Chapter 3: Acute Inflammation I Flashcards
Acute inflammation has 3 major components. What are they?
dilation of small vessels, increased permeability , emigration of leukocytes
What is vasodilation induced by primarily?
histamine
What is stasis?
the engorgement of small vessels with slowly moving red cells
What is the source of histamine?
mast cells, basophils, and platelets
What is the source of prostaglandins and leukotrienes?
mast cells and leukocytes
What are two mechanisms that are responsible for the increased permeability of postcapillary venules?
contraction of endothelial cells and endothelial injury
What elicits the contraction of the endothelial cells?
histamine, bradykinin, and leukotrienes
What do the effects on the microvasculature (flow and permeability) direct affect?
the recruitment of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
What do the presence of red streaks near a skin wound represent?
inflamed lymphatic channels and they are diagnostic of lymphangitis
The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by what?
adhesion molecules and cytokines called chemokines
The journey of leukocytes from the vessel lumen to the tissue is a process that can be divided into sequential phases. What are these phases?
1) In the lumen, margination, rolling, and adhesion to the endothelium 2) migration across the endothelium and vessel wall 3) migration in the tissues
Two additional mediators act on the endothelial cells of postcapillary venules adjacent to the infection and induce the coordinated expression of numerous adhesion molecules. What are these mediators?
TNF and IL-1
The attachment of leukocytes to endothelial cells is mediated by what?
adhesion molecules whose expression is enhanced by cytokines (which are secreted by sentinel cells in tissue in response to microbes)
What are the two major families of proteins involved in leukocyte adhesion and migration?
selectins and integrins and their ligands
What selectin is expressed on the leukocyte?
L-selectin
What does binding of the selectins to their receptors cause?
rolling
What is firm adhesion mediated by?
integrins
What is the main integrin ligand on the endothelium?
VCAM-1 and ICAM-1
In regards to integrins, what do leukocytes normally express? (no integrins, some integrins??)
leukocytes normally express integrins in a low affinity state
What is the name of the process of migration of the leukocytes through intact endothelium?
transmigration or diapedesis
Where does transmigration mostly occur?
in postcapillary venules
Several adhesion molecules present in the intercellular junctions between endothelial cells are involved in the migration of leukocytes. These molecules include a member of the immunoglobulin family called what?
PECAM-1 (or CD31)
After traversing the endothelium, leukocytes pierce the basement membrane how?
a collagenase
After exiting the circulation, leukocytes move in the tissues toward the offending agents by a process called what?
chemotaxis along a chemical gradient
What are the most common endogenous chemoattractants?
cytokines in the chemokine family (IL-8), Complement (C5a), and arachidonic acid (AA) metabolites (LTB4)
Where do the chemotactic agents bind to?
specific seven transmembrane G protein coupled receptors on the surface of leukocytes
What happens once the chemotatic agents bind to the seven transmembrane G protein coupled receptors?
there is a polymerization of actin and reorganization of the cytoskeleton allows the leading edge of the leukocyte to extend filopodia that pull the back of the cell in the direction of the extension
In most forms of acute inflammation, what leukocyte predominates in the inflammatory infiltrate during the first 6-24 hours?
neutrophils
what replaces the neutrophils in 24-48 hours?
macrophages/ monocytes
Once leukocytes (primarily neutrophils and macrophages) have been recruited to a site of infection or cell death what must occur?
their functional properties must be activated so that the offending agents can be removed (phagocytized)
Once leukocytes (primarily neutrophils and macrophages) have been recruited to a site of infection or cell death their functional properties must be activated so that the offending agents can be removed. This requires what?
recognition and attachment of the particle to be ingested by the leukocyte; engulfment with subsequent formation of a phagocytic vacuole; killing of the microbe and degradation of the ingested material
Recognition of microbes or dead cells induces several response in leukocytes that are collectively called what?
leukocyte activation
What are some examples of phagocytic receptors?
mannose receptors, scavenger receptors, and receptors for various opsonins
What is the macrophage mannose receptor?
it is a lectin that binds terminal mannose and fructose residues- these sugars are typically part of molecules found on microbial cell walls
What are scavenger receptors?
molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoprotein (LDL) particles that do not interact with the conventional LDL receptor
The efficiency of phagocytosis is greatly enhanced when?
when microbes are opsonized by specific proteins
what are the major opsonins?
IgG antibodies, the C3b breakdown product of complement, and mannose-binding lectin and collectins
Once phagocytized, killing of microbes is accomplished how?
by reactive oxygen species (ROS) and reactive nitrogen species (mainly derived from nitric oxide); as well as lysosomal enzymes
The other macromolecules destined for catabolism in the lysosomes arrive by one of three ways. What are these?
fluid-phase or receptor mediated endocytosis; autophagy; phagocytosis
How are ROS produced?
by the rapid assembly and activation of NADPH oxidase
In neutrophils, how is this oxidative reaction triggered? and what is this called?
by activating signals accompanying phagocytosis; called the respiratory burst
How is NO produced?
from arginine by the action of NOS
There are three different types of NOS, which type is involved in microbial killing?
iNOS- induced when macrophages are activated by cytokines
Neutrophils and macrophages contain lysosomal granules that contribute to microbial killing and when released may cause tissue damage. Neutrophils have two main types of granules: What do the smaller specific (or secondary) lysosomal granules contain?
lysozyme, collagenase, gelatinase, lactoferrin plasminogen activator, histaminase, and alkaline phosphatase
Neutrophils and macrophages contain lysosomal granules that contribute to microbial killing and when released may cause tissue damage. Neutrophils have two main types of granules: What are the larger granules called and what do they contain?
azurophil (or primary) lysosomal granules; contain myeloperoxidase, bactericidal factors, acid hydrolases, and neutral proteases
Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues; these harmful proteases however are normally controlled by what?
a system of antiproteases in the serum of tissue fluids
What is the main antiprotease/ what is the major inhibitor of neutrophil elastase?
alpha-1-antitrypsin
What happens if there is a deficiency of these inhibitors of neutrophil elastase?
sustained action of leukocyte proteases- they are at risk for emphysema due to destruction of elastic support fibers in the lung
What does toxic granulation refer to?
changes in granulocyte cells seen on examination of the peripheral blood film of patients with inflammatory conditions; they are dark course granules found in granulocytes- particularly neutrophils
when are toxic granulations commonly found?
in patients with sepsis
What is the purpose of Neutrophil extracellular traps (NETs)?
they are extracellular fibrillar networks that concentrate antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in fibrils
What do the extracellular traps of the NETs consist of?
a viscous meshwork of nuclear chromatin that binds and concentrates granule proteins
what happens in the process of NET formation?
the nuclei of the neutrophils is lost, leading to the death of the cells
When have NETs been detected in the blood?
during sepsis, and it is believed that their formation in the circulation is dependent on platelet activation
What cell type are also critical cells of chronic inflammation and tissue repair after inflammation has subsided?
macrophages
What cell type of adaptive immunity contributes to acute inflammation?
T lymphocytes- specifically Th17 cells (they produce IL-17)
What happens in the absence of effective Th17 responses?
individuals are susceptible to fungal and bacterial infections, and they tend to develop “cold abscesses” particularly in the skin that lack the classic features of acute inflammation
What are the active termination mechanisms of inflammation?
a switch in the type of arachidonic acid metabolite produce, from pro-inflammatory leukotrienes to anti-inflammatory lipoxins, and the liberation of anti-inflammatory cytokines (TGF-beta and IL-10)
