Acute Inflammation - Purpose and Process

What is inflammation?

A complex and integrated host response to injury

What is involved in inflammation?

Microvasculature, blood elements, and local extracellular matrix

What are the three main purposes of inflammation?

To isolate, dilute, neutralize, confine, and remove the offending agent

To clear the area of debris

To initiate healing and repair

What are causes of inflammation?

Microorganisms

Chemicals

Trauma

Foreign body

Necrosis

Etc.

What are the three outcomes of inflammation?

Elimination of the agent and return to normal

Ongoing inflammation

Death of the host

What are the cardinal signs of acute inflammation?

Rubor (redness)

Tumor (swelling)

Calor (heat)

Dolor (pain)

Function leasa (loss of function)

What are the series of vascular events in response to inflammation?

Transient arteriolar vasoconstriction

Arteriolar vasodilation

Capillary congestion

Increased vascular permeability

Slowing of blood flow

Redistribution of blood cell elements

Blood flow stasis

What are the five cardinal signs of acute inflammation?

Ruber (redness)

Tumor (swelling)

Calor (heat)

Dolor (pain)

Function leasa (loss of function)

What causes the transient arteriolar vasoconstriction in acute inflammation?

Stimulus on arteriolar smooth muscle

What regulates the transient arteriolar vasoconstriction in acute inflammation?

Release of local mediators

How long can the transient arteriolar vasoconstriction in acute inflammation last?

Several seconds up to 5 minutes

What causes hyperemia in acute inflammation?

Vasodilation

Where does vasodilation start and end in acute inflammation?

Starts at the arteriole and progresses to the venule

What are mediators of vasodilation?

Histamine

Bradykinin

Substance P

Complement (C3a and C5a)

Etc.

What does the wave of vasodilation seen in acute inflammation result in?

Hyperemia

What does increased vascular permeability in acute inflammation lead to?

Edema formation

What do vasodilation and fluid leakage during acute inflammation lead to?

An eventual slowing of blood flow

What are the two types of mediators that regulate vascular permeability?

Immediate transient response

Delayed sustained response

What mediators cause the immediate transient response in acute inflammation leading to vascular permeability?

Histamine, bradykinin, leukotrienes, substance P, etc.

What mediators cause the delayed sustained response in acute inflammation leading to vascular permeability?

TNF, IL-1, gamma-IFN

What vascular change leads to edema formation in acute inflammation?

Increased vascular permeability

What two vascular changes in acute inflammation cause a slowing of blood flow?

Vasodilation

Fluid leakage (due to vascular permeability)

What does increased vascular permeability do in acute inflammation?

Moves fluid with proteins into the extravascular space to help dilute the inciting stimulus of inflammation

What happens to the fluid as time passes in inflammation?

Changes from a transudate to an exudate

What are the differences between a transudate and an exudate?

Transudates are clear with little protein or cells, associated with edema. Clear and watery

Exudates have increased protein and cells. Colored fluid

What is in an exudate?

Positive acute phase proteins

Coagulation factors

Cytokines

Others

What does exudate usually contain a lot of?

Fibrin

Why does exudate contain fibrin?

Fibrinogen and coagulation factors are secreted, leading to the cleavage of fibrinogen into fibrin

What is fibrinogen/fibrin a mediator of?

Inflammation, both anti- and pro- pathways

What does fibrinogen/fibrin influence in inflammation?

Leukocyte emigration

Chemotaxis

Phagocytosis

Cytokine production

NF-κB-mediated transcription

Degranulation

What does fibrinogen/fibrin act as a ligand for?

B2 integrins

Why does blood slow down in acute inflammation?

Large vascular diameter

Increased number of blood cells (congestion)

Increased blood viscosity due to plasma loss

Increased adhesiveness of erythrocytes

What disrupts the laminar flow of blood cell elements during acute inflammation?

Vasodilation and congestion

Which blood cells become centrally located during inflammation?

Erythrocytes

Which blood cells become peripherally located during inflammation?

Leukocytes

What is a critical event in inflammation?

Movement of cells (leukocytes) from the blood vessel to the site of injury

What are the major steps to move cells outside the blood vessel?

Migration and adhesion to endothelium

Emigration

Chemotaxis

Acculumation

What is migration in inflammation?

Movement of leukocytes to the periphery of the vessel, adjacent to the endothelium

What is pavementing?

Lining of the endothelial surface with leukocytes

Where does migration of leukocytes occur?

In capillaries and postcapillary venules

What are the normal, non-circulating neutrophils attached to non-activated endothelium referred to as?

Marginated pool

What happens after leukocytes marginate to the endothelium?

They transiently adhere (roll) and then attach

What on the endothelium mediates leukocyte rolling?

E and P-selectins

What on the leukocytes mediates rolling?

L-selectin

What mediates leukocyte rolling on the endothelium?

E-selectin on the endothelium

P-selectin on the endothelium and platelets

L-selectin on the leukocyte

What on the endothelium causes leukocyte attachment?

ICAM-1

VCAM-1

What on leukocytes allows adhesion to the endothelium?

B2 integrins

What receptors cause leukocyte adhesion?

I-CAM1 and V-CAM1 on the endothelium

B2 integrins on leukocytes

What is leukocyte emigration?

Movement of leukocytes from the endothelial surface into the extravascular space

What interactions occur in the inter-endothelial junction during leukocyte emigration?

PECAM-1 on the endothelium interacts with Junction Adhesion Molecules (JAMs)

Which leukocyte emigrates first during inflammation?

Neutrophils

How quickly can neutrophils emigrate to a site of inflammation, and for how long do they predominate?

Emigrate within 30-40 minutes

Predominate for 6-24 hours

Which leukocyte is the second to emigrate during inflammation?

Monocytes

Which leukocyte is the last to emigrate and only does so if there is an ongoing inflammatory stimulus?

Lymphocytes

What is chemotaxis?

Directed movement of leukocytes to the site of an inflammatory stimulus

What are examples of chemical attractants that cause chemotaxis of leukocytes?

Activated complement components

Bacterial products

Leukocyte products

Chemokines

What is the mechanism of chemotaxis?

Chemotactic factors interact with leukocyte membrane receptors

Phospholipase C is activated, and results in localized release of Ca2+

Ca2+ results in localized assembly of microtubules and microfilaments, creating the pseudopod

Leukocyte B1 integrin binds to ECM components to pull itself in the direction of the stimulant

What cells are the first to accumulate at the site of inflammation?

Neutrophils

When do macrophages start to accumulate at the site of inflammation?

After 24-48 hours

Why are macrophages cells of chronic inflammation?

Emigration is sustained, they live longer, and can replicate locally, causing increased numbers during chronic inflammation

What happens after cells accumulate at the site of inflammation?

Phagocytosis

What is phagocytosis?

Cellular process of uptake and elimination of particles

What are the "professional" phagocytes?

Macrophages

Neutrophils

Monocytes

Dendritic cells

Osteoclasts

What is the purpose of phagocytosis in inflammation?

Destroy and remove inflammatory stimulus

Clean up debris and apoptotic cells to stimulate the healing process

What are the three stages of phagocytosis?

Attachment

Ingestion

Killing and degradation

What allows easy attachment of phagocytes to materials?

Opsonization of the material

What is opsonization?

Coating of foreign material by factors that enhance phagocytosis

What are the major opsonins?

C3b

IgG

Collectins

What is a phagosome?

Vacuole in the cytoplasm of a cell that contains foreign material

What regulates leukocyte cytoskeletal changes?

Ca2+ fluxes

What is a phagolysosome?

A lysosome fused to a phagosome

What are the two ways phagocytic cells can kill microorganisms?

Oxygen-independent killing mechanisms

Oxygen-dependent killing mechanisms

What are the two oxygen-dependent killing mechanism pathways in a phagocyte?

Myeloperoxidase-independent pathway

Myeloperoxidase-dependent pathway

What mediators are in lysosome contents and are part of oxygen-independent killing?

Acid hydrolases

Bactericidal permeability-increasing protein

Lysozyme

Lactoferrin

Defensins

What happens in the oxygen-dependent, myeloperoxidase-independent killing pathway?

Killing is mediated by the direct oxidative effects of oxygen metabolites

What are the oxygen metabolites in phagocytes?

Superoxide anion

Hydrogen peroxide

Hydroxyl radical

What initiates the myeloperoxidase-independent pathway?

Formation of NADPH oxidase during the respiratory burst

What is the most potent killing mechanism of phagocytes?

Myeloperoxidase-dependent pathway where bleach is formed

What is formed in the oxygen-dependent killing, myeloperoxidase-dependent pathway?

Hypochlorous acid (bleach)

Which phagocyte predominantly has the myeloperoxidase-dependent pathway?

Neutrophils

What happens to neutrophils after phagocytosis?

They undergo apoptosis and are removed

What happens to macrophages after phagocytosis?

They persist and continue to function until no longer needed