dr. mahra nourbakhsh's presentation, inflammation and repair
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Inflammation and Repair
AHD presentationNovember 2015
Mahra Nourbakhsh
Definition• 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 needed, in order to eliminate the offending agents.
• The Purpose:o To get rid of initial cause of injuryo To get rid of consequences of such injury
Historical Aspects• Celsus a Roman writer:
1. Rubor: Redness2. Tumor: Swelling3. Color: Heat4. Dolor: Pain
• Virchow:5. Functio Laesa: Loss of function
Inflammation: Useful VS. Harmful
• Protective but may be the cause of diseases:1. Misdirected reaction:• Autoimmune
2. Inadequate reaction:• Hypersensitivity reactions type I to IV
3. Chronic reaction• Fibrosis: pulmonary, cirrhosis, constrictive
pericarditis.
Injurious Agents (Causes of Inflammation)
• Infection: Viral, bacterial, fungal, parasites or toxins• Tissue Necrosis: Ischemia, trauma, physical and
chemical injuries.• Foreign Bodies: Urate crystals, cholesterol crystals,
lipids.• Immune Reactions: Hypersensitivity syndromes.
Sequential Steps of Typical inflammatory reaction
• Recognition of offending agents.• Recruitment of leukocytes and plasma protein to
the site of injury.• Elimination of the offending agents by activated
leukocytes and proteins.• Control and termination of the inflammatory
reaction.• Damages tissue is repaired.
Inflammation: Acute VS. Chronic
Feature Acute Chronic
Onset Fast: minutes or hours Slow: days
Cellular infiltrate Mainly neutrophils
Monocytes/macrophages and lymphocytes
Tissue injury, fibrosis
Usually mild and self-limited
Often severe and progressive
Local and systemic signs Prominent Less
Innate Adaptive?
Question
How a pathogen is recognized by innate immune system? Is there a specific structure or pattern?
If yes bring two examples
Recognition of offending agents
• Specific molecular pattern on offending agents help to recognize the pathogens; Pathogen Associated Molecular Pattern (PAMP):
1. Lipopolysacharides (LPS) on gram negatives2. Lipoteicoic acids on gram positives3. Flagellin on bacteria4. Unmethylated CpG5. Ds RNA in viruses.
Recognition of offending agents • Sensing the presence of foreign invaders:
Pattern Recognition Receptors (PRRs) 1. Membrane bounds (plasma membrane and endosomes) receptors: Toll-Like
Receptors (TLRs), C-Type Lectin Receptors (CLRs)2. Cytosolic Receptors: NOD-Like Receptors (NLRs)
• Sensing the cell damage: activation of inflammasomes and production of IL-1
1. Mitochondria damage: ATP2. Break down of DNA : Uric acids3. Damage to Na+/ K+ pump: Increased intracellular K+
4. DNA fragments: DNA damage response, Ataxia Telangiectasia Mutated (ATM) and ATM RAD3-Related (ATR) kinases
• Leukocytes Receptors for FC tail of antibodies and C3b of complement system: Opsonization
• Circulating proteins: Complement system, Mannose-binding lectins and collectins
Question
Which cells from innate immune system are able to recognize the foreign invaders?
How do they activate the remainder of the innate system?
Recognition of offending agents (Cells and Chemicals)
• Cells:1. Tissue Macrophages2. Mast Cells
• Chemicals for example:1. Tumor necrosis factor (TNF)2. Interleukin-1 (IL-1)3. Chemokines4. Histamine5. Kinin and bradykinin6. Thrombin
• Leading to initiation of acute inflammatory response
Acute Inflammation
Question
What is the major cell of acute inflammation in the first 24h?What is the major cell of acute inflammation after the first 24h?
Acute InflammationCells
Cells:
6-24h: Neutrophils24-48h: MonocytesException: Pseudomonas infection, viral infection, allergic reaction
Acute InflammationSteps
1. Vascular reaction and changes.2. Recruitment of Neutrophils to the site of
inflammation.3. Phagocytosis and clearance of offending agents
Question
What are the two common vascular changes that are seen in acute inflammation?
What is the difference between exudate and transudate?
Acute Inflammation (Step 1: Vascular Reaction)
• Vasodilation of arterioles by mediators such as histamine: 1. Increased capillary bed and blood flow (Rubor and Color), brings more
neutrophils2. Increases the hydrostatic pressure, helps filtration of fluid to
extravascular spaces.3. Slower blood flow helps the margination and attachment of
neutrophils to endothelial cells (see the following)• Increased Permeability (vascular leakage):
1. Immediate transient response (15-30 mins): contraction of endothelial cells
2. Endothelial Injury (several hours):injury by toxins, direct chemical or physical injuries, is healed by thrombosis and repair.
3. Transcytosis: Transport of protein and fluids through endothelial cells, activated by VEGF.
• Transudate VS. Exudate: Exudate means vascular damage
Question
Can you recall three steps of leukocyte recruitment??
Acute Inflammation Step 2: Leukocyte recruitment
• Margination: vasodilation results in slower blood flow, therefore reduced wall shearing force and accumulation of cells in periphery rather than central column of blood.
• Rolling: Leukocytes sequentially binds and detaches to the receptors with low affinity on the surface of endothelial cells. This results in rolling of leukocytes on the surface of endothelial cells.
• Attachment: Leukocytes binds to the receptors with high affinity on the surface of endothelial cells
Acute Inflammation Step 2: Leukocyte recruitment
• Rolling: Is mediated by family of cell surface receptors found on endothelial and leukocyte surface called Selectin (CD62)
• Leukocytes: L-selectin• Endothelial cells : E-selectin• Platelets and Endothelial cells: P-selectin
Acute Inflammation Leukocyte recruitment1. Increase TNF, IL-1 and chemokine
o Endothelial cells: increase E-selectin and ligands for L-selectin.o Neutrophils: increase L-selectin and ligands for E-selectin.
2. Increase histamin and thrombin
o Endothelial cells: redistribution of P-selectin from Wiebel Palade bodies.
o Neutrophils: Increase ligands for P-selectin.
Question
Can you recall the family of receptors for the attachment of Leukocytes ??
Acute Inflammation Leukocyte recruitment (Attachment)
Molecules Distribution Ligands
LFA-1(CD11aCD18)
Neutrophils, monocytes, T cells (naïve, effector,memory)
ICAM-1 (CD54), ICAM-2 (CD102);expressed on endothelium(upregulated on activatedendothelium)
MAC-1(CD11bCD18)
Monocytes, DCs ICAM-1 (CD54), ICAM-2 (CD102);expressed on endothelium(upregulated on activatedendothelium)
VLA-4(CD49aCD29)
MonocytesT cells (naïve, effector,memory)
VCAM-1 (CD106); expressed onendothelium (upregulated on activatedendothelium)
α4β7(CD49DCD29)
Monocytes, T cells (gut homing naïve effector, memory)
VCAM-1 (CD106), MAdCAM-1;expressed on endothelium in gut andgut-associated lymphoid tissues
Acute Inflammation
Step 3: Phagocytosis and clearance of the offending
agentsRecognition and attachment of the particle to be ingested by leukocytes:
1. Mannose and Fucose terminal residue of glycoprotein and glycolipids on microbial walls (human does not contain these residues)
2. Scaveneger recptors on phagocytes: Integrin CD11b/CD8
3. Engulfment with clathrin based coated pit4. Formation of phagosome5. Merging with lysosomes and formation of
phagolysosomes.
Question
Can you name three methods for destruction of offenders in lysosomes?
Phagocytosis and clearance of the offending agents
Intracellular destruction:
1. ROS: Respiratory burst, NADPH oxidase produce O2
Which later changes to H2O2 and reacts with CL- to form OCl2- (mediated by myeloperoxidase).
2. RNS: NO is formed by inducible NO synthase (iNOS) and reacts with O2
- to form ONOO-.3. Lysosomal Enzyme and Proteins:
o Specific Granules: Lysosyme, collagenase, lactoferin, plasminogen, alkaline phosphatase.
o Azurophilic gransules: Myeloperoxidase, bactericidal factors (defensin), acid hydrolase, neutral protease.
Question
Can you recall some of the antioxidant mechanisms?
Antioxidant and antiproteases
Anti oxidants:• Superoxide Dismutase• Catalase• Glutathione peroxidase• Ceruloplasmine• Iron free transferrin
Anti Proteases:• α1- Antitrypsin• α2-macroglubin
Question
Two Vasoactive amines and roles in inflammation??
Mediators of InfllamationVasoactive Amines
• Histamine:1. Richest source: Mast cells but also in basophils and platelets2. Released By: attachment of Ab to mast cells, anaphylatoxines (C3a
and C5a) and by direct injury (cold, warm), substance p and IL-1 and IL-8.
3. Function: vasodilation on arterioles through H1 receptors
• Serotonin:1. Richest source: Platelets and NEC2. Function: vasoconstrictor, function in inflammation unknown.
Question
Name two pathways for formation of Arachidonic Acid derivatives that are involved in inflmmation?? Name the
products.
AA derivative (Eicosanoids)
Cyclooxygenase Pathway and Prostaglandins (PG)
COX-1 and COX-2, COX-2 is activated specifically for inflammation.• TXA2: Secreted by platelets, platelets aggregators and also a
potent vasoconstrictor.• PGI2 (prostacyclin): Secreted by endothelial cells, potent
inhibitor of platelet aggregation, vasodilators.• PGD2: Secreted by mast cells, chemoattractant for neutrophils,
vasodilator, increase permeability of post-capillary veins.• PGE2: similar to PGD2 but secreted by almost any cell.• PGF2α: smooth muscle contraction (uterine, bronchial walls,
small arterioles).• PGE2: Hyperalgesia, is involved in cytokine induced fever.
Inhibitors: NSAID, Aspirin for both COX-1 and 2 and Coxib for COX-2
Lipooxygenase Pathway and Leukotrienes (LT)
5-Lipooxygnease is one of the most important lipooxygenases.• 5-hydroxyeicosatetranoic acid: an intermediate product, a
potent chmeoattractant for neutrophils• LTB4: potent chmeoattractant for neutrophils• LTC4, LTD4 and LTE4: Vasoconstriction, bronchospasm,
increases vascular permeability• Lipoxin: inhibits recruitment of leukocytes therefore is an anti
inflammatory. Requires two steps for production; 1) intermediate lipoxin released by neutrophils then converted to lipoxin by platelets.
Inhibitors:1) lipooxygnease inhibitors: Zileuten, 2)leukotrienes receptor antagonists (Monteleukast).
Cytokines and ChemokinesTNF and IL-1
• Secreted by dendritic cells and macrophages• Stimulated by immune complex, foreign bodies,
microbial products, physical injury.• Role: 1. Formation of other cytokines, chemokines,
growth factors, eicosanoids.2. Activation of leukocytes, production of NO.3. Systemic acute phase reactant: Fever, SIRS,
decrease appetite, regulates energy balance. TNF causes Cachexia
Chemokines • Proteins 8-10 KDa, classified based on the
position of terminal Cysteines (C).1. C-X-C: like IL-8 secreted by macrophages and
endothelial cells chmotactic agent for neutrophils.
2. C-C: Like Monocytes chemoattractant protein 1 (MCP-1)
3. C: like Lymphotactin, chemoattractant for lymphocytes.
4. C-X3-C: Fractalkine, chemoattractant factor for monocytes
Question
Name three pathways lead to activation of complement system.
Complement System
Three activation pathways
Complement System• All three pathways lead to activation of an enzyme called
C3 convertase which cleaves C3 to C3a and C3b.• C3b accumulates and activates more formation of C3b,
then activates C5 convertase which cleaves C5 to C5a and C5b
• C5b activates late complement protein (C6-C9) to form membrane attack complex (MAC).
• C5b and C3b are important for opsonization.• Released C3a and C5a: activates anaphylaxis by release
of histamines, chemotactic agents, activation of AA pathways.
• MAC is important for lysis of microbes such as N.Gonnorhea, deficiency causes predisposition
Complement SystemInhibitors and disease• C1 inhibitor (C1-INH):inhibits C1 activity Deficiency of C1-INH causes hereditary angioedema
• Decay Accelerating Factor (DAF): prevents formation of C3 convertase
• CD59: Prevents formation of MAC
CD59 and DAF are attached to Glycophosphatidyl inositol (GPI) anchor. Deficiency of formation of GPI, prevents the action of CD59 and DAF on RBCs can causes paroxysmal nocturnal hemoglobinuria (PNH)
Morphologic Pattern of Acute Inflammation• Serous inflammation: Low vascular permeability, Exudation
of cell-poor fluid. Examples Blister, Parapneumonic effusion.• Fibrinous Inflammation: Higher vascular permeability,
Fibrinous exudate, mostly seen in the lining of body cavity, such as pericardium or meninges, can dissolve completely or changes to scar tissue (organization).
• Purulent inflammation (Abscess): necrotic tissue in the middle, neutrophiles around the central core and fibroblasts, vascular tissue at the outside of this lesion. Example: appendicitis.
• Ulcer: a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue, Example: Gastric ulcer.
Outcomes of Acute Inflammation
• Complete resolution with no or minimal scar tissue.
• Healing by connective tissue repair, scar formation and fibrosis.
• Progression to chronic infection, due to persistence of the injurious agent or difficulties in repair processing.
Chronic Inflammation
Chronic InflammationCauses
• Persistent infection: o Infection is not cleared by innate inflammation,o Examples: MTB, Some viral infection, parasites, fungal infection
• Hypersensitivity and autoimmune Diseases:o Hypersensitivity type I-IVo Autoimmune disease such as SLE, RA
• Prolong exposure to toxic agents:o Talk, Slilcosis, Asbestosis
Question
Name two major type of cells involved in chronic inflammation.
Question
Where are the macrophages derived from?Name three tissue macrophages.
Name Two methods of activation of macrophages.
Chronic InflammationCells: Macrophages
• Macrophages:o Derived from bone marrow, embryonic yolk sac and fetal liver.o Circulate in blood as monocytes and transfer to tissue and resident
macrophages such as Kupfer cells, microglial cells, Langerhans cells, alveolar macrophages .
• Activation:o Classical activation: by TLR or IFN-Υand foreign substance, Classically
activated macrophages (M1) are acting as the effector cells in inflammation.o Alternative activation: By IL-4 and IL-13 of T-lymphocytes. These activated
macrophages (M2) are important in tissue repair by secreting growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.
• Function:o Phagocytosiso Tissue repairo Secrete mediator of inflammation such as TNF and IL-1o Antigen presenting cells
Question
Can you recall three major forms of CD4+ T cells and their function in inflammation?
Chronic InflammationCells: Lymphocytes
• Lymphocytes:o Major cells of chronic inflammation and major cells of adaptive
immunity.o Antigen stimulated lymphocytes are recruited to the site of injury
similar to neutrophils.• CD4+ T cells:
o TH-1 cells secrete IFN-Υand activates M1 macrophages .o TH-2 cells secrete IL-4, IL-5 and IL-13 and activates M2 macrophages
and also eosinophils.o TH-17 secrete IL-17 induces secretion of chemokines responsible for
neutrophil recruitment.• Function:
o TH-1 and TH-17: against bacteria and viruses.o TH-2: against helminthic parasites.o Macrophages present the antigen to T cells and also secrete IL-12 to
activate these cells.
Chronic InflammationCells: Others
• Eosinophils:o Major basic protein extremely toxic for parasites.
• Mast Cells:o Part of primary innate response by scereting inflammaotry mediators.o Contains Fcε RI receptor for FC protion of IgE, therefore involves in
allergic reaction• Neutrophils:
o Although involves in acute inflammation, they can be seen in burst of inflammation as acute on chronic inflammation..
Systemic Effects of Inflammation
• Acute phase response is mediated by TNF, IL-1 and IL-6.
1. Fever: Bacterial products such as LPS (exogenous pyrogens) stimulates leukocytes to secrete TNF and IL-1 (endogenous pyrogens), induces COX which increases PGE2, PGE2 at hypothalamic area increases neurotransmitters that set the temperature at higher points.
2. Acute Phase Proteins: Examples are SAA, CRP and fibrinogen. They are produced by liver and their levels increase 100 times following inflammation.1. Fibrinogen binds to RBC causes rouleuax formation (bases of ESR)2. Long time activation of SAA causes amyloidosis3. Hepcidin another phase reactant protein reduce availability of iron and
causes anemia of chronic disease.3. Leukocytosis4. Other manifestations: such as rigors and chills, loss of appetite, malaise.5. Septic shock: High levels of TNF and f IL-1 associated with DIC, hyperglycemia,
hypotension.
Question
Can you recall two types of reaction for tissue repair?Hint: in regards to tissue that can proliferate vs. not.
Repair
• Two types of reaction:1. Regeneration: by
proliferation of remained uninjured cells and/or by activation of stem cells.
2. Connective tissue deposition and scar formation: if injured tissue is incapable of proliferation or damage is so severe
Tissue RegenerationThree types of cells:
1. Labile/Continuously dividing cells: such as majority of surface epithelia, can regenerate as long as pool of stem cells are preserved.
2. Stable quiescent (G0 phase) cells: such as solid organs, fibroblast, endothelial and smooth muscle cells, only regenerates in response to injury and have a limited capability of regeneration.
3. Permanent tissue: Such as neuron, cardiac myocytes and skeletal muscles, except to very limited stem cell proliferation, they never regenerate
Tissue Regeneration Liver
• Priming phase: priming the hepatocyte by IL-6 secreted from Kupffer cells.
• Growth factor phase: From G0 to G1 and then S phase on primed hepatocytes by HGF and TGF-α.
• Termination phase: return to quiescence, by TGF-β.
Scar FormationSteps of scar formation:1. Angiogenesis2. Deposition of connective tissue
These two first steps forms a tissue with a loose extracellular matrix, proliferated fibroblasts and thin-walled leaky vessels with presence of macrophages. This tissue is called Granulation Tissue.
3. Remodeling of connective tissue
Scar FormationAngiogenesis
1. Vascular Endothelial Growth Factor (VEGF): specifically VEGF-1 stimulates capillary sprouting
2. Fibroblast Growth Factor (FGF): Specifically FGF-2 stimulates endothelial proliferation.
3. Angiopoeitin 1 and 2: stabilized newly formed vessels by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue.
4. PDGF and TGF-β: stabilizing the tissue by enhanced production of extracellular matrix
Deposition of Connective Tissue
• M2 Macrophages release TGF-β, PDGF and FGF-2 which lead to migration and proliferation of fibroblast into the site of injury.
• TGF-βstimulates synthesis and deposition of ECM (collagen, fibronectin and elastin) by fibroblast and inhibits matrix metalloproteinase (MMP), therefore increases the net accumulation of collagen.
• Some of the fibroblasts also acquire features of smooth muscle cells (myofibroblast) and are important in scar contraction.
Remodeling of connective tissue
• Removal and remodeling of extracellular matrix by Matrix Metalloproteinase (MMP).
• MMP-1 to -3: are collagenase which cleaves fibrillar collagen.
• MMP-2 and -9 are gelatinase which cleaves fibronectin.• MMP-3, -10 and -11 are stromelysins which cleaves ECM
constituents, including proteoglycans, laminin, fibronectin,• tissue inhibitors of metalloproteinases (TIMPs),
inhibits MMP and contorls the remodeling.• ADAMs (a disintegrin and metalloproteinase) family
are attached to plasma membrane and deactivates TNF, TGF-β, and members of the EGF family.
Question
Give some examples for the factor that are able to affect tissue repair?
Factor influencing repair
• Infection• Diabetes• Nutritional status: protein deficiency and Vit. C
deficiency.• Steroids: preventing TGF-B production.• Mechanical factors: pressure, torsion• Poor perfusion• Foreign body• Type of tissue and extent of damage
Question
What is the difference between hypertrophic scar and keloids?
Abnormal Tissue Repair
• Fibrosis in internal organs activated by TGF-B.• Inadequate formation of granulation tissue
and scar: leads to wound dehiscence and ulceration
• Excessive formation of the components of the repair process can give rise to hypertrophic scars (raised edge) and keloids (beyond the boundaries of original wound.
• Exuberant granulation tissue, prevents reepithelialization
• contraction
Acute Inflammation (Step 1: Vascular Reaction)
• Increased number of lymph vessels to remove the exudates:
• Inflammation of Lymph Vessels: Lymphangitis• Inflammation of draining lymph node: Reactive
Lymphadenitis
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