Inflammation & Hematopoiesis Flashcards

1
Q

Inflammation

Characteristics

A

Redness

Swelling

Heat

Pain

Loss of function

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2
Q

Factors Stimulating

Inflammation

A

Endogenous

  • Tissue necrosis
  • Bone fracture
  • Urate crystals

Exogenous

  • Mechanical injury (cut)
  • Physical injury (burn)
  • Chemical injury (caustic)
  • Foreign bodies
  • Immunicological process
    • Hypersensitivity reactions
    • Immune complex deposition
  • Biological injury
    • Microorganism infection
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3
Q

Identifying Characteristics

of

Inflammatory Pathways

A
  1. Mechanism of induction
  2. Time course
  3. Types of cellular infiltrates
    • Kind of inflammatory cells that enter the tissue
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4
Q

Inflammatory

Enzyme Cascades

A
  • Coagulation system
  • Fibrinolytic system
  • Complement cascade
  • Kinin system
  • Lipid inflammatory mediators
    • Arachidonic derivatives
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5
Q

Complement Role

in

Inflammatory Response

A
  1. Destruction of target membranes via MAC complex
  2. Recruitment of phagocytes
    • C5a > C3a
      • activate cells of vascular endothelium
      • chemoattractants
    • C5a > C3a >>> C4a
      • anaphylatoxins that induce mast cell degranulation
      • stimulates release of histamine and arachidonic acid breakdown products
      • induces smooth muscle contraction and increased vascular permability
  3. Opsonization
    • C3b on target binds complement receptors (CRs) on phagocytes
  4. Promote the clearance of immune complexes
    • CR1 on RBC’s
    • Reticuloendothelial system
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6
Q

Proinflammatory Cytokines

A

IL-1, IL-6, TNF-α

IL-8 = chemokine

  • Role
    • Contribute to the inflammatory response prior to or in the absence of adaptive immune response
  • Sources
    • Resident macrophages
      • 1st phagocytic cells to encounter bacteria in the tissue
    • Damaged epithelial & endothelial cells
    • Inflammatory macrophages
      • Recruited to the site of infection/injury
  • Induced by
    • PAMPs
    • DAMPs
    • Tissue damage/stress
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7
Q

Proinflammatory Mediators

A
  • Products of arachidonic pathway
  • Products of clotting cascade
  • Products of fibronolytic cascade
  • Pro-inflammatory cytokines
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8
Q

Acute Inflammation

Local Actions

Proinflammatory Mediators

A
  • Induce changes in blood flow and leukocyte flow patterns
    • Larger vessels = slower flow
      • Easier diapedesis
      • Causes redness & warmth
  • Increase vascular permeability
  • Activates the vascular endothelium
    • Leads to expression of cellular adhesion molecules on endothelium
    • Aids in extravasation of WBC’s
  • Creates a chemotactic gradient for WBC to site of inflammation
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9
Q

Acute Inflammation

Systemic Actions

A

Generally attributed to IL-1, IL-6, TNF-α.

Concentration of cytokines high.

Known as acute-phase response.

Typically induced by bacterial infections.

  • Fever
    • Caused by endogenous pyrogens
      • IL-1, IL-6, TNF-α, prostaglandins
    • Induces change in the hypothalamus which increases temperature set point
    • Mechanism used by body to kill bacteria
  • Leukocytosis
    • High # of WBC’s
    • Significant infections with extracellular bacteria usually associated with elevated IL-1 & IL-6 levels that induce neutrophilia
      • Increased # of band cells in peripheral blood
  • Increased production of acute-phase proteins
    • IL-1, IL-6, TNF-α, MBP, CRP
    • Liver can increase production of acute phase proteins 1,000 fold in response to cytokines
    • Onset 12-24 hours
    • Responsible for increase ESR
      • Due to increased protein concentration in peripheral blood
  • Mobilization of energy from fat and muscle stores
    • Triggered by TNF-α
  • Blood vessel occlusion
    • Triggered by TNF-α
    • Changes in endothelial cell surface molecules triggers blood clotting in small blood vessels
    • Local: prevent microbial migration into circulation
    • Systemic: disseminated intravascular coagulation (DIC)
      • failure to profuse tissues/organs can lead to organ failure/death
      • consumption of clotting factors can lead to bruising, failure to clot, bleeding
  • Endotoxic shock / septicemic shock
    • Occurs when there is massive release of TNF-α, IL-1, and IL-6 induced by bacterial products
      • Ex. LPS from gram neg bacteria
    • Results in life threatening consequences
      • Fever
      • Circulatory collapse
      • Disseminated intravascular coagulation
      • Consumption of clotting proteins
      • Hemorrhagic necrosis
      • Multi-organ failure
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10
Q

Neutrophil

Characteristics

A

(PMN’s)

  • Hallmark of acute inflammation
  • Most common WBC
  • Generated in bone marrow in a manner responsive to demand
    • Bands = immature peripheral blood neutrophils
  • Circulates in blood for 1-2 days
  • Mobilized into tissues within hours of stimulus
    • Short-lived in tissues (Half-life ~ 7 hours)
    • Die via necrosis at site of infection forming pus
    • Undergoes apoptosis in absence of infection
  • Kill via oxygen-dependent & independent mechamisms
  • Sources/reserves
    • # 1 - blood
    • # 2 - bone marrow
    • # 3 - hematopoiesis
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11
Q

Steps of WBC Recruitment

A
  1. Activation of vascular endothelium
  2. Adherence
  3. Diapedesis
    • The movement of the cell between the endothelial cell junctions into the tissues
  4. Chemotaxis
    • the movement of the cell towards the “threat”
    • travels along a chemotactic gradient
      • C5a or IL-8
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12
Q

Activation of Vascular Endothelium

A
  • infection or tissue damage leads to the release of pro-inflammatory mediators
    • bradykinin, IL-1, IL-6, TNF-α, C5a
  • mediators activate the endothelium
    • stimulates expression of P & E - selectins
    • increased expression of ICAM
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13
Q

Neutrophil Recruitment

A
  1. Rolling/tethering
    • P-selectin and E-selectin on activated endothelium binds the sialyl Lewisx expressing carbohydrate ligand PSGL-1 on neutrophils (& most other WBC’s)
    • interaction produces a weak “adhesion” between WBC & endothelium
    • Promotes tethering/rolling along the endothelium causing WBC to dramatically slow down
  2. Sampling & chemoattractant-mediated activation (stimulation)
    • Rolling allows WBC to “sample” its environment looking for chemoattractants
      • Ex. C5a, IL-8, histamine
    • Chemoattractants “activate” the WBC and cause integrin molecules on the neutrophil to undergo a conformational change that significantly increases the integrin’s affinity for it’s ligand leading to firm adhesion
    • Different chemoattractant expression allows the recruitment of different cell types to the site of inflammation/infection
      • IL-8 ⇒ neutrophils
      • IL-5 ⇒ eosinophils
  3. Firm adhesion & pavementing (flattening)
    • Integrin:ICAM interactions cause the cell to:
      • stop rolling
      • firmly adhere
      • flatten
    • Integrin = LFA-1
    • ICAM = intercellular adhesion molecule
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14
Q

Secondary Capture

A

Another method of neutrophil recruitment.

  1. PSGL-1 on free flowing neutrophils can bind to P-selectins presented on adherent platelets
  2. L-selectin on free flowing neutrophils can interact with PSGL-1 presented by adherent leukocytes or leukocyte-derived fragments
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15
Q

Neutrophil Receptors

A

Neutrophils express > 40 different receptor types:

  1. Fc receptors (FcR)
    • allows the cell to bind the Fc region of an Ab
  2. Complement receptors (CR1 and CR3)
  3. Collectin Receptors
    • Allows cell to bind acute phase proteins
      • MBP & CRP

Both Fc and complement receptors act in synergy.

Direct attachment of neutrophil and pathogen can induce ingestion.

(Ex. toll receptors, macrophage mannose receptors, scavenger receptors)

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16
Q

Neutrophils & Macrophages

Methods of Killing

A
  • Oxygen-dependent mechanisms
    • ROI
  • Oxygen-independent antimicrobial activities
    • Defensins
    • Cathepsin G
    • Lysozyme
    • Bactericidal permeability increasing (BPI) proteins
  • Nitric oxide and reactive nitrogen intermediates

Use multiple strategies hoping that bacteria is not resistant.

Needs to be able to work in an environment which is oxygen poor such as an injury site.

17
Q

Inflammation

Normal Resolution

A
  1. Several hours after arrival of PMNs, mononuclear cells begin to accumulate.
    • Attracted by cytokines, proinflammatory complement components, collagen, elastin, and fibronectin breakdown products
  2. Recruited monocytes become activated macrophages.
    • Mop-up bacteria, dead PMNs, and tissue cells
    • Macrophages and T-cells release:
      • Inhibitory cytokines that suppress inflammation
        • Transforming growth factor β (TGF-β)
      • IL-10
        • inhibit macrophage activation and cytokine production
        • alter/inhibit certain T cell functions
  3. Drainage of interstitial fluid (extravascular edema)
    • accumulated fluid drains via lymphatics
    • promotes movement of cells (dentritic/macrophages) and antigen to naive/memory lymphocytes in secondary lymphoid organs
    • promotes an adaptive immune response
    • facilitates lymphocyte activation
  4. Lymphocytes
    • increased trafficking of antigen-activated lymphocytes increases the recruitment of threat specific lymphocytes (CD4/CD8 effector cells)
  5. Tissue repair and scar formation
    • Fibrosis
    • Granuloma formation
18
Q

IL-10

A

Produced by alternatively-activated macrophages and T-cells.

Suppresses macrophage function:

cytokine production

respiratory burst

Alters adaptive CD4 T-cell response

19
Q

Transforming growth factor β

(TGF-β)

A

Produced by T-cells.

  • role in limiting inflammatory response
  • inhibits many components of innate and adaptive immunity
  • promotes accumulation of alternatively activated macrophages
  • promotes accumulation and proliferation of fibroblasts and deposition of ECM
  • alters cell cycle to stop lymphocyte proliferation
20
Q

Acute Inflammation Summary

A
  1. Event
  2. Release of proinflammatory mediators following tissue damage or macrophage activation
  3. Change in blood flow, increased vascular permeability, and activation of vascular endothelium
  4. Recruitment and killing by neutrophils
    • Adherence
      • Rolling/tethering by selectin mediated interactions
      • Sampling and activation by chemoattractants
      • Firm adhesion by integrin:ICAM interactions
    • Attachment of neutrophil to pathogen
    • Phagocytosis
    • Killing by oxygen dependent & independent mechanisms
  5. Normal resolution and repair
    • Recruitment of macrophages and lymphocytes
    • Drainage of insterstitial fluid
    • Adaptive immune response
    • Repair of tissue and scar formation
21
Q

Chronic Inflammation

A
  • Occurs when the offending material or pathogen cannot be destroyed and cleared by neutrophils or macrophages.
  • Macrophage accumulation and activation are the hallmarks of chronic inflammation.
  • Prolonged Ag stimulation leads to continued arrival of new macrophages and T cells.
  • Chronic inflammation can lead to fibrosis or granuloma formation which can alter tissue function.
22
Q

Fibrosis

A
  • Thought to occur when macrophages and TH cells interact together over many weeks to years.
    • TH cells make IFN-γ that activate macrophages
    • Macrophages stimulate TH cells
  • Macrophages synthesize growth factors that:
    • promote inflammation
    • stimulate fibroblast proliferation
    • cause excessive collagen deposition
  • If offending material cannot be removed or is toxic to macrophages, macrophage enzymes released into the tissues leading to excessive damage
23
Q

Granulomas

A
  • If macrophage unable to clear pathogen then T-cells release IFN-γ which stimulate macrophage to become epitheloid cell or giant cell
  • T-cells form a barrier around the outside of macrophages to form granuloma.
  • If T-cell function drops then granulomas fail and pathogens may re-emerge.
24
Q

Hematopoiesis

Characteristics

A

The continual process by which blood cells grow, divide, and differentiate.

Goal to generate sufficient cell numbers for the body while maintaining survival of progenitor cells.

All cells from a pluripotential hematopoietic stem cell:

  • undergoes proliferation and differentiation
  • eventually results in decreased or loss of proliferative ability
25
Q

Sites of Hematopoiesis

A
  1. Yolk sac
    • First few weeks of gestation
  2. Fetal liver & spleen
  3. Bone marrow
    • Site of hematopoiesis in humans by birth
    • Axial skeleton in adults
      • Pelvis
      • Sternum
      • Skull
    • Can be pushed back to liver with pathology
26
Q

Pluripotential Hematopoietic

Stem Cells

A
  • CD34+
  • self-renewing
  • can be isolated from:
    • bone marrow
    • umbilical cord blood
    • human peripheral blood
27
Q

Bone Marrow Stroma

A
  • Provides nurturing enviroment
  • Impacts hematopoietic cell development via:
    • cell-cell contact
    • cell-bound cytokines & hormonal factors
      • Ex. stem cell factor
    • diffusible factors
28
Q

Hematopoietic Cell Growth Factors

(HCGFs)

A

Commonly termed colony-stimulating factors (CSF).

Secreted by bone marrow stromal cells, macrophages, T-cells, and many other cell types.

Early

Proliferation and differentiation of primitive hematopoietic cells requires multiple cytokines:

stem cell factor (SCF)

IL-3 (multi-SCF)

Intermediate:

As cells differentiate cytokine receptors change.

Type of receptor determines path.

GM-CSF → myelocytes

IL-7 → lymphocytes

Late:

Some cytokines act on committed cells and induce a single linage.

G-CSF → neutrophils

IL-5 → eosinophils

M-CSF → monocytes/macrophages

IL-4 → basophils

erythropoietin (EPO) → RBC

29
Q

Clinical Cytokines

A
  • EPO used in anemia
  • G-CSF, GM-CSF, IL-3, and M-CSF used in congenital and acquired neutropenias
  • G-CSF and GM-CSF used to increase mobilization of hematopoietic progenitor cells into peripheral blood prior to collection
30
Q

Erythrocyte Sedimentation Rate

(ESR)

A

Nonspecific test used as an indicator of inflammation and active disease.

  • Reflects tendency of RBC to settle more rapidly in some disease states
  • Sensitive but nonspecific test
  • Causes of elevated ESR
    • infection and inflammation
    • monoclonal gammopathy
    • pregnany
    • malignancies
    • autoimmune diseases
    • rheumatic heart disease
    • HIV
  • Uses
    • screening tool to aid in decision for further tests
    • follow course of disease state
    • monotring for a relapse of malignancies