Chapter 3 - Inflammation and Repair Flashcards
Inflammation definition
Inflammation is a response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are n eeded, in order to eliminate the offending agents.
Sequential steps of the typical inflammatory reaction
- The offending agent in extravascular tissues is recognized by host cells and molecules.
- Leukocytes and plasma proteins are recruited from the circiulation to the site where the offending agent is located.
- The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance.
- The reaction is controlled and terminated.
- The damaged tissue is repaired.
Components of the inflammatory response
Blood vessels: dilate to slow blood flow, increase permeability to enable certain proteins to enter site of damage. Endothelial characteristics change to let circulating leukocytes roll and adhere.
Leukocytes: Once recruited, they activate and ingest/destroy microbes and other antigen
Sequence of events in an inflammatory reaction. Macrophages and other cells in tissues recognize microbes and damaged cells and liberate mediators, which trigger the vascular and cellular reactions of inflammation.
Harmful consequences of inflammation
Protective responses to infections often involve local tissue damage and its associated signs (pain, functional impariment); These are usually self-limited and leave no permanent damage.
Many diseases are caused by misdirected inflammatory reactions:
(1) Autoimmune disease: against self tissues
(2) Allergies: against normally harmful substances
TABLE: Diseases caused by inflammatory reactions
Local and systemic inflammation
Local inflammation:
- reaction is largely confined to site of infection/damage
- may have some systemic manifestations (e.g. fever with bacterial/viral pharyngitis)
Systemic inflammation:
- Rare situations when inflammatory reaction is systemic and causes widespread pathologic abnormalities (i.e. Systemic Inflammatory Response Syndrome, SIRS)
Concept: Mediators of inflammation
Soluble factors produced by cells or derived from plasma proteins are generated or activated in response to an inflammatory stimulus; these trigger the vascular and cellular reactions of inflammation.
Microbes, necrotic cells, hypoxia can trigger elaboration of inflammatory mediators and elicit inflammation.
These mediators initiate and amplify inflammatory response, determining its pattern, severity, and clinical/pathologic manifestations.
Acute and chronic inflammation
- *Acute inflammation**: The initial, rapid response to infections and tissue damage.
- Develops within minutes/hours and is of short duration (hours to a few days)
- Main characteristics: exudation of protein-rich fluid (edema), leukocyte (mainly neutrophil) emigration
Acute inflammation should subside if the offenders are eliminated, but if the stimulus isn’t cleared, it progresses to chronic inflammation
- *Chronic inflammation:** Protracted phase of inflammation that occurs if the stimulus is not cleared in the acute phase.
- Longer duration, associated with more tissue destruction
- More lymphocytes and macrophages
- Main characteristics: proliferation of blood vessels, deposition of connective tissue
Acute inflammation is part of innate immunity, and chronic inflammation is more prominent in adaptive immunity.
Termination of inflammation and initiation of tissue repair
Inflammation is terminated when the offending agent is eliminated. Mediators are broken down, leukocytes have short life spans in tissues.
Anti-inflammatory mechanisms are activated, controlling the response and preventing it from causing excessive host damage.
Tissue repair is initiated once offending agent is cleared in order to heal damaged host tissue. Injured tissue is replaced through regenerataion of surviving cells and filling of residual defects with connective tissue (i.e. scarring)
TABLE: Features of acute and chronic inflammation
Inflammatory reactions may be triggered by a variety of stimuli, including:
- *1. Infections** (bacterial, viral, fungal, parasitic, microbial toxins)
- Can range from mild acute inflammation to severe systemic reactions
2. Tissue necrosis: elicits inflammation regardless of cause of cell death (e.g. ischemia, trauma, physical/chemical injury)
3. Foreign bodies: Exogenous or endogenous (e.g. urate crystals in gout, ruptured keratin cysts)
4. Immune reactions (i.e. hypersensitivity): Autoimmune disease or allergic reactions
Recognition of microbes and damaged cells
This is the first step in all inflammatory reactions.
1. Cellular receptors for microbes: Plasma membrane receptors (for extracellular microbes), endosomal receptors (for ingested microbes) and cytosolic receptors (for intracellular microbes) enable cells to sense foreign invaders (e.g. TLRs, NLRs, RLRs). These are expressed on leukocytes and epithelial cells. Engagement of the receptors triggers a signaling cascade to ultimately produce inflammatory molecules (i.e. adhesion molecules, cytokines, etc.)
2. Sensors of cell damage: All cells have cytosolic receptors that recognize diverse molecules which are liberated when the cell is damaged (e.g. uric acid from DNA breakdown, ATP from mitochondrial damage, reduced intracellular [K+] from plasma membrane injury). These receptors activate the inflammasome, a multiprotein cytosolic complex which induces IL-1 production. IL-1 recruits leukocytes. Gain-of-function mutations in these receptors cause rare autoinflammatory syndromes
3. Other cellular receptors involved in inflammation: Many leukocytes express receptors for Fc tails of antibodies and for complement proteins. These recognize microbes coated with antibodies and complement (i.e. opsonization) and promote their destruction
4. Circulating proteins: The complement system reacts against microbes and produces inflammatory mediators (e.g. mannose-binding lectin recognizes microbial sugars and promotes their ingestion and complement activation, collectins also bind microbes)
KEY CONCEPTS: General features and causes of inflammation
Acute inflammation definition
- *Acute inflammation has three major components:
(1) dilation of small vessels leading to an increase in blood flow
(2) increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave circulation
(3) emigration of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate offending agent**
Formation of exudates and transudates.
A, Normal hydrostatic pressure (blue arrow) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrow), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil.
B, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.
C, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure.
Reactions of blood vessels in acute inflammation
The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury.
- Changes in vascular flow and caliber - these begin early after injury
- Vasodilation is induced by several mediators (histamine) acting on vascular smooth muscle. One of the earliest manifestations of acute inflammation. First involves arterioles, then opens new capillary beds –> increased blood flow
- Increased permeability of microvasculature quickly follows. Exudates pour into extravascular spaces
- Small vessel engorgement with slowly-moving red cells (i.e. stasis) resulting from slower blood flow, increased concentration of red cells in small vessels, and increased viscosity following the loss of fluid and increased vessel diameter
- Blood leukocytes (mainly neuts) accumulate along vascular endothelium while endothelial cells are activated by mediators. Leukocytes then adhere to endothelial cells and emigrate to extracellular space. - Increased vascular permeability (vascular leakage) due to:
(1) Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism. Elicited by histamine, bradykinin, leukotrienes, others. Called immediate transient response - lasts 15-30 minutes. May be delayed (i.e. burns, irradiation, certain bacterial toxins)
(2) Endothelial injury, resulting in endothelial cell necrosis and detachment. Direct damage may occur (e.g. burns, microbial toxins), but adhered neutrophils can also injure endothelial cells.
(3) Increased transcytosis through endothelial cell (stimulated by VEGF) promotes vascular leakage. This process’s contribution to acute inflammation is uncertain. - Responses of lymphatic vessels and lymph nodes
- Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load.
- Lymph flow is increased to help drain edema fluid from vascular permeability.
Definitions releated to fluid leaving vessels
- Exudation* - escape of fluid, proteins, cells into interstitial tissue or body cavities. An exudate implies increased vascular permeability
- Transudate* - Low protein fluid with little to no cellular material; results from increased capillary hydrostatic, or decreased plasma oncotic pressure.
- Edema* - escape of fluid from vessels, can be a transudate or an exudate
- Pus* - purulent exudate with many neutrophils, often due to bacteria
Principal mechanisms of increased vascular permeability in inflammation and their features and underlying causes.
KEY CONCEPTS: Vascular reactions in acute inflammation
Leukocyte recruitment to sites of inflammation
The changes in blood flow and vascular permeability are quickly followed by an influx of leukocytes into the tissue. These leukocytes phagocytize microbes, and produce growth factors and cytokines.
- *The journey of leukocytes from the vessel lumen to the tissue is a multistep process mediated and controlled by adhesion molecules and cytokines called chemokines** There are three sequential phases:
(1) Margination, rolling, adhesion to endothelium. In inflammation, endothelium is activated and can bind leukocytes.
(2) Migration across endothelium and vessel wall
(3) Migration in the tissues toward a chemotactic stimulus
Leukocyte adhesion to endothelium
In normally flowing blood in venules, red cells are central and leukocytes are toward vessel wall. With inflammation, blood flow slows (i.e. stasis), decreasing wall shear stress, and more leukocytes are marginated, allowing for leukocyte rolling and adhesion to the vessel wall.
The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines.
Initial rolling interactions are mediated by selectins (e.g. L-selectin on leukocytes, E-selectin on endothelium, P-selectin on platelets and endothelium). Ligands for selectins are sialylated oligosaccharides bound to mucin-like glycoproteins.
Selectin expression is mediated by inflammatory cytokines (e.g. TNF, IL-1)
After rolling has slowed leukocytes, they can bind more firmly to the endothelium (adhesion). This is mediated by integrins, expressed on leukocytes. TNF and IL-1 induce endothelial expression of integrin ligands (e.g. VCAM-1 for VLA-4, ICAM-1 for LFA-1, and MAC-1)
Leukocytes normally express integrins in a low-affinity state; chemokines bind the leukocytes, activating them to convert VLA-4 and LFA-1 integrins to high-affinity state
The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Intercellular adhesion molecule 1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor.
TABLE: Endothelial and leukocyte adhesion molecules
Leukocyte migration through endothelium
The next step in the process of leukocyte recruitment is migration of the leukocytes through endothelium, called transmigration, or diapedesis.
This occurs mainly in postcapillary venules.
PECAM-1 (platelet endothelial cell adhesion molecule) (a.k.a. CD31) is expressed in intercellular junctions of endothelial cells, and mediates leukocyte migration through endothelium.
Leukocytes then pierce basement membrane by secreting collagenases, and enter extravascular space.
Chemotaxis of leukocytes
After exiting the circulation, leukocytes move in the tissues toward the site of injury by chemotaxis.
Exogenous chemoattractants: bacterial products (peptides with N-formylmethionine terminal aa)
Endogenous chemoattractants: Cytokines (IL-8), components of complement systme (C5a), arachadonic acid metabolites (leukotriene B4).
All of these bind to specific 7-transmembrane G protein-coupled receptors on leukocytes –> activate messengers that increase cytosolic calcium and activate small guanosine triphosphates (Rac/Rho/cdc42 family) –> polymerization of actin at leading edge of cell and localization of myosin filaments at the back –> leukocyte moves by extending filopodia
The nature of the leukocyte infiltrate varies with the age of the inflammatory response and the type of stimulus. Usually in acute inflammation, neutrophils predominate the first 6-24 hours, replaced by monocytes in 24-48 hours.
Exceptions:
- Pseudomonas infection continuously recruits neutrophils for days
- Viral infections may have lymphocytes arrive first
- Some hypersensitivity reactions are dominated by lymphs, macs, plasma cells
- Allergic reactions often are mostlyeosinophils
Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs show an inflammatory reaction in the myocardium after ischemic necrosis (infarction).
A, Early (neutrophilic) infiltrates and congested blood vessels.
B, Later (mononuclear) cellular infiltrates.
C, The approximate kinetics of edema and cellular infiltration. For simplicity, edema is shown as an acute transient response, although secondary waves of delayed edema and neutrophil infiltration can also occur.
KEY CONCEPTS: Leukocyte recruitment to sites of inflammation
What happens to leukocytes when they recognize microbes or dead cells?
Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation.
Activation results in increased cytosolic [Ca2+], enzyme activation (protein kinase C, phospholipase A2)
Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details). LPS first binds to a circulating LPS-binding protein (not shown). IFN-γ, Interferon-γ; LPS, lipopolysaccharide.
What are the three sequential steps of phagocytosis?
- Recognition and attachment of the particle to be ingested by the leukocyte
- Engulfment, with subsequent formation of a phagocytic vacuole
- Killing or degradation of the ingested molecule
Phagocytosis and intracellular destruction of microbes. Phagocytosis of a particle (e.g., a bacterium) involves binding to receptors on the leukocyte membrane, engulfment, and fusion of the phagocytic vacuoles with lysosomes. This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes and by reactive oxygen and nitrogen species. The microbicidal products generated from superoxide () are hypochlorite (HOCl−) and hydroxyl radical (−OH), and from nitric oxide (NO) it is peroxynitrite (OONO−). During phagocytosis, granule contents may be released into extracellular tissues (not shown). MPO, Myeloperoxidase; iNOS, inducible NO synthase; ROS, reactive oxygen species.
Phagocytosis: phagocytic receptors
Mannose receptors, scavenger receptors, and receptors for various opsonins bind and ingest microbes.
The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues on glycoproteins/glycolipids found in microbial cell walls (mammalian cells contain terminal sialic acid or N-acetylgalactosamine).
Scavenger receptors bind and endocytose oxidized or acetylated LDL particles that can’t interact with conventional LDL receptors. Macrophage scavenger receptors also bind microbes.
Phagocytosis efficiency is greatly enhanced when microbes are opsonized with complement (C3b) or antibodies (IgG), for which phagocytes express high-affinity receptors
Phagocytosis: Engulfment
After a particle is bound to phagocyte receptors, cytoplasmic pseudopods flow around it and the membrane pinches off to form a vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, which discharges contents into the new phagolysosome.
Phagocytosis: Intracellular destruction of microbes and debris
Killing of microbes is accomplished by reactive oxygen species and reactive nitrogen species (mainly derived from NO), and these as well as lysosomal enzymes destroy phagocytosed debris.
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Reactive oxygen species (ROS)
- Produced by rapid assembly and activation of NADPH oxidase (a.k.a. phagocyte oxidase), which oxidizes NDADPH, reducing oxygen to superoxide (O2*). In neutrophils, this accompanies phagocytosis and is called respiratory burst. In response to activating stimuli, plasma membrane and cytosolic components translocate to phagosomal membrane and assemble into NADPH oxidase, which produces ROS within the lysosome, and phagolysosome.
- O2* is then converted to H2O2 by spontaneous dismutation. MPO in neutrophilic granules uses Cl- to convert H2O2 to hypochlorite (OCl2- - hypochlorite, bleach) which destroys microbes by halogenation
- H2O2 also is converted to hydroxyl radical (-OH)
- MPO deficiency leads to only minimal increase in susceptibility to infection - emphasizes redundancy of microbicidal mechanisms
- These ROS are implicated in tissue damage with inflammation
- Antioxidants (superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, iron-free transferrin) are in serum, tissue fluids, and host cells -
Nitric oxide
- NO is a soluble gas produced from arginine with nitric oxide synthase (NOS)
- endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutively expressed at low levels to maintain vascular tone and as a neurotransmitter, respectively
- inducible NOS (iNOS) is involved in microbicidal killing and is induced when macrophages and neutrophils are activated by cytokines (e.g. IFN-y) or microbial products
- NO reacts with O2* to generate highly reactive free radical peroxynitrite (ONOO-)
- nitrogen-derived free radicals, like ROS, attack and damage lipids, proteins, nucleic acids of microbes -
Lysosomal enzymes and other lysosomal proteins
- Neutrophils and monocytes contain lysosomal granules that contribute to microbial killing and tissue damage
- Neutrophils have smaller specific (secondary) granules with lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, alkaline phosphatase)
- They also have larger azurophil (primary) granules with MPO, bactericidal factors (lysozyme, defensins), acid hydrolases, a variety of neutral proteases (elastase, cathepsin G, proteinase 3)
+ Acid proteases - degrade bacteria and debris within phagolysosomes, which are acidified by membrane H+ pumps
+ Neutral proteases can degrade various extracellular components (collagen, BM, fibrin, elastin, cartilage) resulting in tissue damage
+ Neutrophil elastase can degrade virulence factors of bacteria
- Both types of granules can fuse with phagosomes or release contents into extracellular space
- Excessive tissue damage from proteases are controlled by antiproteases (e.g. a1-antitrypsin is major inhibitor of neutrophil elastase, a2-Macroglobulin)
- Defensins: cationic arginine-rich granules toxic to microbes
- Cathelicidins: antimicrobial proteins in neutrophils
- Lysozymes: hydrolyzes muramic acid-N-acetylglucosamine bond in bacteria coat
- Lactoferrin: iron-binding protein in specific granules
- Major basic protein: cationic protein of eosinophils, cytotoxic to many parasites
Neutrophil Extracellular Traps (NETs)
NETs are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils.
They are produced by neutrophils in response to infectious pathogens and inflammatory mediators.
They consist of a meshwork of nuclear chromatin that binds granule proteins.
This leads to death of the neutrophils involved
NETs have been seen in blood during sepsis - formation thought to be dependent on platelet activation
Leukocyte-Mediated tissue injury
- *Leukocytes are important causes of injury to normal cells and tissues under several circumstances:**
(1) Part of normal defense reaction against infection, when adjacent tissue suffers collateral damage. In infections that are tough to clear (tuberculosis, certain viral diseases) the host response can be more damaging than the infection
(2) When inflammatory response is inappropriately directed at host tissue (i.e. autoimmune diseases)
(3) When the host reacts excessively against usually harmless environmental substances (i.e. allergic disease)
In all these situations, mechanisms by which leukocytes damage normal tissues are the same as mechanisms involved in microbicide (i.e. ROS, NO, lysosomal enzymes)
Other functional responses of activated leukocytes
- Produce cytokines that can amplify or limit inflammatory reactions, growth factors that stimulate endothelial and fibroblast proliferation, and synthesis of collagen and enzymes for tissue repair (mainly macrophages)
- T lymphocytes contribute to acute inflammation (Th17 cells produce IL-17, which amplifies neutrophil response)
Termination of the acute inflammatory response
Inflammation declines after offending agents are removed because mediators are produced in rapid bursts and have short half-lives and neutrophils die quickly in tissue by apoptosis
As inflammation develops, stop signals are built in that actively terminate the reaction (e.g. switch from proinflammatory leukotrienes to antiinflammatory lipoxins, liberation of antiinflammatory cytokines like TGF-b, IL-10
KEY CONCEPTS: Leukocyte activation and removal of offending agents
Inflammatory mediators: definition and some important facts
Mediators of inflammation are substances that initiate and regulate inflammatory reactions.
1. Most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins, leukotrienes), cytokines (including chemokines), and products of complement activation.
2. Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are either stored in granules and can be rapidly exocytosed (e.g. histamine in mast cells) or are synthesized de novo (e.g. prostaglandins, leukotrienes, cytokines) in response to a stimulus. Sentinels that detect invaders and damage in tissues (macrophages, dendritic cells, mast cells) are the major producers of acute inflammation mediators. Platelets, neutrophils, epithelial and endothelial cells also elaborate some. Plasma-derived mediators (e.g. complement proteins) are produced mostly in the liver and circulate as inactive precursors.
3. Active mediators are produced only in response to various stimuli. Stimuli include microbial products, stuff from necrotic cells
4. Most of the mediators are short-lived. They decay quickly or are inactivated by enzymes, or are scavenged/inhibited.
5. One mediator can stimulate the release of other mediators.
TABLE: Principal mediators of inflammation
Mediators of inflammation: Vasoactive amines
The two major vasoactive amines are histamine and serotonin. These are stored as pre-formed molecules in cells and are among the first mediators released in inflammation.
Mast cells in perivascular connective tissue are the richest source of histamine; it is also found in basophils and platelets.
Mast cells degranulate, releasing histamine due to (1) physical injury, (2) binding of antibodies to mast cells - allergic reactions, (3) products of complement called anaphylatoxins (C3a, C5a)
Histamine causes dilation of arterioles and increases permeability of venules. It is the principal mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules.
Serotonin is a preformed vasoactive mediator in platelets and certain neuroendocrine cells (e.g. GI tract). It is a neurotransmitter in GI tract and a vasoconstrictor.
Mediators of inflammation: Arachadonic acid metabolites
The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation.
With mechanical, chemical, physical, or other (e.g. C5a) stimuli, phospholipases (e.g. phospholipase A2) are activated by increased cytoplasmic [Ca2+], and various kinase activation
AA-derived mediators (a.k.a. eicosanoids) are synthesized in 2 pathways:
(1) cyclooxygenases (COX): generate prostaglandins
(2) lipoxygenases (LOX): Produce leukotrienes and lipoxins
Mediators of inflammation: Arachadonic acid metabolites - Prostaglandins
Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation.
Generated by:
(1) COX-1: constitutively expressed in most tissues (e.g. fluid and electrolyte balance in kidneys, cytoprotection in GI tract), also produced in response to inflammation
(2) COX-2: Induced by inflammatory stimuli to create pro-inflammatory prostaglandins, but otherwise is low or absent in normal tissue
Most important prostaglandins for inflammation:
PGE2, PGD2, PGF2a, PGI2 (prostacyclin), and TxA2 (thromboxane A2)
Some are tissue specific:
- TxA2 is produced in platelet with thromboxane synthase: vasoconstriction, platelet aggregation
- PGI2 is produced in vascular endothelium with prostacyclin synthase: vasodilation, inhibitor of platelet aggregation, promotes vascular permeability
- PGD2, and PGE2 (more widely distributed) are produced in mast cells: vasodilation, increased permeability of postcapillary venules –> edema
- PGF2a stimulates contraction of uterine and bronchial smooth muscle
- PGD2 is a chemoattractant for neutrophils
PGs also involved in pain and fever pathogeneses
Mediators of inflammation: Arachadonic acid metabolites - Leukotrienes
Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment.
5-LOX predominant one in neutrophils: converts AA to 5-hydroxyeicosatetraenoic acid) 5-HPETE, which is chemotactic for neutrophils and is the precursor of the leukotrienes
LTB4 is a potent chemotactic agent and activator of neutrophils
LTC4, LTD4, LTE4 cause intense vasoconstriction, bronchospasm, increased venule permeability
Mediators of inflammation: Arachadonic acid metabolites - Lipoxins
Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike PGs and LTs, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes.
Require two cell types for production: leukocytes (mostly neuts) produce intermediates in lipoxin synthesis, that are then converted to lipoxins by platelets interacting with the leukocytes
TABLE: Principal actions of AA metabolites in inflammation
Production of arachidonic acid metabolites and their roles in inflammation. Note the enzymatic activities whose inhibition through pharmacologic intervention blocks major pathways (denoted with a red X). COX-1, COX-2, Cyclooxygenase 1 and 2; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.
Major roles of cytokines in acute inflammation. PDGF, Platelet-derived growth factor; PGE, prostaglandin E; PGI, prostaglandin I.
TABLE: Cytokines in inflammation
The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).
TABLE: Role of mediators in different inflammatory reactions
KEY CONCEPTS: Actions of the principal mediators of inflammation
Serous inflammation
Serous inflammation is marked by the exudation of cell-poor fluid into spaces created by cell injury or into body cavities lined by mesothelium (i.e. effusions).
Typically the fluid does not have organisms and only has a few leukocytes.
Fibrinous inflammation
A fibrinous exudate develops when vascular leaks are large or there is a local procoagulant stimulus (e.g. cancer cells). Large molecules (i.e. fibrin) leak out and are deposited extracellularly.
Conversion of fibrinous exudate to scar tissue is called organization
Purulent (suppurative) inflammation, Abscess
Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. Most frequent cause of pus is bacterial infection
Abscesses are localized collections of purulent tissue.
Ulcers
An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue.
Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation. The components of the various reactions and their functional outcomes are listed.
A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows).
B, In contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.
Maturation of mononuclear phagocytes.
A, In the steady state, some tissue macrophages, including microglia and alveolar macrophages, may be derived from embryonic precursors and populate the tissues. The development of macrophages from hematopoietic precursors and monocytes may be more prominent when tissue macrophages need to be increased or replenished, as after injury and during inflammation.
B, The morphology of a monocyte and activated macrophage.
Classical and alternative macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ. They phagocytose and destroy microbes and dead tissues and can potentiate inflammatory reactions. Alternatively activated macrophages are induced by other cytokines and are important in tissue repair and the resolution of inflammation.
Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) and others that activate macrophages (IFN-γ). Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines such as IL-12.
KEY CONCEPTS: Chronic inflammation
KEY CONCEPTS: Systemic effects of inflammation
Mechanisms of tissue repair: regeneration and scar formation. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation.
Liver regeneration by proliferation of hepatocytes. Following partial hepatectomy, the liver regenerates by proliferation of surviving cells. The process occurs in stages, including priming, followed by growth factor-induced proliferation. The main signals involved in these steps are shown. Once the mass of the liver is restored, the proliferation is terminated (not shown).
KEY CONCEPTS: repair by regeneration
Steps in repair by scar formation. Injury to a tissue, such as muscle (which has limited regenerative capacity), first induces inflammation, which clears dead cells and microbes, if any. This is followed by the formation of vascularized granulation tissue and then the deposition of extracellular matrix to form the scar.
Angiogenesis. In tissue repair, angiogenesis occurs mainly by sprouting of new vessels. The steps in the process, and the major signals involved, are illustrated. The newly formed vessel joins up with other vessels (not shown) to form the new vascular bed.
A, Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point.
B, Trichrome stain of mature scar, showing dense collagen, with only scattered vascular channels.
KEY CONCEPTS: Repair by scar formation
Steps in wound healing by first intention (left) and second intention (right). In the latter, note the large amount of granulation tissue and wound contraction.
Healing of skin ulcers.
A. Pressure ulcer of the skin, commonly found in diabetic patients. The histologic slides show a skin ulcer with a large gap between the edges of the lesion
B. a thin layer of epidermal re-epitehlialization and extensive granulation tissue formation in the dermis
C. Continuing re-epithelialization of the epidermis and wound contraction
Mechanisms of fibrosis. Persistent tissue injury leads to chronic inflammation and loss of tissue architecture. Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other extracellular matrix proteins. The net result is replacement of normal tissue by fibrosis.
KEY CONCEPTS: Cutaneous wound healing and pathologic aspects of repair
Keloid.
A, Excess collagen deposition in the skin forming a raised scar known as keloid.
B, Note the thick connective tissue deposition in the dermis.
