Acute Inflammation

Question 1

Five Cardinal Symptoms of Inflammation

Answer 1

Calor (heat)

Rubor (redness)

Tumor (swelling)

Dolor (pain)

Functio laesis (loss of function)

Question 2

Waves of acute inflammation

Answer 2

Question 3

amplification cascades

Answer 3

one mediator activates the next one

Question 4

Change in vascular flow during acute inflammation

Answer 4

Question 5

Major mediators of vasodilation in acute inflammation

Answer 5

1. Histamine
2. Nitric oxide
3. Eicosanoids

Question 6

Effects on endothelium during inflammation

Answer 6

histamine, bradykinin, and leukotrienes -> endothelial contraction

IL-1, TNF-a -> endothelial retraction

Question 7

endothelial injury

Answer 7

As acute inflammation progresses, endothelial cells may die either by necrosis or by apoptosis, resulting in further increases in vascular permeability.

In addition, leukocytes may injure endothelium through the reactive oxygen species, enzymes, and prostaglandins that they release.

Endothelial injury is a major element in the pathology of vascular disease, and in particular atherosclerosis.

Question 8

Transudation vs Exudation

Answer 8

Transudate: filtrate of blood plasma that contains little protein.

Exudate: protein-rich fluid and even cells. Increases the osmotic pressure of the interstitial fluid and creates edema.

Question 9

Leukocyte rolling

Answer 9

Question 10

Major selectins involved in leukocyte adhesion/rolling

Answer 10

• E-selectin (also called CD62E), confined to endothelium
• P-selectin (CD62P), present on endothelium and platelets
• L-selectin (CD62L), on the surface of most leukocytes

Selectins bind oligosaccharides (e.g., sialyl-Lewis X on leukocytes) that decorate mucin-like glycoproteins on their target cells.

Question 11

E-selectin is expressed in response to . . .

Answer 11

IL-1 and TNF-a

Question 12

Principal integrin interactions that mediate endothelial arrest

Answer 12

Endothelium: ICAM-1 (binds to neutrophils, MO, Lymphocytes), VCAM-1 (binds to MO and Lymphocytes, but not neutrophils)

ICAM-1 ligands: LFA-1, Mac-1

VCAM-1 ligands: VLA-4

Question 13

Phagocytic Engulfment

Answer 13

Question 14

Diapedesis

Answer 14

PECAM-1 and CD99-mediated

Question 15

Chemokine Receptors

Answer 15

seven-transmembrane spanning, G protein-coupled receptors to generate diacylglycerol (DAG) and inositol triphosphate (IP3 ), downstream triggering Ca²⁺ release.

Question 16

Histamine

Answer 16

Preformed histamine is stored in mast cell granules and is released in response to a variety of stimuli:

• physical injury such as trauma or heat
• Immune reactions involving IgE
• anaphylatoxins (C3a and C5a)
• leukocyte-derived histamine-releasing proteins
• neuropeptides (Substance P)
• Certain ​cytokines

Question 17

Nitric oxide in smooth muscle

Answer 17

Activates guanylyl cyclase in vascular smooth muscle, resulting in increased cyclic guanosine monophosphate (cGMP) and ultimately smooth muscle relaxation (vasodilation).

Question 18

Roles of nitric oxide in inflammation

Answer 18

(1) vascular smooth muscle relaxation (vasodilation)
(2) antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation)
(3) reduction of leukocyte recruitment at inflammatory sites
(4) acting as a microbicidal agent (with or without superoxide radicals) in activated macrophages.

Question 19

Arachadonic acid metabolism overview

Answer 19

Question 20

Leukotriene antagonists

Answer 20

montelukast and zafirlukast

Block leukotriene receptors, inhibiting the lipoxygenase arm of the eicosanoid pathway, and are used to treat asthma. Antagonizes LTC₄-mediated vasoconstriction.

Question 21

Corticosteroids and AA metabolsim

Answer 21

Inhibit phospholipase A2 and prevent release of arachidonic acid, blocking both the cyclooxygenase and lipoxygenase pathways.

Question 22

Complement

Answer 22

Question 23

Kinin and Clotting Cascades

Answer 23

Question 24

Kinins

Answer 24

Factor XIIa cleaves prekallikrein to kallikrein, resulting in kinin production.

Most notable among the kinins is bradykinin.

Kinins are responsible for the pain associated with acute inflammation.

Question 25

fibrinolytic system

Answer 25

Also activated by kallikrein following Factor XIIa cleavage. Kallikrein cleaves **plasminogen to plasmin**, which **lyses fibrin clots**, and also **activates the complement cascade.**

Question 26

Thrombin

Answer 26

Final target of the coagulation cascade. In addition to **making fibrin** (which forms the clot), thrombin is also a **direct activator of neutrophils**, and thus contributes to acute inflammation.

Question 27

Platelet activating factor (PAF)

Answer 27

Like the eicosanoids, is generated from membrane phospholipids by **phospholipase A2**. PAF acts directly on target cells via a specific **G protein-coupled receptor.** PAF can elicit most of the features of inflammation, including enhanced leukocyte adhesion (via integrin conformational changes), chemotaxis, leukocyte degranulation, and the oxidative burst

Question 28

Lysosomal constituents

Answer 28

The lysosomal granules of neutrophils and monocytes contain multiple mediators of acute inflammation While acid proteases have acidic pH optima, and are generally active only within phagolysosomes, **neutral proteases**, including enzymes such as **elastase, collagenase, and cathepsin**, are active in the **extracellular matrix** and cause destructive tissue injury by degrading elastin, collagen, basement membrane, and other matrix proteins. Neutral proteases can also **cleave C3 and C5 to generate the C3a and C5a anaphylatoxins**, and can promote the generation of **bradykinin-like peptides** from kininogen.

Question 29

Acute inflammation mediator summary

Answer 29

Question 30

Acute-phase reactions

Answer 30

The systemic effects of acute inflammation. Fever as well as somnolence, malaise, and anorexia. Degradation of skeletal muscle proteins, hypotension, hepatic synthesis of complement and clotting factors, and alterations in the circulating white blood cell pool. Important mediators include **IL-1, IL-6, and TNFα**.

Question 31

How inflammation induces fever

Answer 31

**TNF and IL-1** act on the **thermoregulatory center of the hypothalamus** (via **local PGE₂** production) to induce fever. Hence the efficacy of aspirin and NSAIDs in reducing fever by inhibiting PGE₂ production at the hypothalamus.

Question 32

Leukocytosis

Answer 32

Increased white blood cell count Extreme leukocytosis is referred to as **leukemoid reaction,** since it mimics leukemia. Most **bacterial infections** induce a relatively selective increase in neutrophils (**neutrophilia**), while **parasitic infections** and **allergies** induce **eosinophilia**, and certain **viruses** cause selective increases in lymphocytes (**lymphocytosis**).

Question 33

Answer 33

Edema

Question 34

Abcess formation

Answer 34

Question 35

Fibrinous exudate

Answer 35

Fibrin is visible on H&E-stained sections as amorphous, pink, proteinaceous material. It can be distinguished from fibrous connective tissue because it lacks the inherent structure of collagen or reticulin.

Question 36

Ulceration

Answer 36

Question 37

Active neutrophils

Answer 37

Active neutrophils look less like the “classic” neutrophil, their nucleus is less segmented. You will typically see many cells without nuclei indicating neutrophils that have undergone NETosis.

Question 38

Major neutrophil/macrophage growth factors

Answer 38

GM-CSF G-CSF IL-17