Inflammation I Flashcards by Joel Glotfelty

A set of host responses to injury in which there is an attempt to destroy or limit the spread of the injurious agent

Inflammation

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These responses are mediated by the microvasculature and involve both

Innate and adaptive immunity

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Attributed bacterial killing solely to the effects of soluble substances that we now recognize as antibodies and that are present in the blood plasma

Paul Ehrlich’s “humoral theory” of inflammation

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Established that chemical substances such as histamine, locally generated in inflammation, can mediate vascular changes of inflammation

Thomas Lewis, a British cardiologist

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Illustrated in the “triple” response, which can be induced by firmly stroking the skin with a hard object

Action of histamine

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Almost anything that can adversely influence cell viability can induce some aspect of

-ex: sunburn

Inflammation

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The bacteria bind to mast cell surfaces, inducing degranulation of vasoactive amines and secretion of cytokines in

Acute inflammation from bacterial invasion

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These agents cause arteriolar dilation and then venular leakage of fluid and proteins. The result is the development of

Interstitial edema

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About 12 hours following injury, the walls of the post-capillary venules begin to be lined with

Neutrophils

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They then penetrate the wall and emigrate (diapedesis) to the site of injury through the interstitium. This is followed by the

Phagocytosis of bacteria

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If the inflammation lasts more than a day, we will see emigration of

-peak at 2 days

Macrophages

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The macrophages will engulf the remaining

Neutrophil debris

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Provides an example of a severe acute inflammatory reaction

Bacterial bronchopneumonia

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What is the difference between bronchopneumonia from lobar pneumonia?

Lobar involves entire lobe

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As a bacterial pneumonia develops, the initial phase is an edematous phase with few inflammatory cells in which the alveoli fill with

Exudate

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This is followed by the so-called “red-hepatization” stage in which we see a prominent

Neutrophil response

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The next phase is the so-called “grey-hepatization” stage in which neutrophils are replaced by a less dense array of

Macrophages

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During the grey-hepatization, we see the alveolar accumulation of

Fibrin

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Filled with membrane-bound vesicles that contain a variety of potent vasoactive agents

Mast cells

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Released following different stimuli that occur through injury, non-immune and immune reactions

Mast cell vasoactive agents

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One of the principal activations of mast cells that result in degranulation is mediated through the

IgE Fc antibody receptor

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Signaling is initiated by aggregation followed by signaling sequence of phosphorylations. It results in histamine, cytokine and arachidonic acid metabolite production, and release of

Histamine (via degranulation)

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A variety of local and systemic (e.g. fever) effects are mediated by

Arachidonic acid metabolites

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What are the two synthetic pathways for these eicosanoids?

) Prostaglandins and prostacyclins

2. ) Leukotrines

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The products of the pathway mediate such processes as vasodilation, vasoconstriction, edema, fever and

Leukocyte chemotaxis

Aspirin and other non-steroidal anti-inflammatory agents (NSAIDs) act by blocking

Cyclooxygenase

Potent anti-inflammatoryagents that prevent the synthesis of arachidonicacid

Glucocorticoids

Phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types

Macrophages

Secrete a variety of factors to coordinate and stimulate immune responses to specific antigen

T cells

Several cytokines act on conjunction with colony-stimulating factors to increase the bone marrow production of different classes of

Leukocytes

We see shifts in the population of leukocytes in

Acute infections

Inflammation from a severe infection will result in immature forms of -important diagnostic indicator

Neutrophils

Refers to the presence of increased proportions of younger, less well differentiated neutrophils and neutrophil-precursor cells in the blood

"Left Shift"

Increase in blood lymphocytes to greater than 4000 -can be caused by acute viral infections

Lymphocytosis

The capillary and venules present two barriers to the migration of fluid, solutes and cells into the tissue spaces. What are they?

1. ) Endothelium | 2. ) Basal Lamina

There are three main types of microvascular leakage that follow an injury. The most specific and “physiological” of these is the

Histamine type response

More severe injury, in which permanent damage occurs to the microvascular walls, results in the more prolonged leakages seen with

Mild direct and severe direct injury

In the more severe form of direct injury, the leakage is seen across a destroyed wall and is limited by local

Thrombosis

Mediates an increased in transcytosis across the endothelial cell in the microvasculature -recently reckognized

VEGF

One way of studying the events of inflammation with the light microscope is to use

Fluorescent dextran

The leakage for the dextrin does not occur from all vessels. Rather, it occurs selectively from the post-capillary venules that are intermediate in size between

Capillaries and arterioles

Quantitation reveals that the leakage follows a stereotypic time course within a given

Vascular bed

The time course of leakage is independent of the duration of histamine treatment, suggesting a

Gating phenomenon

Furthermore, there is a refractory period within which a second histamine injection does not produce a

Second leakage peak

Post-capillary venules do not possess smooth muscle in their walls, unlike arterioles. Nonetheless, venular constriction is observed following

Histamine exposure

Whereas endothelial cell transport normally is mediated primarily by small vesicles, there is no increase of vesicular transport during

Inlammation

Studies on horseradish peroxidase transport indicate that macromolecules instead rapidly pass down

Inter-endothelial junctions

At an ultrastructural level, endothelial gaps are seen to form at the inter-endothelial junctions of previously -induced by histamine

Continuous venule

Seen as an exudate that is localized and has high protein concentration

Inflammatory Edema

The transudate of general edema is of low protein concentration and occurs from an imbalance

Hydrostatic and osmotic pressures

In inflammation, pre-capillary sphincters open up, increasing hydrostatic pressure AND the venules become leaky such that the osmotic gradient across the wall is

Removed

As fluid leaves the vasculature, the blood in the microcirculation, now becomes more viscous with increasing

Hematocrit

The sequence of events in leukocyte infiltration can be divided into which 4 steps?

1. ) Margination 2. ) Sticking 3. ) Emigration 4. ) Phagocytosis

In a typical course of inflammatory events, vasodilation, transudation, and then slowing of circulation occurs as the

Blood viscosity increases

As stasis develops, one begins to see the peripheral orientation of leukocytes along the vascular epithelium, principally

Neutrophils

Leukocytes first stick transiently and then more

Avidly

How does induction of the neutrophil interaction with the endothelium occur?

1. ) Redistribution of intracellular receptor stores to the cell surface 2. ) Induction of expression 3. ) Activation of receptors

Normally is intracellular in endothelium and unavailable for cell surface glycoconjugate binding

P-selectin

Will induce new expression of receptors on the endothelial surface

Cytokines

Cell surface integrins can be activated by soluble agents that bind to other receptors. This phenomenon has been called

Inside-out signaling

Transmembrane heterodimeric adhesion molecules that form noncovalent associations with extracellular matrix and cell surface ligands such as the ICAMs

Integrins

Integrins associate with the cell surface ligands

ICAMs

Bind to injured vascular walls and fibrin

Platelet integrins

Enable leukocyte binding to the venular wall and subsequent migration through that wall

Leukocyte integrins

In acute inflammation, first, there is an initial and rapid loose adhesion that accounts for

Rolling

First, there is an initial and rapid loose adhesion that accounts for rolling. It involves mainly the

P-selectin, L-selectin, and E-selectin

Factors such as histamine and thrombin induce the cell surface movement of

Selectins

These same agents [i] indirectly initiate arteriolar vasodilation by inducing the endothelial cell to secrete vasoactive prostacyclin and

Nitric oxide

Cytokines such as IL-1, TNF, IFN-y appear to induce synthesis of the endothelial cell

ICAMs

The leukocytes are activated by agents made by endothelium or other cells, to increase the avidity of their

Integrins

These integrins bind stably to endothelium, largely through the interaction of

B2-integrin w/ ICAM-1

In the following hours, we see release of themajor soluble ligands

IL-1 and TNF

These agents produce a more sustained vasodilation and vascular leakage, increased leukocyte delivery, further neutrophil adhesion and chemokinesis, secretion of IL-8 and expression of endothelial ELAM-1

IL-1 and TNF

Closely associated with sticking is the function of directed cell migration out of the vasculature. This is called

Diapedesis

Neutrophils and mononuclear phagocytes enter inflammatory foci for the purpose of ingesting and disposing of unwanted particulate material such as bacteria or broken-down cells. This is the process of

Phagocytosis

Neutrophils possess large numbers of cytoplasmic granules: The primary granules are? -peroxidase positive

Azurophilic granules

The neutrophils and macrophages also possess -peroxidase negative

Secondary granules

Larger dense granules that contain various lysosomal hydrolases such as acid phosphatase, cationic proteins, myeloperoxidase and the antibacterial protein lysozyme

Azurophilic granules

The smaller specific granules also contain lysozyme, but also have

Alk-phos and lactoferrin

Have gelatinase and cathepsins. These are released at the leading edge of migrating neutrophils and are thought to act primarily in disrupting extracellular matrix

Tertiary particles (from tertiary granules)

Phagocytosis can be subdivided into which three phases?

Recognition/attachment, engulfment, digestion

Coating or "opsinization" of the microbe precedes recognition and attachment by

Phagocytes

There are two main groups of opsonizationfactors: What are they?

1. ) Heat stabile IgG | 2. ) Heat labile C3b (complement)

The Fc portion of IgG is recognized by the

FcgR receptor

C3b is recognized by complement receptors

CR-1, 2, and 3

In addition, the b2 integrin Mac-1 binds to certain bacterial wall lipopolysaccharide (LPS), mediating so-called

Non-opsonic phagocytosis

After binding of opsonin molecules to the particle surface, the particle then sticks to the phagocyte surface because the phagocyte has receptors for the

Fc portion of antibody and C3b

As the phagosome is being formed during ingestion, it is converged on by

Lysozymes

Phagocytosis is an energy-requiring process that is accompanied by a tremendous burst of metabolic activity in the cell. Oxygen consumption increases

2-3 fold

The amount of glucose metabolized via the hexose monophosphate shunt (HMS) increases from a resting level of 1% to an active level

10%

The most important agents for bacterial killing is

Superoxide anion and hydrogen peroxide

A highly reactive radical derived from oxygen and NADPH -sequestered in vacuoles

Superoxide anion

The cell removes any cytoplasmic superoxide with the enzyme

Superoxide dismutase

An inherited disease usually affecting males (X-linked) -due to deficiency of NADPH oxidase

Chronic Granulomatous Disease (CGD)

The major defect of CGD is that the leukocytes fail to show the burst of metabolic activity that normally accompanies

Phagocytes

This in turn leads to a failure of the halide/myeloperoxidalsystem, which is seen in

CGD

CGD patients develop serious infections with catalase producing bacteria such as

Staphylococcus aureus

This is because the catalse negative bacteria essentially commit

Suicide

Considerably more benign than chronic granulomatous disease, indicating that NADPH oxidase and superoxide production is more important than the peroxidase reaction in bacterial killing

Myeloperoxidase

Mutations affecting lysosomal membrane trafficking leads to increased CNS infections in

Chediak-Higashi syndrome