)

(1) Autosomal recessive disorders

(2) LAD type 1 is a deficiency of CD11a:CD18.

(3) LAD type 2 is a deficiency of a selectin that binds neutrophils.

(4) Clinical findings


Delayed separation umbilical cord: selectin or CD11a:CD18 deficiency



(a) Delayed separation of the umbilical cord (∼︀1 month)

• Neutrophil enzymes are important in cord separation.

(b) Severe gingivitis, poor wound healing, peripheral blood neutrophilic leukocytosis (loss of marginating pool)

5. Transmigration (diapedesis)

a. Neutrophils dissolve the basement membrane and enter interstitial tissue.

b. Fluid rich in proteins and cells (i.e., exudate) accumulates in interstitial tissue.

c. Functions of exudate

(1) Dilutes bacterial toxins

(2) Provides opsonins (IgG, C3b) to assist in phagocytosis

6. Chemotaxis


Chemotaxis: directed migration of neutrophils



a. Neutrophils follow chemical gradients that lead to the infection site.

b. Chemotactic mediators bind to neutrophil receptors.

• Mediators include C5a, LTB4, bacterial products, and interleukin (IL) 8.

c. Binding causes the release of calcium, which increases neutrophil motility.

7. Phagocytosis

a. Multistep process, consisting of three steps

(1) Opsonization

(2) Ingestion

(3) Killing

b. Opsonization

(1) Opsonins attach to bacteria (or foreign bodies).


Opsonins: IgG and C3b



(a) Opsonins include IgG, C3b fragment of complement, and other proteins (e.g., C-reactive protein).

(b) Neutrophils have membrane receptors for IgG and C3b.

(2) Opsonization enhances neutrophil recognition and attachment to bacteria.


Bruton’s agammaglobulinemia: opsonization defect


(3) Bruton’s agammaglobulinemia is an opsonization defect.

c. Ingestion

(1) Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic vacuoles.

(2) Primary lysosomes empty hydrolytic enzymes into phagocytic vacuoles producing phagolysosomes.


Chédiak-Higashi syndrome: cannot form phagolysosomes



• In Chédiak-Higashi syndrome (refer to Chapter 1), a defect in microtubule function prevents phagolysosome formation.

d. Bacterial killing

(1) O2-dependent myeloperoxidase (MPO) system (Fig. 2-4)

image

2-4: Oxygen-dependent myeloperoxidase system. A series of biochemical reactions occurs in the phagolysosome, resulting in the production of hypochlorous free radicals (bleach; HOCl•) that destroy bacteria. Fe2+, reduced iron; GSH, reduced glutathione; G6-P, glucose 6-phosphate; GSSG, oxidized glutathione; H2O2, peroxide; MPO, myeloperoxidase; NADP, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OH•, hydroxyl free radical; 6PG, 6-phosphogluconate; SOD, superoxide dismutase.



O2-dependent MPO system: most potent microbicidal system



(a) Only present in neutrophils and monocytes (not macrophages)

(b) Production of superoxide free radicals (O2•¯)

• Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase converts molecular O2 to O2•¯, which releases energy called the respiratory, or oxidative, burst.

(c) Production of peroxide (H2O2)


End-product O2-dependent MPO system: bleach



• Superoxide dismutase converts O2•¯ to H2O2, which is neutralized by glutathione peroxidase.

(d) Some peroxide is converted to hydroxyl free radicals by iron.

(e) Production of bleach (HOCl•)

• MPO combines H2O2 with chloride (Cl−) to form hypochlorous free radicals (HOCl•), which kill bacteria.

(f) Chronic granulomatous disease and MPO deficiency are examples of diseases that have a defect in the O2-dependent MPO system.


Chronic granulomatous disease: absent NADPH oxidase and respiratory burst




Chronic granulomatous disease (CGD) is an X-linked recessive (XR) disorder (65% of cases) or autosomal recessive disorder (35% of cases). The X-linked type is characterized by deficient NADPH oxidase in the cell membranes of neutrophils and monocytes. The reduced production of O2•¯ results in an absent respiratory burst. Catalase-positive organisms that produce H2O2 (e.g., Staphylococcus aureus) are ingested but not killed, because the catalase degrades H2O2. Myeloperoxidase is present, but HOCl• is not synthesized because of the absence of H2O2. Catalase-negative organisms (e.g., Streptococcus species) are ingested and killed when myeloperoxidase combines H2O2 with Cl− to form HOCl•. Granulomatous inflammation occurs in tissue, because the neutrophils, which can phagocytose bacteria but not kill most of them, are eventually replaced by cells associated with chronic inflammation, mainly lymphocytes and macrophages. Macrophages fuse together to form multinucleated giant cells. Patients have severe infections involving lungs, skin, visceral organs, and bones. The classic screening test for CGD is the nitroblue tetrazolium (NBT) test. In this test, leukocytes are incubated with a colorless NBT dye, which is converted to a blue color if the respiratory burst is intact. This test has been replaced by a more sensitive test involving oxidation of dihydrorhodamine to fluorescent rhodamine. Bone marrow transplantation is the treatment of choice for the XR type of CGD.


Myeloperoxidase (MPO) deficiency, an autosomal recessive disorder, differs from CGD in that both O2•¯ and H2O2 are produced (normal respiratory burst). However, the absence of MPO prevents synthesis of HOCl•.



MPO deficiency: normal respiratory burst


(g) Deficiency of NADPH (e.g., glucose-6-phosphate dehydrogenase deficiency) produces a microbicidal defect.


↓ NADPH: microbicidal defect


(2) O2-independent system

(a) Refers to bacterial killing from substances located in leukocyte granules

(b) Examples—lactoferrin (binds iron necessary for bacterial reproduction) and major basic protein (eosinophil product that is cytotoxic to helminths)

F. Chemical mediators (Table 2-1)


Table 2-1 Sources and Functions of Chemical Mediators

image


Histamine: most important chemical mediator of acute inflammation



1. They derive from plasma, leukocytes, local tissue, bacterial products.

• Example—arachidonic acid mediators are released from membrane phospholipids in macrophages, endothelial cells, and platelets (Fig. 2-5).

2. They have short half-lives (e.g., seconds to minutes).

3. They may have local and systemic effects.

image

2-5: Arachidonic acid metabolism. Arachidonic acid is released from membrane phospholipids. It is converted into prostaglandins (PGs), thromboxane A2 (TXA2), and leukotrienes (LTs).See text for further discussion.



Chemical mediators: short half-lives


• Example—histamine may produce local signs of itching or systemic signs of anaphylaxis.

4. They have diverse functions.

a. Vasodilation

• Examples—histamine, nitric oxide, PGI2

b. Vasoconstriction

• Example—thromboxane A2 (TXA2)

c. Increase vessel permeability

• Examples—histamine, bradykinin, LTC4-D4-E4, C3a and C5a (anaphylatoxins)

d. Produce pain

• Examples—PGE2, bradykinin

e. Produce fever

• Examples—PGE2, IL-1, TNF

f. Chemotactic

• Examples—C5a, LTB4, IL-8

G. Types of acute inflammation

• Location, cause, and duration of inflammation determine the morphology of an inflammatory reaction.

Related posts:

  1. Skin Disorders
  2. Vascular Disorders
  3. Genetic and Developmental Disorders
  4. Red Blood Cell Disorders

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Jun 25, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Inflammation and Repair

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