Hunter: Inflammation Flashcards
(blank) is a component of the innate immune response to pathogenic microorganisms.
inflammation
In addition to the anti-microbial response, inflammation plays a key role in dealing with the consequences of cell and tissue (blank) caused by microbes and other physical and chemical insults
injury
What would happen without inflammation?
pathogenic microbes would overwhelm us
injured tissues would never heal
T/F: Inflammation is sometimes inappropriately triggered or poorly controlled, and is sometimes the CAUSE of tissue injury in many disorders.
True
Give an example of inflammation having a protective response. Give an example of inflammation having a harmful response.
protective: Streptococcus pyogenes (impetigo)
harmful: rheumatoid arthritis
Inflammation was recognized long ago. What were the four cardinal signs of inflammation noted? What is a 5th?
rubor (redness)
tumor (swelling)
calor (heat)
dolor (pain)
T/F: Inflammation is not a disease, but a nonspecific response that can be both protective and harmful to the host.
True
Pluripotent hematopoietic stem cells can give rise to two lines of cells. Which lineage produces dendritic cells, granulocytes (neutrophils, eosinophils, basophils), platelets, mast cells, and erythrocytes?
myeloid lineage
What two cells are the primary sensors of acute inflammation?
mast cells
macrophages
What’s this: source of mediators, such as histamine
mast cell
What’s this: cell involved in elimination of microbes and dead tissue. A source of mediators. Has a role in immune response. Also, Dr. H’s favorite cell.
macrophage
Describe the inflammatory process in a simple way. What four components are involved?
Inducers –> sensors –> mediators –> target tissues
INDUCERS of inflammation can be exogenous signals or endogenous signals that report on tissue stress, injury, or malfunction. What do these respond to?
danger signals!!
SENSOR CELLS, such as tissue-resident macrophages and mast cells, detect inducers with specific mediators and respond by producing what?
inflammatory mediators
Inflammatory mediators act on TARGET TISSUES to alter their functional states, promote elimination of inducers, adaptation to the noxious state, and restore (blank)
tissue homeostasis
Although leukocytes are the primary effector cells of inflammation, what other cells play a critical role?
endothelial cells
Give an example of a mediator that modifies endothelium adjacent to various mediators and attracts leukocytes to allow them to pass into the tissues
TNF-alpha
The endothelium also becomes permeable to (blank), thus allowing molecules like antibodies to gain access to the tissues.
plasma
List some stimuli for inflammation.
infections and microbial toxins
tissue necrosis for any cause (ex: trauma, physical/chemical injury, hypoxia)
hypersensitivity reactions (normally protective immune system damages cells and tissues)
List a few examples of hypersensitivity reactions or immunopathology
autoimmune diseases
allergies
Inflammation can be triggered by (blank) from pathogens. Phagocytic cells have (blank) on their surface and bind to highly conserved molecular motifs on pathogens called (blank).
danger signals; pattern recognition receptors; pathogen-associated molecular patterns
What does recognition of PAMPs trigger?
production of inflammatory mediators –> INFLAMMATION –>
destruction of the pathogen
These are expressed on phagocytic cells and recognize highly conserved PAMPs found on viruses, bacteria, etc. List a couple PRRs.
Toll-like receptors (can be extracellular or intracellular) Other PRRs (ex: Dectin-1)
In addition to pathogens, what else can induce inflammation?
tissue injury (necrosis)
Does necrosis trigger inflammation? Does apoptosis trigger inflammation?
YES; no
Cell injury or necrotic death causes the release of damage-associated molecular patterns (DAMPs). What are these also referred to as?
alarmins
Phagocytic cells recognize DAMPs and activate intracellular signaling pathway and the production of inflammatory mediators. What does this lead to?
inflammation and tissue regeneration or repair
Inflammation can cause (blank) to normal tissues. When it is inappropriately directed against self tissues it can becomes the CAUSE of injury/disease. List some common chronic diseases in which this is the case.
collateral damage; rheumatoid arthritis, atherosclerosis
Is inflammation critical to tissue repair? When does tissue repair begin? When does it end?
Yes; repair begins during inflammation, ends after the injurious agent has been neutralized
Through what two processes is injured tissue replaced?
regeneration of native parenchymal cells
filling of defect with fibrous tissue
OR…both!
T/F: Inflammation can be acute OR chronic, and this depends on the nature of the stimulus and how effective the initial reaction is in eliminating the stimulus and damaged tissues.
True
What happens after an offending agent is eliminated to prevent excessive damage to the host?
mediators rapidly broken down
neutrophils are short-lived
anti-inflammatory mechanisms
Is a sunburn an acute or chronic inflammation? What about psoriasis?
acute; chronic
Rapid host response that delivers leukocytes and plasma proteins to site of infection
acute inflammation
During acute inflammation, what happens to blood supply and flow? What happens to vascular permeability? What does this lead to? What happens to leukocytes?
VASODILATION increases blood supply (hyperemia), but actually decreases flow rate (stasis). Increased vascular permeability, which leads to edema. Recruitment, adhesion, transmigration of leukocytes across blood vessels.
What is it called when leukocytes flock to the site of infection or tissue injury? What is the process called in which pathogens are engulfed, destroyed, and eliminated.
chemotaxis; phagocytosis
What is the first manifestation of inflammation? What is this often preceded by? What is it caused by? What is it the result of?
vasodilation; preceded by vasoconstriction; caused by specific mediators released from tissue phagocytic cells; it is the result of relaxation in smooth muscle surrounding blood vessels
What mediators cause vasodilation? Dilation results in greater blood volume but slower flow. What is this called? What does dilation cause tissue to show?
histamine and NO; stasis; vascular congestion
Two ways in which vascular permeability can be increased.
Retraction of endothelial cells, induced by histamine or NO - rapid or short lived.
Endothelial injury, ex: burns - may be long-lived.
Leukocyte mediated vascular injury - associated with late stage of inflammation.
In leukocyte-mediated vascular injury, what cells adhere to the endothelium and injure the endothelial cells, amplifying the reaction?
neutrophils
A fluid with low protein content, with little or no cellular material. Essentially an ultrafiltrate of the blood plasma, as the result of osmotic or hydrostatic imbalance across the vessel wall WITHOUT an increase in vascular permeability.
transudate
An extravascular fluid with high protein concentration that contains cellular debris and cells. Its presence implies increased permeability of small blood vessels in injured area and an INFLAMMATORY response.
exudate
Lymphatic vessels may also become secondarily inflamed. What is this process called? What is it called when draining lymph nodes become inflamed?
lymphangitis; lymphadenitis
What causes lymph nodes to become enlarged?
hyperplasia of lymphoid follicles
increased lymphocytes and macrophages
What do macrophages produce to mediate leukocyte recruitment to the site of injury?
chemokines, like CXCL8
What is the movement of leukocytes from the vessel lumen to the interstitial tissue called?
extravasation
The extravasation process involves margination, rolling, and then adhesion to endothelium
In inflammation the endothelium is activated and can bind leukocytes via (blank) interactions
Migration across the endothelium and vessel wall is called (blank).
Migration in the tissues toward the inflammatory stimulus (blank)
adhesion molecule; diapedesis; chemotaxis
What enhances the expression of adhesion molecules?
secreted proteins called cytokines (TNF-alpha)
What are these: selectins vascular addressins integrins immunoglobulin superfamily proteins
groups of adhesion molecules
Explain leukocyte adhesion to the endothelium.
Rolling adhesion of leukocyte via E-selectin –> tight binding via LFA-1 and ICAM-1 –> diapedesis –> migration
In what vessels does diapedesis of leukocytes primarily occur?
post-capillary venules
What stimulates leukocytes to migrate through interendothelial spaces?
chemokines (ex: CXCL8)
How do leukocytes enter the extravascular tissue?
collagenases break down the basement membrane
Once in the extravascular tissue, what do leukocytes do?
They migrate up the chemokine gradient via chemotaxis and accumulate at site of injury.
Both endogenous and exogenous substances can act as chemoattractants. List some endogenous chemoattractants. List some exogenous agents.
chemokines (CXCL8)
complement system
leukotrienes;
bacterial products (peptides with N-formylmethionine terminal amino acid)
Once leukocytes have reaches the site of inflammation, what is the process by which they remove the offending agents?
phagocytosis
List the three steps of phagocytosis.
- recognition and attachment of the particle to be ingested by the leukocyte
- enfulfment of the particle and formation of a phagosome
- fusion of the phagosome with lysosomes to form phagolysosomes
What assembles at the phagolysosome membrane to generate a hostile microenvironment that kills off the ingested materials
NADPH oxidase
In regards to histopathology, what would you notice during an acute inflammatory response?
LARGE NUMBER OF LEUKOCYTES
Acute inflammation can have 1 of 3 outcomes. List them.
- resolution (acute inflammation is enough to return to normal function)
- healing by fibrosis (significant tissue injury & loss of some function)
- progression to chronic inflammation (continued tissue injury)
Acute inflammation can become chronic. However, does acute inflammation always precede chronic inflammation?
NO
Acute inflammation causes (blank) infiltration, while chronic inflammation involves (blank) infiltration.
neutrophilic; monocytic
In which process, acute or chronic, is tissue destruction common, followed by angiogenesis (new blood vessel proliferation) and fibrosis?
chronic inflammation
Do the stimuli of chronic inflammatory responses differ from stimuli of acute responses? What are the typical stimuli of chronic inflammation?
yes; pathogens like mycobacteria, certain viruses, fungi, parasites
Stimuli of chronic inflammation often evoke what type of response? What is a clinical example of this?
delayed-type hypersensitivity; TB skin test
(blank) are important causes of chronic inflammation - inappropriately triggered against harmless antigens
immune-related diseases
ex: autoimmune diseases, allergic diseases
How do monocytes emigrate into extravascular tissues? What happens when monocytes reach the tissues?
blood monocytes emigrate in a similar manner to neutrophils (adhesion molecules/chemotactic factors); monocytes undergo transformation into a larger tissue macrophage
Macrophages are often the predominant cell type by hour (blank)
Macrophages may be activated by a variety of stimuli, including microbial products and cytokines (e.g., IFN-g) secreted by sensitized T lymphocytes and other cells
48;
These are responsible for much of the tissue injury in chronic inflammation, but can also be stimulated to effect tissue repair
macrophages
In contrast to acute inflammation with NEUTROPHILIC infiltrate, what does chronic infection with TB result in? What other cells are present?
mononuclear infiltrate; multi-nucleated giant cells and epitheloid cells
What produces active mediators of inflammation? What is the stimuli?
cells and plasma proteins produce the active mediators of inflammation; the stimuli include microbial products and substances released from necrotic cells
Why is it important that it requires microbes or dead tissue to initiate/stimulate inflammation?
this ensures that inflammation is only triggered when and where it is neded
T/F: Once activated and released, most inflammatory mediators are short-lived, providing a system of checks and balances that regulates mediator actions.
true
What are two ways in which mediators are derived?
- sequestered in intracellular granules and can be rapidly secreted by granule exocytosis
- synthesized de novo and secreted in response to a stimulus
List the major cell types that produce mediators of acute inflammation
platelets neutrophils monocytes macrophages mast cells
(blank) and most epithelia can also be induced to elaborate some of the mediators. Some are derived from (blank) that are components of complex pathways
mesenchymal cells; plasma proteins
A system of over 30 preformed proteins that can recognize particular pathogens
complement system
3 systems that work in conjunction with the complement cascade to induce a reaction
coagulation, fibrinolytic, and kinin systems
Two vasoactive amines. Where are they stored as preformed molecules? When are they released?
histamine and serotonin; both stored in cellular granules; among the first mediators to be released during inflammation (within minutes)
(blank) is abundant in mast cells found in CT adjacent to blood vessels. It is also found in blood basophils and platelets.
histamine
How is histamine released? What is it released in response to?
mast cell degranulation; in response to stimuli like physical injury, antibodies bound to mast cells, complement, anaphylatoxins, and cytokines
Considered to be the principle mediator of the immediate transient phase of increased vascular permeability
histamine
What’s this: mechanical/chemical/physical stimuli release arachidonic acid from membrane phospholipids thru the action of cellular phospholipases.
arachidonic acid pathway
Eicosinoids are synthesized by two major classes of enzymes. What are they?
cyclooxygenases (which produce prostaglandins and thromboxanes) and lipooxygenases (which produce leukotrienes and lipoxins)
(blank) bind to GPCRs on many cell types and can mediate virtually every step of inflammation.
eicosanoids
Induces vasodilation and increased vascular permeability at extremely low concentrations with a potency 100 to 10,000 times greater than that of histamine
Increases leukocyte adhesion to endothelium, chemotaxis, degranulation, and the oxidative burst, and boosts the synthesis of other mediators, particularly eicosanoids
Can elicit most of the vascular and cellular reactions of inflammation
platelet activating factor
Phospholipid-derived mediator initially shown to induce platelet aggregation, but now known to have multiple inflammatory effects
Produced by a variety of cells including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells
platelet activating factor
Oxygen-derived free radicals such as superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (•OH) released extracellularly from leukocytes after exposure to microbes, chemokines, and immune complexes, or following a phagocytic challenge
reactive oxygen species (ROS)
Their production is dependent on the activation of the multi-component NADPH oxidase system
Extracellular release of low levels of these potent mediators can increase the expression of other inflammatory mediators
ROS
T/F: Although the physiologic function of ROS in leukocytes is to destroy phagocytized microbes, release of these potent mediators can be damaging to the host
True
Soluble gas produced by endothelial cells, macrophages, and some neurons in the brain.
Half-life is only seconds, acts on nearby cells.
Is a mediator of host defense against infection.
NO
NO has dual actions in inflammation. It promotes (blank), but also reduces (blank) aggregation and adhesion, so it inhibits several features of mast cell-induced inflammation and inhibits leukocyte recruitment.
vasodilation; platelet
Three major cytokines that mediate inflammation. Produced mainly by activated macrophages.
TNF-alpha
interleukin 1
interleukin 6
The most important local effects of proinflammatory cytokines are on endothelium, leukocytes, and fibroblasts. They also trigger systemic (blank)
acute-phase reactions
Cytokines mediate (blank), which includes: expression of endothelial adhesion molecules; synthesis of chemical mediators (including other cytokines, chemokines, growth factors, eicosanoids, and NO); production of enzymes associated with matrix remodeling; and increases in the surface thrombogenicity of the endothelium (platelet aggregation)
endothelial activation
TNF, produced by activation of macrophages, has local effects on what three things? It also produces systemic effects of inflammation. List a few.
- vascular endothelium
- leukocytes
- fibroblasts
systemic: fever, leukocytosis, decreased appetite, increased sleep
