Exam III: Inflammation Part I Flashcards
Typical Inflammatory Reaction
The offending agent is located in extravascular tissues and recognized by host cells and molecules
Leukocytes and plasma proteins are recruited from the circulation to the site of offending agent
Leukocytes and proteins are activated and work together to destroy and eliminate the offending substance
Reaction is controlled and terminated
The damaged tissue is repaired
Steps of Inflammatory Process
(1) recognition of the injurious agent
(2) recruitment of leukocytes
(3) removal of the agent
(4) regulation (control) of the response
(5) resolution (repair)
Acute vs. Chronic: General
Acute or chronic inflammation
Depends on the nature of the stimulus
Effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues
Acute Inflammation
Rapid in onset/host response (minutes)
Short duration (hours or a few days)
Exudation of fluid and plasma proteins (edema)
Delivers leukocytes and plasma proteins to the sites of infection or tissue injury
Three major components:
- Alterations in vascular caliber
- Structural changes in the microvasculature
- Emigration of the leukocytes (neutrophils)
Chronic Inflammation
May follow acute inflammation
May be insidious in onset
Longer duration
Presence of lymphocytes and macrophages
Proliferation of blood vessels and fibrosis
Tissue destruction
Granulomatous inflammation is a subset of chronic inflammation
Cardinal Signs of Inflammation
Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Loss of function (functio laesa)
Signs are typically more prominent in acute inflammation
Stimuli for Acute Inflammation
Infections (bacterial, viral, fungal, parasitic) and microbial toxins- most common and medically important causes
Tissue necrosis: ischemia, trauma, physical, and chemical injury
Foreign bodies: impaled finger or foot with something = cuts can cause bad infections
Immune reactions: allergies
Exudate
Inflammatory extravascular fluid
High protein concentration
Specific gravity > 1.020
Usually due to increased permeability
An inflammatory process caused by something causing increased vascularity to allow leukocytes to come in
Transudate
Fluid with low protein concentration (albumin)
Specific gravity < 1.012
Permeability usually not increased (due to a pressure response)
changes in pressure= renal failure, liver failure, heart failure, etc.
Edema
Excess interstitial fluid
Can be either an exudate or transudate
Excess INTERSTITIAL fluid/ vascular tissue; can be a pressure change or vascular change
Absorb water with sponge and stick needle in sponge you will not be able to get out the water because it is trapped in many compartments… same with patient, cannot just “drain” the fluid, need to restore lymphatic system
Pus
Purulent exudate containing leukocytes (neutrophils), debris of dead cells, and microbes/bacteria
When you write in a patient chart that you found a pocket of pus = purulent exudate
Hydrostatic and Colloid Pressure Changes
Normal: balance of hydrostatic and colloid osmotic pressure to keep plasma proteins to stay within the vessels
Transudate: fluid leakage caused by pressure change; proteins are still within the vessel; increased hydrostatic pressure due to venous outflow obstruction like in congestive heart failure; decreased colloid pressure due to decreased protein synthesis like in liver disease or increased protein loss like in kidney disease
Exudate: increased protein concentration because leakage of fluid and proteins outside of the vessels due to increased interendothelial spaces
Steps of Inflammatory Process
Vasodilation with exudation leads to an outpouring of fluid with fibrin into the alveolar spaces, along with PMN’s. The series of events in the process of inflammation are:
- Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat.
- Vascular permeability: endothelial cells become “leaky” from either direct endothelial cell injury or via chemical mediators.
- Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure intravascularly
- Vascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to collect and respond to the stimulus.
Vascular Changes
Earliest manifestations of acute inflammation
Follows a transient constriction of arterioles
Lasts a few seconds
First involves the arterioles
Leads to opening of new capillary beds
Result is increased blood flow causing heat and redness (erythema) at the site of inflammation
Induced by the action of several mediators such as histamine and nitric oxide
Followed by increased permeability of the microvasculature causing an outpouring of protein-rich fluid into the extravascular tissues
Loss of Fluid and Increase in Diameter of Vessels
Leads to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood
Changes result in dilation of small vessels
Packed with slowly moving red cells
Increased vascular permeability created by inter-endothelial spaces
When protein rich fluid leaks out = slows down blood flow to get hemo-concentration (cells concentrate in inflammation so neutrophils can come), increased concentration of RBCs causing the blood to thicken= stasis
See leukocytes that start in center and migrate outwards to get into the vascular tissue; endothelial cells become activated by mediator depending on process occur and see leukocytes adhering to them
As Stasis Progresses
Leukocytes (neutrophils) accumulate along the vascular endothelium
Endothelial cells are activated by mediators produced at sites of infection and tissue damage
Express increased levels of adhesion molecules
Leukocytes then adhere to the endothelium then migrate through the vascular wall into the interstitial tissue
Hallmark of Acute Inflammation
Hallmark of acute inflammation= increased vascular permeability
Leads to the escape of a protein-rich exudate into the extravascular tissue causing edema
Mechanisms of Increased Permeability
Contraction of endothelial cells
Results in increased interendothelial spaces
Most common mechanism of vascular leakage
Elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other mediators
Called the immediate transient response, which occurs rapidly after exposure to the mediator- usually short-lived (15-30 minutes)
Endothelial Injury and Transcytosis
Endothelial injury
Results in endothelial cell necrosis and detachment
Direct damage to the endothelium from trauma, injury, or iatrogenic (physician cause)
Transcytosis
Increased transport of fluids and proteins through the endothelial cell
seen in transudate through endothelial cells without any other kind of damage
Principle Mechanisms of Increased Vascular Permeability
Endothelium on basement membrane with leukocytes and plasma proteins; laminar flow causes white cells to be in the center of the vessels, but when blood flow slows down the cells start to tumble and come out of the endothelial cells
Retraction of Endothelial Cells: occurs in venules, short lived/rapid leakage of protein and fluid; induced by NO, histamine, and other mediators
Endothelial Injury: chemical, burn, toxin, etc. and causing the endothelial cells to die- can last longer (hours to days depending); rapid process and occurs in arterioles, capillaries and venules
Leukocyte-Mediated Vascular Injury: leukocytes adhere to endothlelial cells – hours and later stages of process; occurs in venules and pulmonary capillaries
Increased Transcytosis: occurs in venules and induced by VEGF; fluid can get to vascular lumen into surrounding tissue
Responses of Lymphatics
Lymphatics and lymph nodes filter and police the extravascular fluids
Normally drain the small amount of extravascular fluid that leaked out of capillaries
Inflammation
Lymph flow is increased and helps drain edema fluid
Accumulates due to increased vascular permeability
Lymphatic vessels proliferate during inflammatory reactions
Lymphatics may become secondarily inflamed (lymphangitis)
Draining lymph nodes may become inflamed (lymphadenitis)
Hyperplasia of the lymphoid follicles (increase in cell #)
Increased numbers of lymphocytes and macrophages
Recruitment of Leukocytes
Recruitment from the blood into extravascular tissues
Recognition of microbes and necrotic tissues
Removal of the offending agent
Extravasation
Journey of leukocytes: vessel lumen to the interstitial tissue
Lumen: margination, rolling, and adhesion to endothelium via P and E-selections causing them to adhere and integrins cause them to go through the basement membrane
Migration across endothelium and vessel wall
Migration in the tissues toward a chemotactic stimulus
Margination
Blood flow slows early in inflammation (stasis)
Hemodynamic conditions change (wall shear stress decreases)
More white cells assume a peripheral position along the endothelial surface
Rolling on the vessel wall- individual and then rows of leukocytes adhere transiently to the endothelium, detach, and then bind again
Cells finally come to rest at some point and firmly attach
Leukocyte Migration
Transmigration or diapedesis
Occurs mainly in post-capillary venules
Chemokines act on the adherent leukocytes
Stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient
Toward the site of injury or infection where the chemokines are being produced
It crawls all the way along using its pseudopod to get to area of injury via chemokines (specific chemical mediators that have chemotactic signaling to the white cells) that bring leukocytes to the area or you would get crazy amounts of inflammation everywhere in the body
Chemotaxis of Leukocytes
After exiting the circulation leukocytes emigrate in tissues toward the site of injury
Chemotaxis: locomotion oriented along a chemical gradient
Chemoattractants: exogenous substances, bacterial products, lipids, endogenous substances
Chemical mediators: cytokines, components of the complement system, arachidonic acid (AA)
Leukocyte movement: extending filopodia/pseudopods to pull the back of the cell in the direction of extension and migrate toward the inflammatory stimulus
Leukocytic Infiltrate
Nature of the leukocyte infiltrate varies with the age of the inflammatory response and with the type of stimulus
Acute inflammation: neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours, but then replaced by monocytes in 24 to 48 hours
When monocytes turn into tissue macrophages they survive longer and may proliferate in the tissues becoming the dominant population in chronic inflammatory reactions
Exceptions in Leukocytic Infiltration Populations
Pseudomonas bacteria: cellular infiltrate is dominated by continuously recruited neutrophils for several days instead of only lasting 6-24 hours
Viral infections: lymphocytes may be the first cells to arrive instead of neutrophils
Hypersensitivity reactions and parasitic infections: eosinophils may be the main cell type
Recognition of Microbes and Dead Tissue
Leukocyte recruitment to site of infection
Must be activated to perform their functions
Recognition of the offending agents
Deliver signals
Activate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction
Trends of an MI
First 1.5 days = edema of tissues peaking at 12 hours
First 2.5 days = neutrophil infiltration peaking at 24 hours
Monocytes and Macrophages from beginning, but peak at 48 hours and slowly decrease population
3 Steps of Phagocytosis
Clean up of inflammation
- 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 material
Engulfment & Degradation
After a particle is bound to phagocyte receptors:
Extensions of the cytoplasm (pseudopods)
Plasma membrane pinches off to form a vesicle (phagosome)
Encloses the particle and fuses with a lysosomal granule
Discharge of the granule’s contents into the phagolysosome
Final step in the elimination of infectious agents and necrotic cells occurs within neutrophils and macrophages
Microbial killing involving ROS and reactive nitrogen species
Microbial Killing
Can also occur through the action of other substances in leukocyte granules
Granules contain many enzymes such as elastase, defensins, cathelicidins, and lysozymes, lactoferrin, major basic protein, and bactericidial
Major basic protein: in eosinophil granules that is toxic to parasites
Responses of Activated Leukocytes
Produce a number of growth factors to stimulate the proliferation of endothelial cells and fibroblasts, synthesis of collagen, and enzymes that remodel connective tissues
Drive the process of repair after tissue injury
Defects in Leukocyte Function
Inherited and acquired types
Lead to increased vulnerability to infections
Inherited defects in leukocyte adhesion and phagolysosome function
Chédiak-Higashi Syndrome
Autosomal recessive condition
Defective fusion of phagosomes and lysosomes in phagocytes causing susceptibility to infections
Abnormalities in melanocytes (leading to albinism)
Cells of the nervous system (associated with nerve
defects)
Platelets (causing bleeding disorders)
Leukocyte abnormalities:
Neutropenia (decreased numbers of neutrophils)
Defective degranulation
Delayed microbial killing
Chronic Granlomatous Disease
Impairments of leukocyte function
Inherited defects in microbicidal activity
Chronic granulomatous disease: defects in bacterial killing that render patients susceptible to recurrent bacterial infection that starts during childhood
Inherited defects in the genes encoding components of phagocyte oxidase
Initial neutrophil defense is inadequate
Granulomas: collections of activated macrophages that wall off the microbes
Can occur all over the body which starts to replace functional tissue
Example granulomas in the lungs can replace lung tissue and lungs cannot function properly
Acquired Leukocyte Deficiencies
Acquired deficiencies—causes of leukocyte defects Bone marrow suppression Decreased production of leukocytes Seen following therapies for cancer Radiation and chemotherapy Marrow space is compromised by tumors Leukemias Metastatic from other sites
Mediators of Inflammation: General
Mediators are generated either from cells or from plasma proteins
Cell-derived mediators are normally sequestered in intracellular granules, and can be rapidly secreted by granule exocytosis: histamine in mast cell granules
Synthesized de novo in response to a stimulus: prostaglandins, cytokines
Mediators: Producing Cells & Plasma Derived
Cells that produce mediators: platelets, neutrophils, monocytes/macrophages, and mast cells, mesenchymal cells (endothelium, smooth muscle, fibroblasts), most epithelia
Plasma-derived mediators
Complement proteins, kinens
Produced mainly in the liver
Present in the circulation as inactive precursors
Must be activated to acquire their biologic properties
Active Mediators
Produced in response to various stimuli such as microbial products and substances released from necrotic cells, and proteins of the complement, kinin, and coagulation systems
Activated by microbes and damaged tissues
Ensures that inflammation is normally triggered only when and where it is needed
Mediators are Short Lived
Once activated and released from the cell
Quickly decay: arachidonic acid metabolites
Inactivated by enzymes: kininase inactivates bradykinin
Otherwise scavenged or inhibited
Antioxidants scavenge toxic oxygen metabolites
Inhibited: complement regulatory proteins break up and degrade activated complement components
Vasoactive Amines
Two major vasoactive amines
Histamine and Serotonin
Stored as preformed molecules in cells and are
Among the first mediators to be released during inflammation
Richest Source of Histamine
Richest sources: mast cells
Normally present in the connective tissue adjacent to blood vessels
Found in blood basophils and platelets
Present in mast cell granules
Mast cells hangout in CT near the blood supply/vessels
Action of Histamine
Causes dilation of arterioles
Increases the permeability of venules
Considered to be the principal mediator of the immediate transient phase of increased vascular permeability
Producing interendothelial gaps in venules
Serotonin
Preformed vasoactive mediator
Actions similar to those of histamine
Present in platelets
Stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate, and antigen-antibody complexes
Platelet release reaction: key component of coagulation
Present in certain neuroendocrine cells and gastrointestinal tract
Arachidonic Acid Metabolites
Prostaglandins, Leukotrienes, and Lipoxins
Arachidonic Acid (AA)
Arachidonic acid
20-carbon polyunsaturated fatty acid
Derived from dietary sources
Conversion from the essential fatty acid linoleic acid
Does not occur free in the cell
Normally esterified in membrane phospholipids
Mechanical, chemical, and physical stimuli
Release AA from membrane phospholipids through the action of cellular phospholipases such as phospholipase A2
Eicosanoids
AA-derived mediators (eicosanoids)
Synthesized by two major classes of enzymes
1. Cyclooxygenases- generate prostaglandins
2. Lipoxygenases- produce leukotrienes and lipoxins
Bind to G protein-coupled receptors on many cell types
Can mediate virtually every step of inflammation
Prostaglandins
Produced by mast cells, macrophages, endothelial cells, and many others
Involved in the vascular and systemic reactions of inflammation
Produced by the actions of two cyclooxgenases
Constitutively expressed COX-1
Inducible enzyme COX-2
COX 1 and 2- targets of anti-inflammatory meds
If block COX 1- prevents some cancers because some are inflammatory to start with
Divided into series based on structural features
Coded by a letter: PGD, PGE, PGF, PGG, and PGH
Subscript numeral: 1, 2 indicating the number of double bonds in the compound
Most Important Prostaglandins in Inflammation
Most important ones in inflammation
PGE2, PGD2, PGF2α, PGI2 (prostacyclin), and TxA2 (thromboxane)
Prostacyclin
Prostacyclin = PGI2
Vasodilator
Potent inhibitor of platelet aggregation
Markedly potentiates the permeability-increasing and chemotactic effects of other mediators
Wants inflammation to continue so leukocytes can get through, increase chemotactic effect and inhibit platelet aggregation
PGD2
Major prostaglandin made by mast cells along with PGE2 (which is more widely distributed)
Causes vasodilation
Increases the permeability of post-capillary venules
Potentiating edema formation
Chemoattractant for neutrophils
PGF 2alpha
Stimulates the contraction of uterine and bronchial smooth muscle and small arterioles
Vasoconstrictor
PGE2
Hyperalgesic- makes skin hypersensitive to painful stimuli
Involved in cytokine-induced fever during infections
FEEEVER= PGEEEE 2… trick to remember; cannot even brush your hair because so painful
Leukotrienes
Produced by lipoxygenase enzymes Secreted mainly by leukocytes Chemoattractants for leukocytes Vascular effects Will self perpetuate because recruits more leukocytes to the area of injury
Leukotrienes: Three Different Lipoxygenases
- 5-lipoxygenase: predominant one in neutrophils that converts AA to 5-hydroxyeicosatetraenoic acid
Chemotactic for neutrophils
Precursor of the leukotrienes - LTB4: potent chemotactic agent and activator of neutrophils and causes aggregation and adhesion of the cells to venular endothelium
Generation of ROS and releases lysosomal enzymes - Cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4)
Intense vasoconstriction, bronchospasm and increased vascular permeability
Lipoxins
Generated from AA by the lipoxygenase pathway
Inhibitors of inflammation
Two cell populations are required for their biosynthesis
Leukocytes (esp. neutrophils): produce intermediates in lipoxin synthesis, and converted to lipoxins by platelets interacting with the leukocytes
Principal Actions of Lipoxins
Principal actions of lipoxins
- Inhibit leukocyte recruitment and the cellular components of inflammation
- Inhibit neutrophil chemotaxis and adhesion to endothelium
Inverse relationship between the production of lipoxin and leukotrienes
Suggests that lipoxins may be endogenous negative regulators of leukotrienes
May thus play a role in the resolution of inflammation
Inhibition of Eicosanoid Synthesis
Anti-inflammatory drugs work by inhibiting the synthesis of eicosanoids:
- Cyclooxygenase Inhibitors
- Lipoxygenase inhibitors
- Broad-Spectrum Inhibitors
Modify the intake and content of dietary lipids
Increasing the consumption of fish oil
Polyunsaturated fatty acids in fish oil serve as poor substrates for conversion to active metabolites and excellent substrates for the production of anti-inflammatory lipid products
Resolvins and protectins
Cyclooxygenase Inhibitors
Cyclooxygenase inhibitors: Aspirin Non-steroidal anti-inflammatory drugs like Indomethacin Inhibit both COX-1 and COX-2 Inhibit prostaglandin synthesis
Inhibition of Eicosanoid Synthesis
Lipoxygenase Inhibitors
Lipoxygenase inhibitors
5-lipoxygenase is not affected by NSAIDs (cyclooxygenase inhibitor)
Inhibit leukotriene production (Zileuton)
Block leukotriene receptors (Montelukast)- useful in the treatment of asthma
Inhibition of Eicosanoid Synthesis
Broad-Spectrum Inhibitors
Broad-spectrum inhibitors Corticosteroids Powerful anti-inflammatory agents Reduces the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF) Inhibit wound healing
Inhibition of Eicosanoid Synthesis
Platelet Activating Factor (PAF)
Phospholipid-derived mediator
Causes platelet aggregation
Known to have multiple inflammatory effects
Variety of cell types can elaborate PAF: platelets, basophils, mast cells, neutrophils, macrophages, and endothelial cells
Causes vasoconstriction and bronchoconstriction
At extremely low concentrations: induces vasodilation and increased venular permeability
Causes increased leukocyte adhesion, chemotaxis, degranulation, and the oxidative burst
Boosts the synthesis of other mediators (eicosanoids)
Reactive Oxygen Species (ROS)
Oxygen-derived free radicals may be released extracellularly from leukocytes after exposure to microbes, chemokines, and immune complexes
Production is dependent on the activation of the NADPH oxidase system
Superoxide anion, hydrogen peroxide, and hydroxyl radical are major species produced within cells, and if combine with nitric oxide = reactive nitrogen species
Causes tissue damage and oxygen derived free radicals
Have many leukocytes to fix inflammatory process and release oxygen derived free radicals… good process occurring but also does damage to surrounding tissue
Responses to Inflammation that Elicit ROS Release
Implicated in responses in inflammation:
- Endothelial cell damage, with resultant increased vascular permeability
- Injury to other cell types (parenchymal cells, red blood cells)
- Inactivation of antiproteases (α1-antitrypsin)
NO
Discovered as a factor released from endothelial cells
Caused vasodilation called endothelium-derived relaxing factor
Soluble gas: produced by endothelial cells, macrophages and some neurons
Acts in a paracrine manner on target cells causing relaxation of vascular smooth muscle cells
In vivo half-life of NO is only seconds: gas acts only on cells in close proximity to where it is produced
Give NO to patient during MI to increase blood flow
Actions of NO
Has dual actions in inflammation
Relaxes vascular smooth muscle
Promotes vasodilation
Inhibitor of the cellular component of inflammatory responses
Reduces platelet aggregation and adhesion
Inhibits several features of mast cell-induced inflammation
Inhibits leukocyte recruitment
NO and its derivatives are microbicidal aka a mediator of host defense against infection
Overall, NO released causing reduced platelets and leukocyte adhesion and vascular smooth muscle relaxation and vasodilation
Cytokines
Proteins produced by many cell types
Principally activated lymphocytes and macrophages
Also endothelial, epithelial, and connective tissue cells
Involved in cellular immune responses
TNF and IL-1
Major cytokines that mediate inflammation
Produced mainly by activated macrophages
Secretion of TNF and IL-1 stimulated by endotoxin and other microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli
Actions of TNF and IL-1
Endothelium: induce a spectrum of changes referred to as endothelial activation
Induce the expression of endothelial adhesion molecules
Synthesis of chemical mediators, including other cytokines, chemokines, growth factors, eicosanoids, and NO
Production of enzymes associated with matrix remodeling
Increases in the surface thrombogenicity of the endothelium
Augments responses of neutrophils to other stimuli like bacterial endotoxin
TNF and IL-1: Endothelial Activation
Induce the systemic acute-phase responses associated with infection or injury
Regulates energy balance by promoting lipid and protein mobilization and by suppressing appetite
Sustained production contributes to cachexia
Pathologic state characterized by weight loss and anorexia
Accompanies some chronic infections and neoplastic diseases
Chemokines
Act primarily as chemoattractants for specific types of leukocytes
Two main functions:
- Stimulate leukocyte recruitment in inflammation
- Control the normal migration of cells through various tissues
Chemokines: 4 Major Groups
Classified into four major groups According to the arrangement of the conserved cysteine (C) residues in the mature proteins 1. C-X-C chemokines (α chemokines) 2. C-C chemokines (β chemokines) 3. C chemokines (γ chemokines) 4. CX3C chemokines
C-X-C chemokines (α chemokines)
One amino acid residue separating the first two conserved cysteine residues
Act primarily on neutrophils
IL-8 is typical of this group
Secreted by activated macrophages, endothelial cells, and other cell types
Causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils
Most important inducers are microbial products and other cytokines, mainly IL-1 and TNF
C-C chemokines (β chemokines)
First two conserved cysteine residues adjacent
Generally attract monocytes, eosinophils, basophils, and lymphocytes but NOT neutrophils
C chemokines (γ chemokines)
Lack two (the first and third) of the four conserved cysteines
Lymphotactin
Relatively specific for lymphocytes
CX3C chemokines
Contain three amino acids between the two cysteines
Fractalkine: two forms
Cell surface-bound protein
Soluble form
Lysosomal Constituents of Leukocytes
Neutrophils and monocytes contain lysosomal granules
Neutrophils have two main types of granules
- Smaller specific (or secondary) granules
- Larger azurophil (or primary) granules
Neuropeptides
Secreted by sensory nerves and various leukocytes
Play a role in the initiation and propagation of inflammation
Substance P and neurokinin A: family of tachykinin neuropeptides produced in the central and peripheral nervous systems
Biologic functions: Transmission of pain signals Regulation of blood pressure Stimulation of secretion by endocrine cells Increasing vascular permeability
