Acute Inflammation (Foundations Exam 1)

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inflammation

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complex reaction of vascularized living tissue to injurious agents that consist of vascular responses, migration, and activation of leukocytes, and systemic reaction

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major components of inflammation

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involves the actions of blood vessels, cells, and chemical mediators

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acute inflammation

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- rapid onset
- short duration (minutes to days)
- may occur over a longer time frame in ongoing or repeated injury

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chronic inflammation

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- longer duration
- variable time course
- granulomatous inflammation (specialized form)

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basic objectives of acute inflammation

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- rapid delivery of leukocytes and plasma proteins to site of injury
- destruction of offending agent
- amplification
- regulation of inflammatory response

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major components of acute inflammation

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1. alterations in vessel caliber --> increased blood flow
2. structural changes in microvasculature --> movement of fluid and plasma proteins into tissues
3. emigration of leukocytes --> movement into tissues
- circulating cells -- neutrophils, monocytes, eosinophils, lymphocytes, basophils and platelets
- cells in tissue -- mast cells, macrophages, and lymphocytes

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stimuli triggering acute inflammation

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1. infections and microbial toxins
2. tissue necrosis - ischemia, trauma, physical and chemical agents
3. foreign bodies
4. immune reactions - autoimmune, hypersensitivity

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exudate

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extravascular fluid
- high protein concentration
- cellular debris
- specific gravity >1.020

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transudate

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- low protein content (mostly albumin)
- specific gravity < 1.020

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edema

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excess fluid in interstitial space or cavities (may be exudate or transudate)

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pus

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(purulent exudate)
- inflammatory exudate
- leukocytes (especially neutrophils)
- cellular debris
- microbes

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vasodilation

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- early event that affects mostly arterioles
mechanism: chemical mediators act on vascular smooth muscle (histamine, nitric oxide)
result: opens capillary beds -> increased blood flow

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increased vascular permeability

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- involves PCVs
- fluid movement into extravascular tissues
- lack of endothelial integrity

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forces favoring fluid movement into tissues

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--> increased intravascular hydrostatic pressure (inc. bf)
--> decreased intravascular oncotic pressure (loss of protein)

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mechanisms of lack of endothelial integrity

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1. formation of endothelial gaps (retraction)
--> immediate response (histamine or other mediators)
--> delayed, prolonged leakage (thermal injury or radiation)
2. direct endothelial injury (burns, microbes)
3. leukocyte mediated vascular injury (inflammatory cells)
4. increased transcytosis (specialized channels)
5. leakage of new blood vessels (angiogenisis) --> leaky

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cellular response in acute inflammation

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1. extravasation
2. chemotaxis
3. leukocyte activaiton
4. phagocytosis
5. release of leukocyte products into extracellular space
6. defects in leukocyte function

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extravasation

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movement of leukocytes from the vessel lumen into the interstitial space
1. margination
2. rolling
3. adhesion
4. transmigration (diapidesis)

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margination

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- leukocyte accumulation in a specific location
- due to changes in blood flow/stasis

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rolling

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- "tumbling" of cells due to transient interaction with endothelium
- adhesion molecules: selectins
-- low affinity binding

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adhesion to endothelium

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- cells come to rest and adhere firmly
- adhesion molecules: integrins
--high affinity binding

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transmigration (diapidesis)

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- cells squeeze through intracellular junctions, then across basement membrane
- adhesion molecules: immunoglobulin family molecules

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inflammatory response time course

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- neutrophils predominate first 6-24 hours
- monocytes replace neutrophils after 24-28 hours

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chemotaxis

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emigration of inflammatory cell towards injury
- stimuli may be endogenous or exogenous (bacterial products)
mechanism: chemotactic agents bind to receptor on inflammatory cell --> activates an intracellular signal --> reorganization of cell cytoskeleton and "contraction" of cytoplasm

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leukocyte activation

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cell signaling pathways triggered within leukocytes
- causes: microbes, necrotic cell products, cytokines, Ab-Ag complexes
- binding of substances to special receptors on leukocyte cell surface -->activation of cascades
- production of multiple substances the help mediate and augment response

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phagocytosis

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inflammatory cells phagocytose the microbial agent or foreign invader
1. recognition and attachment
2. engulfment
3. killing and degradation

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recognition and attachment
(phagocytosis)

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- special receptors on surface of leukocytes bind to microbes (ex: TLRs, GPCRs)

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engulfment
(phagocytosis)

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- extensions of cell cytoplasm (pseudopods) flow around particle and enclose particle in phagosome
- phagosome fuses with cell lysosome
- discharge of lysosomal contents into phagosome (phagolysosome)

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killing and degradation
(phagocytosis)

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- occurs within phagolysosome
- highly oxygen dependent
mechanisms:
1. generation of reactive oxygen species (ROS)
2. myeloperoxidase (MPO) --> enzyme with neutrophil granules
--> converts hydrogen peroxide (H2O2) to a potent antimicrobial agent

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release of leukocyte products into the extracellular space

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- many substances in response intend to destroy the microbe but cause direct injury to the host tissues
- major offenders: lysosomal enzymes and reactive oxygen and nitrogen species
- endogenous protective mechanism exist to help counteract
1. antiproteases - inhibit enzymes that digest proteins
2. antioxidants -protect against free radicals

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defects in leukocyte function

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- increased vulnerability of patient to infection
- defects in leukocyte adhesion (recurrent infections, impaired wound healing)
- defects in phagolysosome function (chediak-higashi syndrome - decreased neutrophils, defective granulation, delayed microbial killing)
- defects in microbicidal activity (chronic granulomatous disease - recurrent bacterial infections)
- bone marrow suppression

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general features of chemical mediators of acute inflammation

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- derived from plasma or elaborated from cells
- production is triggered by microbes or host proteins
- bind to specific receptors on target cells
- short-lived

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vasoactive amines

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1. histamine
2. serotonin

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histamine

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-source: mast cells (most important), basophils, and platelets
- effects: dilation of arterioles, increased permeability of PCVs

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serotonin

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source: mostly platelets
effects: dilation of arterioles, increased permeability of PCVs

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arachidonic acid metabolites

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prostaglandins, leukotrienes, lipoxins
- fatty acid present in the cell membrane that is activated by an enzyme (phospholipase A) as result of stimuli
two main pathways:
1. cyclooxygenase pathway
2. lipoxygenase pathwasy

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cyclooxygenase pathway

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- generates prostaglandins
- effects: vascular tone and permeability, platelet aggregation, pain, and fever
enzymes: COX-1, COX-2

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lipoxygenase pathway

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- generates leukotrienes and lipoxins
- leukotrienes: effects on chemotaxis, vasoconstriction, vascular permeability, and bronchospasm
- inhibited by lipoxins
- lipoxins: regulatory function to inhibit leukocyte recruitment

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anti-inflammatory medications

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- aspirin, NSAIDS --> inhibit prostaglandin pathway (COX-1, COX-2)
- zileuton, montelukast --> inhibit lipoxygenase pathway (asthma)
- corticosteroids --> broad spectrum inhibition of both pathways
- fish oil --> fatty acids that convert to anti-inflammatory lipid products

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platelet activating factor

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- released by various cells: platelets, basophils, mast cells, neutrophils, monocytes/macrophages, and endothelial cells
-acts on blood vessels and smooth muscle --> promotes leukocyte function

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reactive oxygen species (ROS)

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- generated by leukocytes in response to stimuli
- destroys microbe
- also damages host tissue
- most important: superoxide anion, hydrogen peroxide, hydroxyl radical

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nitric oxide (NO)

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- soluble gas produced by endothelial cells and macrophages
- reduces effects of inflammation
- potent vasodilator
- reduces platelet aggregation
- inhibits mast cells
- regulates leukocyte recruitment
- can directly kill microbes

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cytokines

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- proteins produced by cells that modify actions of other cells
- most important: tumor necrosis factor (TNF) and interleukin-1 (IL-1)
- triggers systemic acute inflammation (fever, loss of appetite, slow wave sleep, release of neutrophils)
- TNF mediates effects of septic shock

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chemokines

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-act as chemoattractants to stimulate recruitment of leukocytes and control migration of inflammatory cells through tissues

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neuropeptides

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- small peptides produced in central and peripheral nervous system
- initiation and propagation of inflammation
- substance P --> prominent in lungs and GI tract
effects: transmission of pain signals and regulation of blood pressure

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plasma proteins (cell mediators)

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1. complement system
2. kinin system
3. clotting system

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complement system

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- plasma protein system crucial to defense
effects: lysis of microbial cells, vascular dilation, increased permeability, leukocyte adhesion, chemotaxis, more effective phagosytosis

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kinin system

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- interacts with clotting system
- results in release of bradykinin
--> potent vasoactive peptide
--> increases vascular permeability, contraction of smooth muscle, vasodilation, causes pain (when injected)

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clotting system

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- culminates in formation of fibrin clot
- acute inflammation can trigger activation of clotting cascade
- induces inflammation

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serous inflammation

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- outpouring of thin fluid (skin blister, pleural effusion)

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fibrinous inflammation

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- fluid plus larger molecules leads to formation of fibrinous exudate
- seen with severe injury
- areas lining body cavities

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suppurative or purulent inflammation

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- production of large amounts of purulent exudate (neutrophils, necrotic debris and edema fluid --> acute appendicitis, bronchopneumonia)
- due to bacterial infection
- abscess

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ulcer

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- local defect of the surface of a tissue or organ due to shedding of inflammatory cells and/or necrotic tissue
--> occurs in GI tract, genitourinary tract, and skin

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outcomes of acute inflammation

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1. complete resolution
2. healing by connective tissue replacement (fibrosis)
3. progression to chronic inflammation

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complete resolution

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- injury is limited or short-lived with minimal tissue destruction
- neutralization of chemical mediators
- normal vascular permeability
- cessation of leukocyte infiltration
- apoptosis of neutrophils
- removal of fluid, protein, and cell debris

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healing by connective tissue replacement (fibrosis)

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- common outcome of acute inflammation that follows significant destruction
- connective tissue grows into area of injury creating a mass of fibrous tissue or scar --> organization

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progression to chronic inflammation

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- occurs when the body cannot resolve the acute inflammation due to persistent injury/stimulus or interference