Inflammation and Repair Flashcards
What is inflammation?
•Response of vascularized tissues to infection and damage
–Brings cells and molecules critical for host defense from circulation to sites where they are needed
–Purpose is to eliminate offending agent(s)
•Protective response essential for survival
–Rids the host of cause of cell injury (microbes, toxins)
–Rids host of consequences of such injury (necrotic cells and tissues)
Only for vascularized tissue… ex- enamel and dentin will NOT have inflammation bc are NOT vascularized
*Caries are painless bc not in vascularized tissue UNLESS travels to pulp
Inflammation
•Most mediators of defense normally circulate in blood
–Leukocytes
–Antibodies
–Complement proteins
•Inflammatory mediators are recruited from circulation to site of offending agent
–Activate and cooperate to eliminate offending substance
–Reaction controlled and terminated
–Damaged tissue repaired
•Without inflammation
–Infections would go unchecked, wounds would never heal, injured tissues would remain permanent festering sores
Leukocytes: white blood cells ex neutrophils macrophages etc
Antibodies: immunoglobulins synonymous
Inflammation: fundamental properties
•Major participants
–Blood vessels
–Leukocytes
- Monocytes/ macrophages
- Lymphocytes
- Granulocytes
–Neutrophils
–Eosinophils
–Basophils
•Protective inflammatory reactions often are accompanied by local tissue damage
–Harmful consequences typically self-limited and leave little/no permanent damage
•Disease states may be characterized by mis-directed inflammatory reaction
–Autoimmune disease
–Allergy
- Inflammation contributes to or complicates a wide variety of diseases
- Inflammation: local and systemic
–Inflammation is usually a local response to infection/tissue damage
•Some systemic manifestations (fever) may occur
–Rarely, inflammatory response is systemic
- Causes widespread pathologic abnormalities
- Termination of inflammation and initiation of tissue repair
–Inflammation terminated when offending agent eliminated
–Elimination of offending agent sets into motion process of tissue repair
- Regeneration of surviving cells
- Filling in of residual defects with connective tissue (scarring)
Images will not generate test questions, but are meant for facilitated understanding to complement Dr. Stojanov’s text
Rarely occurs without tissue injury of some kind
Systemic examples: sepsis, shock response etc
Cardinal signs of inflammation
•Rubor
–Redness
•Tumor
–Swelling
•Calor
–Heat
•Dolor
–Pain
•Functio laesa
Loss of function
Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain). These signs are hallmarks of acute inflammation. A fifth clinical sign, loss of function (functio laesa), was added by Rudolf Virchow in the 19th century.
Causes of inflammation
•A variety of stimuli may trigger inflammatory reactions
–Infections
- Bacterial, viral, fungal, parasitic
- Microbial toxins
–Tissue necrosis (death)
- Physical, thermal, chemical injury
- Trauma
- Ischemia (reduced blood flow)
–Foreign bodies
•Splinters, dirt, sutures
–Immune reactions
- Autoimmune disease
- Allergy
How are offending agents (microbes, damaged cells) recognized?
•Cellular receptors for microbes
–Cells express receptors on…
- Plasma membrane: for extracellular microbes
- Endosomes: for ingested microbes
- The cytosol: for intracellular microbes
- Censors of cell damage
–Cells have cytosolic receptors that recognize diverse set of molecules liberated/altered as a result of cell damage
•Circulating proteins:
–Complement system
•Many leukocytes express receptors for antibodies and complement proteins that have opsonized (coated) microbes
Microbe receptors on multiple surfaces
Sensors of cell damage
Complement system = approx. 20 proteins that circulate in blood
Tail of antibody can be recognized by WBC and begin proper function
Acute and chronic inflammation
Acute inflammation:
•Initial, rapid response to infection or tissue damage
–Develops within minutes/hours
–Lasts for several hours or few days
•Characterized by exudation of fluid/plasma proteins and emigration of leukocytes
–Particularly neutrophils (think new)
•Reaction subsides when offending agent cleared
Chronic Inflammation:
•Protracted phase of inflammation occurring if acute inflammation cannot clear offending agent
–Of longer duration
- Lymphocytes and macrophages major cell types
- Associated with more tissue destruction and healing by deposition of connective tissue
Acute inflammation
•Three major components
–Dilation of small blood vessels
•Leads to increase in blood flow
–Increased permeability of small blood vessels
•Allows plasma proteins and leukocytes to leave circulation
–Emigration of leukocytes from microcirculation
•Followed by their accumulation at site of injury and activation to eliminate offending agent
Exudation
•Escape of fluid, proteins, blood cells from vascular system into interstitial tissues or body cavity
–Transudate: extravascular fluid with low protein content and little/no cellular debris
–Exudate: extravascular fluid with high protein content and cellular debris
•Occurs in sites of injury/inflammation
–Pus: exudate rich in neutrophils, dead cell debris, microbes
Neutrophils make things yellow
Transudate is NON inflammatory, results from disease condition causing leakage (kidney/heart disease, swollen ankles is an indicator)
Exudate is inflammatory
Colloid osmotic pressure: aka oncotic pressure, form of osmotic pressure due to proteins (especially albumin) in the blood, tends to draw water into vessels, therefore opposes hydrostatic pressure of blood volume for good balance
Reactions of blood vessels in acute inflammation
•Vasodilation
–Results in increased blood flow
•Cause of heat and redness at site of inflammation
–Results in slower blood flow
•Leukocytes (mostly neutrophils) accumulate along vascular endothelium
–Induced by action of mediators such as histamine on vascular smooth muscle
•Vasodilation quickly followed by increased vascular permeability (vascular leakage)
–Vasoactive mediators such as histamine
•Permeability typically lasts 15-30 minutes and occurs immediately after exposure to mediator
–Mild endothelial damage
•Permeability may begin after delay of 2-12 hours and last for several hours/days
–Severe endothelial injury
- Resultant cell necrosis and detachment lead to permeability
- System of lymphatics/ lymph nodes normally drains and filters extravascular fluids
–In inflammation, lymph flow is increased and helps drain edema fluid
–Lymphadenitis: lymph nodes may become secondarily inflamed
This is why turn red during sunburn AND not turn red until some time later because of endothelial damage
Excess hydrostatic pressure of vascular system necessitates a mechanism for removal of excess fluid
Leukocyte recruitment to sites of inflammation
(Classic board question: Adhesion molecules)
- Immediately follows changes in blood flow and vascular permeability
- Neutrophils and macrophages most important leukocytes
–Capable of phagocytosis
•Ingestion/destruction of microbes, necrotic tissue, foreign substances
–Produce growth factors that aid in repair
•Multistep process mediated/controlled by adhesion molecules and chemokines
–Chemokine: a cytokine with function of leukocyte recruitment
–Cytokines: messenger molecules of immune system
Kines = Kome In
Leukocyte recruitment to sites of inflammation (STEPS)
- Leukocyte adhesion to activated endothelium
–Margination: occurs during vasodilation
–Rolling
- Period of transient attachment/detachment
- Mediated by family of proteins called selectins
–Low affinity attachment and easily disrupted by flowing blood
–Slow leukocytes sufficiently to give them opportunity for firm adhesion
–Adhesion
•Point at which cells become firmly attached to vessel wall
–Cytoskeleton reorganizes and cells spread out on endothelial surface
•Mediated by family of proteins called integrins
- Leukocyte transmigration through endothelium (diapedesis)
–Occurs mainly in post-capillary venules
–Leukocytes migrate between endothelial cells and pierce through underlying basement membrane
3.Following transmigration, leukocytes move towards site of injury by chemotaxis
–Chemotaxis: locomotion along a chemical gradient
•Exogenous and endogenous agents act as chemoattractants
–Exogenous: bacterial products
–Endogenous: cytokines, components of the complement system (C5a), arachidonic acid metabolites
————————-
Selectins slow leukocyte only sufficiently enough for attachments; integrins used for final successful adhesion
leukocyte adhesion deficiency
Diseases such as leukocyte adhesion deficiency (defect in integrin/selectin function) lead to increased vulnerability to bacterial infections, such as periodontal disease
Neutrophils or Macrophages first?
In most forms of acute inflammation: Neutrophils predominate first 6-24 hours Neutrophils replaced by macrophages within 24-48 hours
Neutrophils = NEW
Leukocyte activation: phagocytosis and clearance of the offending agent
•Phagocytosis
–Recognition and attachment of particle to be ingested
- Mannose receptors, scavenger receptors, opsonin receptors
- Efficiency of phagocytosis greatly enhanced by opsonization of microbes
–Coating of microbes by opsonins:
»Specific proteins such as antibodies or complement proteins to facilitate phagocytosis
•Phagocytosis
–Engulfment: plasma membrane pinches off into vesicle (phagosome)
•Phagosome fuses with lysosome (phagolysosome) and lysosomal contents destroy phagocytosed debris
–Intracellular destruction of microbes/debris
- Occurs within phagolysosome to avoid damage to host cell
- Microbial killing accomplished by
–Reactive oxygen species (ROS): oxygen-derived free radicals that damage cellular components
»In neutrophils, produced via respiratory burst
–Reactive nitrogen species: mainly derived from nitric oxide (NO)
–Lysosomal enzymes: proteases, collagenase, lysozyme….
•Neutrophil extracellular traps (NETs)
–Produced and released by neutrophils at the cost of cell survival
•Consists of nuclear chromatin and antimicrobial peptides
–Extracellular fibrillar networks that
- Provide high concentration of antimicrobial substances
- Prevent spread of microbes by trapping them in fibrils
- Leukocyte-mediated tissue injury occurs by same mechanisms involved in anti-microbial defense
–Collateral damage to adjacent tissues
•Some infections difficult to eradicate and prolonged host response contributes more to disease course than microbe
–Autoimmune disease
•Inflammatory response inappropriately directed against host tissues
–Allergy
•Excessive inflammatory response against usually harmless substances
Mannose is never the final sugar on a polysaccharide chain in native molecules (glycoproteins/glycolipids); bacterial glycoproteins always have mannose as final sugar à recognize this unique difference
Neutrophils spill out nuclear chromatin and contentsà creates fiber net, physical barrier with high concentration of antimicrobial
Bullous pemphigoid (childhood): immune system perceives own skin as foreign and attacksà blistering to remove “invader”
What keeps lysosomal enzymes from destroying healthy tissue?
- Lysosomal enzymes, such as elastase released from neutrophils, may cause tissue destruction during inflammation
- Their potency controlled by antiproteases***, such as ***α1-antitrypsin, normally present in blood and tissue fluids
- α1-antitrypsin deficiency: inherited disorder predisposing to emphysema and cirrhosis
Termination of acute inflammatory response
•Potent host defense system requires tight control to minimize damage
–Mediators of inflammation
- Produced in bursts only as long as stimulus persists
- Are rapidly degraded after their release
–Inflammatory response generates anti-inflammatory mediators
–Neutrophils die by apoptosis (programmed cell death) within a few hours of leaving circulation
Mediators of inflammation
•Mediators of inflammation: substances that initiate and regulate inflammatory reactions
–Cell-derived mediators
- Sequestered in intracellular granules and can be rapidly secreted
- Synthesized de novo in response to stimulus
–Plasma-derived mediators
- Produced mainly in liver and circulate as inactive precursors that must be activated
- Generated in active form only in response to various stimuli
–Major producers are macrophages, dendritic cells, mast cells
–Major triggers are microbial products, substances released from necrotic cells
Cell derived ex histamine
Arachidonic acid
•Normally present in phospholipids of cell membrane
–Released during inflammation
–Precursor to variety of mediators
•Steroids inhibit phospholipase-mediated release of AA from cell membrane
–Basis of pharmacologic use of steroids in inflammatory conditions
Steroids inhibit phospholipase enzyme
Selected mediators…
- Prostaglandins
- Leukotrienes
- Lipoxins
- Histamine
- Bradykinin
- Cytokines
Complement system
•Collection of plasma-derived complement proteins functioning in:
–Host defense against microbes
–Pathologic inflammatory reactions
- Consists of more than 20 proteins, some of which are numbered C1-C9
- Critical step in pathway activation is proteolysis (cleavage) of C3 into C3a and C3b
–Classical pathway of activation
•Triggered by fixation of C1 to antibody-antigen complex
–Alternative pathway of activation
•Triggered by contact with microbial components
–Lectin pathway of activation
- Triggered when circulating mannose-binding lectin recognizes microbial sugars
- C3 proteolysis leads to three important functions
–Pro-inflammatory state
•Chemotaxis, histamine release, eicosanoid production
–Opsonization with C3b
•Leading to phagocytosis
–Cell lysis
•Formation of membrane attack complex (MAC) comprised of C5b-C9, particularly important in killing microbes with thin cell walls
C1 inhibitor (C1 INH) blocks activation of C1 and its deficiency is cause of hereditary angioedema
Role of mediators in
different reactions of inflammation
Outcomes of acute inflammation
•All acute inflammatory reactions typically have one of three outcomes
–Complete resolution
•Occurs with removal of offending agent
–Healing by connective tissue replacement (scarring/fibrosis)
- Occurs with substantial tissue destruction involving tissue incapable of regeneration
- Connective tissue grows into area of damage
–Progression to chronic inflammation
- Offending agent cannot be removed
- Normal process of healing interfered with
Monocyte, macrophage and histiocyte: what’s in a name?
- Macrophages ultimately derive from hematopoietic stem cells in bone marrow
- Circulating cells of this lineage termed monocytes
–Emigrate to sites of inflammation and differentiate into macrophages
–Some monocytes physiologically migrate into various tissues and reside as macrophages (old term: histiocytes)
•Lifespan several months/years
Macro and mono are same cell, 2 different locations
Two major pathways of macrophage activation with divergent effects:
- Classical macrophage activation leads to macrophages (M1) with microbicidal and pro-inflammatory effects
- Alternative macrophage activation leads to macrophages (M2) whose principal function is tissue repair
- Lymphocytes and macrophages interact in a bidirectional way important for propagating chronic inflammation
- Major function of lymphocytes is as mediators of adaptive immunity
Repair by connective tissue deposition
•Occurs when repair cannot be accomplished by regeneration alone
–Significant injury
–Damage to non-dividing tissues
•Results in scar formation
–Typically ‘patches’ tissue up with sufficient structural stability so that residual tissue can function
•Begins within 24 hours of injury
–Emigration of fibroblasts to site of injury
–Fibroblast and endothelial cell proliferation
- By 3-5 days, specialized granulation tissue characteristic of healing present
- M2 macrophages play central role in repair
–Phagocytosis of offending agents and dead tissue
–Secretion of cytokines/growth factors for
- Proliferation of various cells
- Collagen synthesis and deposition
Area of ischemic heart tissue remains nonfunctional in heart attach survivials
Steps in scar formation
1.Angiogenesis
–Formation of new blood vessels from existing vessels
•VEGF (vascular endothelial growth factor) initiates capillary sprouting
–Newly formed vessels leaky and allow for delivery of oxygen and nutrients to healing tissue
2.Formation of granulation tissue within site of injury
–Wound healing tissue comprised of:
- Fibroblasts which deposit collagen
- Endothelial cells which form into capillaries (angiogenesis)
- Scattered leukocytes (mainly macrophages)
–TGF-β (transforming growth factor-β) important cytokine
- Limits/terminates inflammatory responses
- Stimulates fibroblast migration and proliferation
- Increases synthesis of collagen and fibronectin
3.Remodeling of connective tissue into dense fibrous scar
–Collagen synthesis begins within 3-5 days of injury and may progress for several weeks depending on wound size
•Remodeled by MMPs (matrix metalloproteinases) and regulated by TIMPs (tissue inhibitors of metalloproteinases)
–Regression of vascular tissue leaving behind pale, largely avascular scar
–Contraction of scar
•(Due to presence of myofibroblasts, fibroblasts with contractile abilities)
fibroblasts secret collagen 1 fibers
Healing of skin wounds:
healing by first or second intention
•Healing by first intention
–Injury superficial and involves mostly epithelial layer
•Such as by a clean, uninfected surgical incision approximated by surgical sutures
–Focal disruption of epithelial basement membrane
–Death of few epithelial and connective tissue cells
–Epithelial regeneration principal mechanism of repair
- Little to no scarring occurs
- Healing by second intention
–Injury involves extensive area of skin
- Intense inflammatory reaction
- Development of abundant granulation tissue
–Repair process consists of combination of regeneration and scarring
First intention: best approximation of original unharmed tissue (ex: very accurate suture replacement of flaps)
Minimal scarring, mostly regen
Second intention: poor approximation of intact surfaces… more scarring
Abnormalities in
tissue repair
•Inadequate formation of granulation tissue
–Alveolar osteitis (dry socket) arising from disruption of blood clot following dental extraction
•Excessive formation of components of repair process
–Hypertrophic scar, keloid
