8-4 Acute Inflammation Flashcards
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A: Purpose of Inflammatory Response is to:
- Neutralize injurious agent
- Remove Dead Tissue
- Facilitates HEALING by preparing damaged organ for repair
B: ACUTE Inflammation= IMMEDIATE & RAPIDLY PROGRESSIVE tissue rxn (vascular & cellular) characterized by accumulated fluid/plasma proteins/& Neutrophils at injury site.
B2: ACUTE Inflammation should only last hours-several days.
C: Intensity of Inflammation depends on:
- Physician Intervention
- Genetics
- Duration of Stimulus/Pathogen
- Type of Injury & blood supply to the area
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A: Clinical Manifestations of ACUTE Inflammation
- Locally*
1. Rubor
2. Tumor (swelling from extravascular edema)
3. Dolor
4. Calor (Heat from INC Vasodilation/blood flow)
Systemically
1. Fever
2. Shaking Chills
3. Malaise
4. Leukocytosis
5. IF SEVERE–> [INC Cardiac Output] & [DEC peripheral vascular resistance]
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B: [Vascular Event] of ACUTE Inflammation involves vasodilation (1st arterioles, and then capillaries) induced by [Nitric Oxide] released by cytokines.
-Vasodilation will INC blood flow and can work with [INC vascular permeability] to allow plasma proteins to leak out and [DEC colloid osmotic pressure] —-> [INC extravascular edema] for better innate cell delivery!
C: Chemo/cytokines also adjust endothelium so that protein-rich fluid with Antibodies/complement/etc. can access the interstitial space at injury site
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A: Chemo/cytokines that operate [ACUTE Inflammation] come from [M1 macrophage inflammasomes] which secrete [IL1/ 6 / 8/ TNFa] when their TLR is activated by a DAMP or PAMP
C: [IL1/ 6 / 8/ TNFa] from activated [M1 macrophages] RECRUITS (specifically IL1) Neutrophils {THE ULTIMATE DESTROYER/SCAVENGER} and enables neutrophil [migration] to site of injury. This occurs thru
1. Margination= chemokines upregulate endothelium receptors which’ll attract neutrophils to [lumen periphery]
2. Rolling Adhesion= Neutrophils roll along endothelium and complimentarily “stick” to it
3. Transmigration= Neutrophils extend pseudopods between endothelial cells and migrate
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D: Neutrophil migration ALSO REQUIRES ACTIN!
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A: INC blood flow INC potential for leukocytes to congregate along endothelium and respond = RHEOLOGIC CHANGE
B: While roaming in peripheral blood, neutrophils have a half life of 12 hrs. Once neutrophils are directed to an inflammatory site this half life drops to 1-2 hours!
C: Neutrophils (AKA “polys”) normally circulate in 2 compartments (50% in core of blood flow / 50% closer to endothelium) BUT.. during [ACUTE Inflammation] polys rapidly shift from core to margin—> possible inaccurate CBC reading since blood is drawn from the core
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A: [IL 8] (and sometimes IL17) from [M1 macrophage Inflammasomes] stimulate bone marrow to accelerate neutrophil maturation, proliferation and release of polys!
B1: Polys move from blood vessels to injury site via chemotaxis. Chemotaxis is unidirectional mvmnt facilitated by chemical substance GRADIENT.
B2: These Chemotaxis agents:
- C5a
- bacterial peptides
- [arachnidonic leukotriene B4]
- [IL1/ 6 / 8/ TNFa] )
…all change Neutrophil cytoskeletons to enable the cell to move along a GRADIENT to inflammatory site.
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A: What does polys do once they get to site?
*Neutrophils undergo phagocytosis (attachment, engulfment and then killing of pathogen) once in site.
{Granulocytes/ Monocytes/ [Tissue macrophages] are the major phagocytes}
B: Although it doesn’t need it, Phagocytosis is more effective when pathogen is first coated with [innate system opsonins (i.e. IgG antibody bound to C3b) ]
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C: Engulfment starts with extending pseudopods around the microbe. Engulfment requires
- actin/myosin
- energy
- [intracellular Ca+]
B4 engulf pocket closes, [Lysosomal granules] fuse with cell membrane lining the pocket, some granule leaks into unclosed pocket (tissue damage) and then tips of pseudopods fuse—> PHAGOLYSOSOME which traps the microbe.
C3: [Lysosomal granules] then release their contents into the vacuole = Degranulation. Degranulation leads to activation of [oxidative respiratory burst] which will generate
- ROS (reactive oxygen species)= Activating NADPH converts Oxygen–>Superoxide ion—>H202 and [free O2 radicals]
- Lysosomal enzymes are isolated in the [Neutrophil azurophilic granules]. Myeloperoxidase is one of the major enzymes inside these granules tht destroys bacteria. Powerful oxidants are dangerous when uncontrolled.
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NETS [Neutrophil Extracellular NeTS] occurs when neutrophils sacrifice their nucleus and cast out its chromatin (loaded with azurophilic granules) & other stuff to trap bacteria/fungi.
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A: CONTROL of ACUTE Inflammation is dependent on [M1 macrophages] which come from circulating monocytes.
B: These monocytes are the
=LARGEST leukocytes with
=LARGE indented nucleus
=abundant lysosomes and large golgi apparatus.
=circulate for 16 hrs before leaving blood
=have MHCII so can act as Antigen presenting cells
=can acquire regional phenotypic modifiers based on final residence (ex. Kuppfer cells in Liver)
C: Once [M1 macrophage] TLRs are no longer stimulated by PAMP/DAMP (i.e. stimulus is eliminated) then ACUTE inflammation will subside.
C2: DEC [M1 macrophage TLR stimulation] –> neutrophils now releasing INHIBITORS of further neutrophil influx from blood vessels and instead RECRUITERS for monocytes to enter inflammatory site —> starts Healing. CIGARETTES IMPEDE THIS PROCESS WHICH ALLOWS FOR NEUTROPHIL-CAUSED VASCULAR DAMAGE
C3: Reduced TLR activation of [M1 macrophages]—>converts them into [M2 macrophages] which secrete [TGF-B and IL10]. These are ANTI-Inflammatory and allow for Healing.
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Outcome of ACUTE Inflammation can either lead to
1. Repair with restoration of initial architecture
OR
2. Transition to Chronic Inflammation
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B: CARDINAL HALLMARK OF ACUTE INFLAMMATION:
*slightly LARGER (represents immature neutrophils) [teenager band cell neutrophils] that are NOT as segmented and only in circulation because bone marrow is pushing polys out early!
B2: [teenager band cell neutrophils] are still functional!
