Week 3: Inflammation Flashcards
Inflammation
Reaction of living tissue to injury
Starts with injury –> healing/repair
Immune response but MAY BE HARMFUL
Agents of Inflammation
- Immune reaction
- Trauma
- Anoxia
- Infection (other biologic agents)
- Physical agents
- Metabolic injury
Acute Inflammation
Duration: Short; minutes to days
Characteristics: Neutrophils and exudation
Pathogenesis: Vascular changes, edema, neutrophil-dominant infiltrate
Exudate
The fluid that filters from the circulatory system into lesions/areas of inflammation
HIGH PROTEIN CONTENT
Chronic Inflammation
Duration: Long; days to years
Characteristics: Lymphocytes, macrophages, plasma cells
Tissue repair
Clinically: 2 weeks or longer
Pathogenesis: mononuclear-predominant inflammatory infiltrate, tissue destruction, tissue replacement by proliferative connective tissue
Can occur without preceding acute inflammation
Vascular Events of Acute Inflammation
- Transient Vasoconstriction of arterioles (not important)
- Vasodilation - redness (rubor) and heat (calor)
- Permeability changes - swelling (tumour)
^Cells and proteins lost from intravascular compartment, blood viscosity increases
Describe endothelial cell contraction
An immediate transient response
Occurs in SMALL VENULES ONLY
Mediated by histamine, bradykinins, leukotrienes
Describe junctional disruption
A delayed prolonged response
Occurs in all VENULES
Structural reorganization of cell’s cytoskeleton, disruption of intercellular junctions
Mediated by cytokines (TNF, IL1)
4-6 hours after stimulus
Direct endothelial injury
Immediate sustained response in severe injuries (burns, infections, cuts, abrasions)
The prolonged response can be delayed (sunburns)
Leukocyte dependent endothelial injury
Delayed prolonged response
VENULES
During the cellular phase, leukocytes adhere to the endothelium and may become activated in the process, releasing ROS and proteolytic enzymes that damage the endothelium
-Activated while still within vessels
This only happens in vascular beds where leukocytes adhere for longer periods of time (Lung, glomeruli in kidneys)
Increased Transcytosis
VENULES
VEGF and other chemical mediators increase permeability
New blood vessel formation
New blood vessels are leaky until they form intercellular junctions Increased receptors for VEGF and histamine)
Starling’s Hypothesis
Normal fluid balance is maintained by TWO opposing sets of forces from the intravascular AND interstitial
HYDROSTATIC PRESSURE and OSMOTIC PRESSURE
Net movement is small and outward under normal conditions because any excess interstitial fluid will drain into the lymphatic system
Transudative Edema
Low level of proteins and cells in the interstitium
Factors that increase intravascular hydrostatic pressure (vasodilation) or decrease intravascular osmotic pressure (decreased albumin) = INCREASE in interstitial fluid and edema (transudate)
Heart Failure (Pleural Effusion) - heart does not pump well, backup of blood in the venous system
Liver failure, kidney failure, malnutrition
Transudate
Fluid that filters from circulatory system into lesions/areas of inflammation
LOW PROTEIN CONTENT
Exudative Edema
High level of proteins and cells in the interstitium
Leaky endothelium causes loss of high protein fluid and nucleated cells with a reduction of intravascular osmotic pressure and increased interstitial osmotic pressure
Fluid cannot return to blood vessels
Produces inflammatory edema
Pneumonia, cancer
Vasodilation
Causes INCREASED intravascular hydrostatic pressure
Rudor, calor (red and heat)
Increased permeability
Causes INCREASED OP of interstitial proteins + DECRASED OP of plasma proteins
Tumour (swelling)
Cellular Events of Acute Inflammation
- Margination - WBCs pushed to vessel periphery
- Rolling - WBCs briefly attach to endothelium with selectin
- Adhesion - WBCs adhere to endothelium using VCAM, ICAM, integrins
- Transmigration/diapedesis - WBCs dissolve basement membrane, squeeze through endothelial cells using PEDCAM1/CD31
- Chemotaxis - chemotactic agents bind to GPCR –> cascade –> actin –> movement toward gradient
- Activation - WBC’s receptors meet offender + is activated
- Phagocytosis - recognition/attachment, engulfment, killing
Mice really are the coolest animals present
Migration (Cellular Event 1)
When blood is viscous, WBCs are pushed to vessel periphery because of sludging RBCs
Rouleaux formation
Rolling (Cellular Event 2)
WBCs tumble and briefly adhere to the endothelium using SELECTIN molecules
Adhesion (Cellular Event 3)
WBCs firmly stick to endothelial surfaces using
VCAM1, ICAM1 (endothelial cells)
INTEGRINS (leukocytes - must be activated by chemicals)
Transmigration/Diapedesis (Cellular Event 4)
Leukocytes (WBCs) squeeze through endothelial cells at intercellular junctions + penetrate the basement membrane
Uses PEDCAM1/CD31 (on both leukocytes AND endothelial cells)
Chemotaxis (Cellular Event 5)
WBCs migrate (unidirectional) to an attractant (chemotactic factors) along a chemical gradient
Chemotactic factors bind to GPCR receptors on WBCs, activate cascade, induce polymerization of actin = increases calcium
Factors: exogenous (bacterial proteins), endogenous (cytokines)
Activation (Cellular Event 6)
WBC surface receptors recognize offending agents (necrotic tissue, microbes) which triggers intracellular signaling pathways within WBCs that activate them
Phagocytosis (Cellular Event 7)
WBC mops up the foreign tissue
- Recognition and attachment: microorganisms are coated with serum factors (opsonins - IgG, C3b)
- Engulfment: pseudopods flow around organisms –> phagolysosome. Enzymes/metabolic products (H2O2) leak into the compartment (it’s like a stomach)
Ca++ and Mg++ are required.
- Killing/Degradation:
a. Oxygen dependent: burst of oxygen use –> ROS (H2O2) –> hypochlorite using enzyme MPO, or hydroxyl radical without MPO
b. Oxygen independent: H+ ion from lactate –> lowered pH OR WBC granules can harm microbes
Chemical Mediators of Inflammation
Direct vascular and cellular events
Produced LOCALLY at site of injury or CIRCULATE as precursors in the plasma
Mediators may stimulate target cells to release secondary effector molecules.
Mediators may act on only one or a very few targets, or they may have widespread activity; there may be widely differing outcomes depending on which cell type they affect.
Mediator function is generally TIGHTLY REGULATED.
A major reason for the checks and balances is that most mediators have the potential to have harmful effects.
Local Mediators
- Histamine and serotonin: vasodilation and inc. vascular permeability through endothelium contraction
- Prostaglandins: vasodilation
-fever and pain (dolor)
-inhibited by NSAIDs (aspirin, ibuprofen) - Leukotrienes: inc. vascular permeability (endothelial contraction), chemotaxis, WBC activation
- Cytokines (TNF, IL1): vasodilation, inc. vascular permeability (junctional retraction), adhesion
-fever, pain, anorexia - Chemokines: chemotaxis
His penis looked corn cob
Systemic Mediators
- Bradykinin (from factor 12): inc. vascular permeability (endothelial contraction)
-pain at injury site - Thrombin: inc. rolling, adhesion (VCAM/ICAM), cytokines/chemokines
- Complement products: vasodilation, inc. vascular permeability, chemotaxis, WBC activation, phagocytosis
Brad the cat
Vasodilation (chemical mediators)
-histamine/serotonin
-prostaglandin
-complement products
Vascular permeability (chemical mediators)
-histamine/serotonin
-leukotrienes
-cytokines
-complement products
-bradykinins
Rolling (chemical mediators)
Thrombin
Adhesion (chemical mediators)
-thrombin
-cytokines
Chemotaxis (chemical mediators)
-chemokines
-leukotrienes
-complement products
Leukocyte activation (chemical mediators)
-leukotrienes
-complement products
Phagocytosis (chemical mediators)
complement products
Defects in Leukocyte Function
- Number of leukocytes
- Leukocyte adhesion (diabetes, alcohol, inherited)
- Leukocyte migration/chemotaxis (C5 deficiency, diabetes, drugs)
- Phagocytosis and microbicidal (MPO deficiency, leukemia, sepsis, diabetes, malnutrition)
Serous Inflammation
Due to mild injuries
Outpouring of thin fluid from PLASMA or MESOTHELIAL CELLS lining cavities
Skin blister from burn, pleural effusion from early pneumonia
Fibrinous Inflammation
Severe inflammations, typically in body cavities.
Vessels are so damaged that large molecules (fibrin) can pass through + deposited in extracellular space
Fibrinous exudate = inflammation in body cavity linings
Gross appearance; deeply acidophilic; can scar if not removed
Suppurative/Purulent Inflammation/Abscess
From bacterial infections
Accumulate pus/purulent exudate (neutrophils, liquefactive necrosis, edema fluid)
Must be DRAINED (not enough just to have antibiotics)
Pyogenic bacteria
Characteristically produce pyogenic infections (pus-producing)
Abscess
Localized collection of purulent exudate (pus) in TISSUE
Empyema
Localized collection of purulent exudate in PLEURAL CAVITY
Ulcer
Defect of organ/tissue surface with EPITHELIAL LINING
The surface is eroded and necrotic with chronic inflammation
Peptic ulcers, skin, mouth, stomach, intestines, TI tract
NOT liver (no lining)
BOTH chronic and acute process
Chronic Inflammation Causes
Viral infections
Persistent microbial infections by organisms of low direct pathogenicity
Prolonged exposure to non-degradable material
Autoimmune diseases
Nonspecific Chronic Inflammation
Mononuclear inflammation (lymphocytes, plasma cells, macrophages)
Tissue destruction
Replacement by connective tissue.
Granulomatous Chronic Inflammation
A special type of tissue reaction
Often an attempt to wall-off and isolate the affected site
The granuloma is composed of a central focus (usually but not always) of (nidus of) necrotic tissue surrounded circularly by macrophages/histiocytes (usually modified to epithelioid cells), which in turn are surrounded by a rim of lymphocytes.
Necrotic tissue –> macrophages/histiocytes –> lymphocytes
Often giant cells (multinucleated histiocytes) are in the inner epithelioid cells.
Certain infections (TB, syphilis, cat-scratch, fungal, protozoan)
Foreign body inflammations (foreign body granuloma, pneumoconiosis, inhaled metals)
Some inflammatory conditions of unknown etiology (Rheumatoid Arthritis, sarcoidosis, granuloma annular of skin, Crohn’s disease)
Local Clinical Manifestations of Inflammation
- Calor - heat
- Tumour - swelling
- Dolor - pain
- Functio Laesa - Impaired Function
- Rubor - redness
Systemic Clinical Manifestations of Inflammation
Systemic Inflammatory Response Syndrome (SIRS)
- Fever
- Acute Phase Reactants (proteins)
- Leukocytosis (high WBC count)
- Other (increase HR, BP, less sweating, rigot, anorexia, somnolence)
In response to infection = septic shock
Pyrogen (LPS)
Any substance capable of producing fever
Bacterial, chemical, endogenous
Stimulates TNF and IL1
TNF and IL1
Cytokines that act on the thermoregulatory center of the hypothalamus –> prostaglandin –> reset body temperature to higher
Cause the release of WBCs from the bone marrow
Left Shift
When immature precursors of WBCs are released (usually by TNF and IL1 in response to inflammation)
