Inflammation I Flashcards
A set of host responses to injury in which there is an attempt to destroy or limit the spread of the injurious agent
Inflammation
These responses are mediated by the microvasculature and involve both
Innate and adaptive immunity
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
Established that chemical substances such as histamine, locally generated in inflammation, can mediate vascular changes of inflammation
Thomas Lewis, a British cardiologist
Illustrated in the “triple” response, which can be induced by firmly stroking the skin with a hard object
Action of histamine
Almost anything that can adversely influence cell viability can induce some aspect of
-ex: sunburn
Inflammation
The bacteria bind to mast cell surfaces, inducing degranulation of vasoactive amines and secretion of cytokines in
Acute inflammation from bacterial invasion
These agents cause arteriolar dilation and then venular leakage of fluid and proteins. The result is the development of
Interstitial edema
About 12 hours following injury, the walls of the post-capillary venules begin to be lined with
Neutrophils
They then penetrate the wall and emigrate (diapedesis) to the site of injury through the interstitium. This is followed by the
Phagocytosis of bacteria
If the inflammation lasts more than a day, we will see emigration of
-peak at 2 days
Macrophages
The macrophages will engulf the remaining
Neutrophil debris
Provides an example of a severe acute inflammatory reaction
Bacterial bronchopneumonia
What is the difference between bronchopneumonia from lobar pneumonia?
Lobar involves entire lobe
As a bacterial pneumonia develops, the initial phase is an edematous phase with few inflammatory cells in which the alveoli fill with
Exudate
This is followed by the so-called “red-hepatization” stage in which we see a prominent
Neutrophil response
The next phase is the so-called “grey-hepatization” stage in which neutrophils are replaced by a less dense array of
Macrophages
During the grey-hepatization, we see the alveolar accumulation of
Fibrin
Filled with membrane-bound vesicles that contain a variety of potent vasoactive agents
Mast cells
Released following different stimuli that occur through injury, non-immune and immune reactions
Mast cell vasoactive agents
One of the principal activations of mast cells that result in degranulation is mediated through the
IgE Fc antibody receptor
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)
A variety of local and systemic (e.g. fever) effects are mediated by
Arachidonic acid metabolites
What are the two synthetic pathways for these eicosanoids?
- ) Prostaglandins and prostacyclins
2. ) Leukotrines
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?
- ) 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?
- ) Margination
- ) Sticking
- ) Emigration
- ) 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?
- ) Redistribution of intracellular receptor stores to the cell surface
- ) Induction of expression
- ) 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?
- ) 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
