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Questions and Answers
Which statement accurately describes plasma-derived chemical mediators?
What is the function of the kinin system in inflammation?
Which of the following mediators is associated with rapid inactivation by kininases?
Which of the following is a characteristic of cytokines in inflammation?
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What role do leukotrienes play in the inflammatory response?
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What primary function does the complement system serve in acute inflammation?
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What is a consequence of mast cell degranulation in the inflammatory response?
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Which component of the complement system is involved in leukocyte chemotaxis?
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What is a potential outcome of acute inflammation that involves minimal tissue damage?
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Which of the following cells are primarily involved in chronic inflammation?
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In which pattern of inflammation is there a presence of pus?
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What type of tissue response occurs when there is persistent injury that cannot be resolved?
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Which cells are responsible for producing antibodies during the immune response?
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What is a characteristic of fibrinous inflammation?
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Which type of white blood cell is particularly prevalent at sites of parasitic infections?
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What systemic effect is commonly recognized in response to inflammation?
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What is the first vascular response that occurs immediately after tissue injury?
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Which molecule primarily mediates early leukocyte rolling along the endothelium during inflammation?
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What type of fluid is first present in the interstitium after vascular permeability increases?
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What process allows leukocytes to exit the blood vessels during inflammation?
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Which cell type primarily dominates the initial inflammatory response to tissue injury?
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Which of the following mediators is known to cause significant vascular leakiness during acute inflammation?
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What occurs during the process of chemotaxis in inflammation?
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During leukocyte activation, which of the following processes occurs?
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What is the primary function of reactive oxygen species produced during the oxidative burst?
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Which mediator is crucial for the retraction of endothelial cell junctions during inflammation?
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What role does the transudate play in the inflammatory process?
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Which type of leukocyte is primarily responsible for degranulation during the immune response?
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Which of the following best describes the process of margination?
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What is the final step that occurs during phagocytosis of pathogens by leukocytes?
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Study Notes
Inflammation
- Inflammation is a vascular connective tissue reaction to injury (physical, chemical, or microbiological) that dilutes, destroys, isolates, and initiates repair.
Acute Inflammation
- Involves an immediate and early response to tissue injury.
- Characterized by vasodilation, vascular leakage and edema, and leukocyte emigration (primarily neutrophils).
Vasodilation
- Brief arteriolar vasoconstriction followed by vasodilation causing warmth and redness.
- Opening of the microvascular beds increases intravascular pressure, leading to an early transudate (protein-poor filtrate of plasma) into the interstitium.
Vascular Leakage
- Vascular permeability increases, resulting in exudate (protein-rich) replacing transudate.
- Elevated interstitial osmotic pressure contributes to edema (water and ions).
- Five mechanisms cause vascular leakiness:
- Histamine, bradykinin, and leukotrienes: immediate transient response (15-30 min) via endothelial cell contraction that widens intercellular gaps of venules.
- Cytokine mediators (TNF, IL-1): induce endothelial cell junction retraction through cytoskeleton reorganization (4-6 hrs post-injury, lasting 24 hrs or more).
- Severe injuries: cause immediate direct endothelial cell damage, making them leaky until repaired (immediate sustained response).
- Delayed damage: occurs in thermal or UV injury, or some bacterial toxins (delayed prolonged leakage).
- Leukocyte-dependent endothelial cell injury: marginating and endothelial cell-adherent leukocytes release toxic oxygen radicals and proteolytic enzymes, damaging the endothelium and causing leakage.
Leukocyte Cellular Events
- Leukocytes leave the vasculature through a series of events:
- Margination and Rolling
- Adhesion and Transmigration
- Chemotaxis and Activation
Margination and Rolling
- As vascular permeability increases, leukocytes settle out of the central flow column and marginate along the endothelial surface.
- Endothelial cells and leukocytes express complementary surface adhesion molecules resulting in brief sticking and releasing, causing rolling along the endothelium.
- Early rolling adhesion is mediated by the selectin family:
- E-selectin (endothelium), P-selectin (platelets, endothelium), and L-selectin (leukocytes) bind to other surface molecules (CD34, Sialyl-Lewis X-modified GP) upregulated on endothelium by cytokines (TNF, IL-1) at injury sites.
Adhesion
- Rolling halts and adhesion occurs.
- Additional adhesion molecules participate:
- Endothelial: ICAM-1, VCAM-1
- Leukocyte: LFA-1, Mac-1, VLA-4
- ICAM-1 binds LFA-1/Mac-1, and VCAM-1 binds VLA-4.
- These adhesion molecules are usually downregulated or in an inactive conformation, but inflammation alters this.
Transmigration (Diapedesis)
- Occurs after firm adhesion within systemic venules and pulmonary capillaries via PECAM-1 (CD31).
- Leukocytes must then cross the basement membrane using collagenases and integrins.
- Early in the inflammatory response, primarily PMNs are involved, but as cytokine and chemotactic signals change, other leukocyte populations (monocytes, lymphocytes) adhere.
Chemotaxis
- Leukocytes follow the chemical gradient to the site of injury (chemotaxis) by responding to soluble bacterial products, complement components (C5a), cytokines (chemokine family, e.g., IL-8), and LTB4 (AA metabolite).
- Chemotactic agents bind to surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements.
Chemotaxis and Activation
- Leukocytes:
- Extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxis.
- Undergo activation:
- Prepare AA metabolites from phospholipids.
- Prepare for degranulation and release of lysosomal enzymes (oxidative burst).
- Regulate leukocyte adhesion molecule affinity.
Phagocytosis and Degranulation
- At the site of injury, leukocytes:
- Recognize and attach.
- Engulf (forming a phagocytic vacuole).
- Kill (degrade).
Recognition and Binding
- Opsonized by serum complement or immunoglobulin (C3b, Fc portion of IgG).
- Corresponding receptors on leukocytes (FcR, CR1, 2, 3) lead to binding.
Oxidative Burst
- Reactive oxygen species are formed through the oxidative burst, which involves:
- Increased oxygen consumption.
- Glycogenolysis.
- Increased glucose oxidation.
- Formation of superoxide ion (2O2 + NADPH ® 2O2-rad + NADP+ + H+).
- Formation of hydrogen peroxide (O2 + 2H+ ® H2O2).
Reactive Oxygen Species
- Hydrogen peroxide alone is insufficient.
- Myeloperoxidase (MPO) in azurophilic granules converts hydrogen peroxide to HOCl- (in the presence of Cl-), an oxidant/antimicrobial agent.
- PMNs kill via halogenation or lipid/protein peroxidation.
Degradation and Clean-Up
- Reactive end-products are only active within the phagolysosome.
- Hydrogen peroxide is broken down to water and oxygen by catalase.
- Dead microorganisms are degraded by lysosomal acid hydrolases.
Leukocyte Granules
- Other antimicrobials found in leukocyte granules include:
- Bactericidal permeability increasing protein (BPI)
- Lysozyme
- Lactoferrin
- Defensins
Mediators of Inflammation
- Chemical mediators can be:
- Plasma-derived: complement, kinins, coagulation factors, and often require activation via enzymatic cleavage.
- Cell-derived: preformed and sequestered (e.g., mast cell histamine) or synthesized as needed (e.g., prostaglandin).
- May or may not utilize a specific cell surface receptor for activity.
- Can signal target cells to release other effector molecules that amplify or inhibit the initial response.
- Are tightly regulated:
- Quickly decay (AA metabolites), are inactivated enzymatically (kininase), or are scavenged (antioxidants).
Specific Mediators
- Serotonin: causes vasodilation similar to histamine, released from platelet dense-body granules by platelet aggregation.
Plasma Proteases
- Clotting system
- Complement
- Kinins (e.g., bradykinin)
Kinin System
- Production of bradykinin from the cleavage of precursor (HMWK).
- Causes vascular permeability, arteriolar dilation, non-vascular smooth muscle contraction (e.g., bronchial smooth muscle), and pain.
- Rapidly inactivated by kininases.
Complement System
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Components C1-C9 exist in inactive form.
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Activated via the classical (C1) or alternative (C3) pathways to generate MAC (C5-C9), which perforate microbe membranes.
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Roles in acute inflammation:
- Vasodilation, vascular permeability, and mast cell degranulation (C3a, C5a).
- Leukocyte chemotaxin and increased integrin avidity (C5a).
- Opsonin, increasing phagocytosis (C3b, C3bi).
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Leukotrienes: produced via the lipoxygenase pathway, act as chemotaxins, vasoconstrictors, increase vascular permeability, and cause bronchospasm.
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PAF (platelet-activating factor): derived from cell membrane phospholipid, causes vasodilation, increased vascular permeability, and increases leukocyte adhesion.
More Specific Mediators
- Cytokines: protein cell products that act as messengers, telling other cells how to behave.
- IL-1, TNF-a and -b, and IFN-g are particularly important in inflammation, increasing endothelial cell adhesion molecule expression, activating and aggregating PMNs, and increasing cytokine release.
Outcomes of Acute Inflammation
- Complete resolution: occurs with little tissue damage and tissues capable of regeneration.
- Scarring (fibrosis): occurs in tissues unable to regenerate or with excessive fibrin deposition organized into fibrous tissue.
- Abscess formation: may occur during bacterial or fungal infections, often walled-off if persistent.
- Progression to chronic inflammation.
Chronic Inflammation
- Involves lymphocyte, macrophage, plasma cell (mononuclear cell) infiltration.
- Tissue destruction by inflammatory cells.
- Attempts at repair with fibrosis and angiogenesis.
- Occurs when the acute phase can't be resolved due to:
- Persistent injury or infection (e.g., ulcer, TB).
- Prolonged toxic agent exposure (e.g., silica).
- Autoimmune disease states (e.g., RA, SLE).
The Players (Mononuclear Phagocyte System)
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Macrophages: scattered throughout the body (e.g., microglia, Kupffer cells, sinus histiocytes, alveolar macrophages), circulate as monocytes, and reach the site of injury within 24-48 hours.
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Become activated by T cell-derived cytokines, endotoxins, and other products of inflammation.
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T and B lymphocytes: antigen-activated via macrophages and dendritic cells.
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Release macrophage-activating cytokines (leading to macrophage-released lymphocyte-activating cytokines until the inflammatory stimulus is removed).
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Plasma cells: terminally differentiated B cells that produce antibodies.
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Eosinophils: found at sites of parasitic infection or at allergic (IgE-mediated) sites.
Patterns of Acute and Chronic Inflammation
- Serous: watery, protein-poor effusion (e.g., blister).
- Fibrinous: fibrin accumulation, either completely removed or becomes fibrotic.
- Suppurative: presence of pus (pyogenic staph spp.), often walled-off if persistent.
- Ulceration: necrotic and eroded epithelial surface, underlying acute and chronic inflammation, caused by trauma, toxins, or vascular insufficiency.
Systemic Effects
- Fever: One of the most easily recognized cytokine-mediated effects (especially IL-1, TNF-a).
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Description
This quiz delves into the concepts of inflammation and acute inflammation, highlighting key processes such as vasodilation and vascular leakage. Understand how the body responds to tissue injury through these mechanisms and their effects on healing. Test your knowledge on the physiological changes that occur during the inflammatory response.
