Inflammation and Repair Flashcards
Inflammation is
a protective reaction of a living tissue to injury.
Eg. of delayed prolonged inflammatory reaction:
Sunburn
Inflammation steps: (5)
- recognition of the injurious agent
- recruitment of leukocytes
- removal of the agent
- regulation (control) of the response
- resolution (repair)
Acute inflammation had 2 majors components:
- Vascular change
2. Cellular events
Vascular change during Acute inflammation:
- Vasodilatation (increase blood flow)
- Increase vascular permeability (plasma proteins leave the circulation)
- Endothelial cell activated (increase adhesion and migration of leukocyte)
Cellular events during Acute inflammation:
- Emigration of the leukocytes from the circulation
- Cellular recruitment (accumulation in the focus of the injury)
- Activation of the leukocytes
Principal leukocytes in acute inflammation:
Neutrophils
When there is decrease osmotic pressure and increase hydrostatic pressure, the fluid leak out and is picked up by the lymphatics. This fluid is call:
Transudate (low proteins content, bc normally, capillaries are not permeable to proteins)
High protein fluid is call:
Exudate
Exudate (high protein fluid) change the balance of osmotic forces due to:
the increase of permeability when inflammation occurs, allows some proteins to escape on the venous side.
Recognition of Microbes, Necrotic cells and foreign substances (distinguish the danger from normal tissues) is done by
Receptor called ‘‘pattern recognition receptors’’ express on the surface of phagocytes, dendritic cells and epithelial cells.
2 most important families of Pattern recognition receptors are:
- Toll-like receptors (TLRs) located in plasma membranes and endosomes
- Inflammasome (detects products from death cells/bacteria)
The Increased vascular permeability is induced by
- Histamine, kinins and other mediators causing gaps between endothelial cells;
- By direct or leukocyte-induced endothelial injury;
- by increase passage of fluids through the endothelium
Endothelial cell contraction leading to intercellular gaps in postcapillary venules is due to:
- histamine, bradykinin and leukotrienes binding to endothelial cell.
- Cytokines (eg. Tumor necrosis factor - TNF) and inter-leukin-1 - IL-1 changing the cytoskeleton.
The sequence of events in the recruitment of leukocytes from the vascular lumen to the extravascular space consists of 4 steps:
- Margination and Rolling along the vessel wall
- Firm adhesion to the endothelium
- Transmigration between endothelial cells
- Migration in interstitial tissues toward a chemotactic stimulus.
WBCs float near the lumen wall doe to:
Laminar flow
RBCs float toward the middle of the lumen because:
they are smaller
During Step 1, Margination and Rolling steps of the recruitment of leukocytes, leukocytes come into contact with the endothelial cells of the capillary walls due to:
Chemoattractants cytokines –> Selectins and CAMs (cellular adhesion molecules) on the endothelial cell surface interact with ligands on the surface of leukocytes.
On the surface of most leukocytes, we can found:
- L-Selectin
2. Sialyl-Lewis X - modified proteins
During step 2, firm Adhesion to the endothelium is due to:
Integrins expressed on leukocytes cells surface interacting with their ligands on the endothelial cell causing adhesion. Increase their ability to bind by changing Integrin affinity and expression of integrin in the surface.
Integrins properties:
Normally expressed on leukocyte plasma membranes in a LOW-AFFINITY FORM and do not adhere until leukocyte are activated by chemotaxis.
'’Endothelial activation’’ during marginalization and rolling steps is due to
Cytokines
Cytokine-stimulated net result is:
Increase Integrin affinity and Increase Expression of integrin ligands to stable attachment of leukocytes to endothelial cells at sites of inflammation.
Transmigration step is due to:
Platelet endothelial cell adhesion molecule-1 (PECAM-1) or (CD31), mediates the binding events needed for leukocytes to traverse the endothelium.
After the leukocyte traverse the endothelium, getting through the vascular basement membrane is due to
Leukocytes secreting collagenases.
After extravasating from the blood, leukocytes move toward sites of infection or injury along a chemical gradient by a process called:
Chemotaxis (follow the concentration gradient from low to high concentration, where the concentration of chemokines is highest–> site of injury)
How is the bone marrow is involve during inflammation?
During inflammation, it requires a large immune response, your bone marrow will respond by making more of the immune cells.
Neutrophils caracteristics:
- Full of granules that contain lysosomal enzymes
- Fight microorganism very effectively due to these enzymes
- Phagocytose and release inflammatory mediators.
Monocyte/macrophage caracteristics:
- Phagocytose and release inflammatory mediators
- initiate the immune response
- Clean up the dead and injured cells/bacteria.
Eosinophils caracteristics:
-involve in reaction with parasites
Lymphocytes caracteristics:
-Involve in immune reaction (B and T cells)
Macrophage precursor:
Precursor are found in the bone marrow, sent into blood as monocytes, change their properties for macrophage or others cells (eg. dendritic cells)
Macrophage Activation by:
Cytokine release by T cells, Natural Killer (NK) cells or Toll-like receptors (TLR).
Action of neutrophils is followed by:
The action of monocytes/macrophages.
Phagocytosis consists on three steps:
- Recognition and attachment of the particle to the ingesting leukocyte (microbes bind to phagocytic receptor)
- Engulfment, with subsequent formation of a phagocytic vacuole
- Killing and degradation of the ingested material.
How is the pathogen are recognized?
Pathogen are marked with complement and antibodies (eg. IgG) called OPSONINS, the coat microbes. Macrophages identify it and target them for phagocytosis.
Opsonization is:
The process of detecting and destroying the pathogens by phagocytosis.
How is the engulfement is possible?
Pseudopods (neutrophils) are extended around it and forming a phagocytic vacuole. The membrane of the vacuole fuses with the membrane of a lysosomal granule (enzyme and free radical), resulting in a discharge of the granule’s contents into the phagolysosome.
During the killing and degradation phase of phagocytosis:
The microbe is now in the phagolysosome, lysosomal enzyme and free radicals are killing the microbe (ROS and NO)
Neutrophil extracellular traps (NETs):
Self-destruct neutrophils, creating sticky, net-like substance that traps pathogen.
Mast cell role in inflammation
Mast cell surround the microcirculation and release of mediator –> histamine. Histamine increase the permeability.
2 majors sources of mediators of inflammation:
- cell-derived
2. Plasma protein-derived
Vasoactive mediators:
Histamine, serotonin, others vasoactive amines
Histamine is founded in:
Mast cell
Serotonin is founded in:
Platelets
The main effect of vasoactive mediators:
Vasodilatation and increases vascular permeability
Arachidonic Acid metabolites:
Prostaglandins, leukotrienes and lipoxins.
The whole Complement cascade roles:
- Lysis of bacteria (cause their destruction)
- Chemotaxis (bring others cells like neutrophils and macrophages)
- Opsonization (make microbes recognizable by phagocytic cells for destruction)
C3b:
opsonin (phagocytosis)
C5a and C3a:
vascular effect, increase vascular permeability.
C1 characteristics:
Bigger molecule with many petals
When is the C1 is activated?
When 2 IgG attached to a cell membrane side-by-side, this triggers the activation of C1 and the rest of the complement.
Plasma proteases is:
Compounds circulating in the plasma that can go to the site.
Plasma proteases included:
- Complement
- Clotting system
- Kinin system
C5a:
Chemoattractant (chemokine) Chemotaxis
C5-C9 sequentially:
Membrane Attack Complex (MAC)
The clotting system
The proteolytic cascade leads to activation of thrombin.
Kinin system role:
Mediator of pain. Bradykinin is activated to mediate vascular reaction and pain.
What is released at the site of injury to stimulate pain and vasodilatation?
Bradykinin, prostaglandins, and histamine.
Formation of Prostaglandins and Leukotrienes:
Activation of phospholipase A-2 –> Arachidonic acid (1.Cyclooxygenases)(2.5-Lipoxygenase) –> 1.Prostaglandins 2.Leukotrienes.
Eg. of Cytokines:
Interleukins (ILs)
Tumor Growth Factors (TGFs)
Tumor necrosis factors (TNFs)
Cytokines help orchestrate systemic effects of inflammation by: (Systemic protective reaction)
- Talk to other parts (brain, bone marrow, and liver)
1. Telling the regulatory center in the brain to increase body temperature (fever)
2. Signaling the liver to release various proteins (Production of acute-phase proteins) for the initial stage of inflammation (Mannose,CRP, fibrinogen..)
3. Signaling the bone marrow, so it will release more neutrophils and macrophages. (Leukocytosis)
Effect of the platelets activator factor (PAF)
Promote the function of neutrophils and monocytes, platelet aggregation, and vasoactive (dilatation and permeability)
Platelets main roles in inflammatory response:
Contain a lot of preformed mediators (Serotonin, TXB2, chemotaxis, growth factors..) and release a lot of inflammatory mediators when needed.
Major role in chronic inflammatory reactions:
Macrophages and lymphocytes.
Role of Macrophages during chronic inflammatory reactions:
Depend on the cytokines, monocytes is activated to form Classically activated macrophages (M1) –> attack bacteria and fungi or Alternatively activated macrophages (M2) –> Tissue Repair.
Powerfull circle of communication between:
Macrophages and lynphocytes. One activation will release more inflammatory mediators for activation of the others….
Granuloma is:
Form after long-standing inflammation. Contain a lot of macrophages surrounded by T-cells. (Increase macrophages by recruitment, division and survival.
Differents patterns of inflammation:
Serous inflammation (no fibrin–> no scare)
Fibrinous inflammation (involve the deposition of fibrin)
Abcess
Ulcer
Membranous inflammation
Three types of cell and their regeneration:
- Labile cells: continuously dividing.
- Stable cells: Capable to proliferated in response to an injury
- Permanent cells: Cannot dividing if damage. (eg. neuron–> Schwann cells)
When only a few motor cells are injure, it can regenerate and replace the non-functionnal neuron by:
Increase the innervation of the neighborhood neurons and send out branches to innervate the surrounding cells.
Angiogenic role of macrophages:
Stimulating process of new blood vessels
Fibrinogenic role of macrophages:
Production of scare tissue
Angiogenesis:
Due to Proteolysis of extracellular matrix (ECM) –> Process of Blood vessels formation.
Extracellular matrix (ECM) formation:
Fibroblasts formation and proliferation –> deposite of collagen. Can become contractile, myofibroblasts (decrease scar size)
Wound of primary intention vs secondary intention:
2e intention have bigger wound/bigger scar.
Keloids:
even small wound, big scar.
