Inflammation & Hematopoiesis Flashcards
Inflammation
Characteristics
Redness
Swelling
Heat
Pain
Loss of function
Factors Stimulating
Inflammation
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
Identifying Characteristics
of
Inflammatory Pathways
- Mechanism of induction
- Time course
- Types of cellular infiltrates
- Kind of inflammatory cells that enter the tissue
Inflammatory
Enzyme Cascades
- Coagulation system
- Fibrinolytic system
- Complement cascade
- Kinin system
- Lipid inflammatory mediators
- Arachidonic derivatives
Complement Role
in
Inflammatory Response
- Destruction of target membranes via MAC complex
- 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
- C5a > C3a
- Opsonization
- C3b on target binds complement receptors (CRs) on phagocytes
- Promote the clearance of immune complexes
- CR1 on RBC’s
- Reticuloendothelial system
Proinflammatory Cytokines
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
- Resident macrophages
- Induced by
- PAMPs
- DAMPs
- Tissue damage/stress
Proinflammatory Mediators
- Products of arachidonic pathway
- Products of clotting cascade
- Products of fibronolytic cascade
- Pro-inflammatory cytokines
Acute Inflammation
Local Actions
Proinflammatory Mediators
- Induce changes in blood flow and leukocyte flow patterns
- Larger vessels = slower flow
- Easier diapedesis
- Causes redness & warmth
- Larger vessels = slower flow
- 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
Acute Inflammation
Systemic Actions
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
- Caused by endogenous pyrogens
-
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
- Occurs when there is massive release of TNF-α, IL-1, and IL-6 induced by bacterial products
Neutrophil
Characteristics
(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
Steps of WBC Recruitment
- Activation of vascular endothelium
- Adherence
- Diapedesis
- The movement of the cell between the endothelial cell junctions into the tissues
- Chemotaxis
- the movement of the cell towards the “threat”
- travels along a chemotactic gradient
- C5a or IL-8
Activation of Vascular Endothelium
- 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
Neutrophil Recruitment
-
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
-
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
- Rolling allows WBC to “sample” its environment looking for chemoattractants
-
Firm adhesion & pavementing (flattening)
-
Integrin:ICAM interactions cause the cell to:
- stop rolling
- firmly adhere
- flatten
- Integrin = LFA-1
- ICAM = intercellular adhesion molecule
-
Integrin:ICAM interactions cause the cell to:
Secondary Capture
Another method of neutrophil recruitment.
- PSGL-1 on free flowing neutrophils can bind to P-selectins presented on adherent platelets
- L-selectin on free flowing neutrophils can interact with PSGL-1 presented by adherent leukocytes or leukocyte-derived fragments
Neutrophil Receptors
Neutrophils express > 40 different receptor types:
-
Fc receptors (FcR)
- allows the cell to bind the Fc region of an Ab
- Complement receptors (CR1 and CR3)
-
Collectin Receptors
- Allows cell to bind acute phase proteins
- MBP & CRP
- Allows cell to bind acute phase proteins
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)
Granulomas
- 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.
Hematopoiesis
Characteristics
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
Sites of Hematopoiesis
- Yolk sac
- First few weeks of gestation
- Fetal liver & spleen
- Bone marrow
- Site of hematopoiesis in humans by birth
- Axial skeleton in adults
- Pelvis
- Sternum
- Skull
- Can be pushed back to liver with pathology
Hematopoietic Cell Growth Factors
(HCGFs)
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
