Inflammation and Wound Healing
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Cardinal signs of inflammation by Celsus?
- Rubor: red
- Tumor: swelling
- Calor: Heat
- Dolor: Pain
- Functio Laesa: loss of function
Acute inflammation is characterized by what cells?
Plasma proteins, leukocytes (neutrophils)
Chronic inflammation is characterized by which cells?
Lymphocytes, macrophages, fibrosis, tissue necrosis
Three major components of acute inflammation?
- 1. Vasodilation
- 2. Endothelial cell contraction
- 3. Emigration of leukocytes to site of injury
When do neutrophils assume a peripheral orientation (margination) along endothelium?
In acute inflammation during the stasis of blood flow due to inc concentration of RBCs
What is the hallmark of acute inflammation?
Exudate: protein rich fluid in to intersititium
The most common mechanism of vascular leakage?
formation of gaps in endothelium in VENULES!!
reversible and short lived (15-30mins)
Histamine, Bradykinin, Leukotrienes, subst P
endothelial cell contraction
Endothelial cell retraction is caused by? (Different than contraction)
Cellular reorganization (delayed response and lasts longer that cell contraction)
induced by IL-1, TNF, INF-gamma, hypoxia, sublethal injury to cells
Mostly venules, but also capillaries.
Direct endothelial injury?
Another form of vascular leakage, immediate and sustained. Affects all levels of vasculature.
Another mechanism of endothelial leakage (mostly venules)
Vesiculovascular organelles are used near the intercellular junctions
Leukocyte-Mediated Endothelial Injury?
Another mech for endotehlial cell leakage (mostly venules)
Neutrophils attempt to engulf endothelial cells but cannot and release ROIs that irreversibly injure cell
Caused by immune complex adherence to the endothelial cells (Igm and Igg)
Sequence of events of leukocyte extravasation?
- 1. Margination
- 2. Rolling
- 3. Adhesion
- 4. Diapedesis
What mediators play a role in endothelial activation?
Selectins E and P (inc expression)
What mediators play a role in rolling of leukocytes?
Initial rapid loose adhesion, selectins binding to Sialyl Lewis X ligand (carbohydrate)
What mediators play a role in leukocyte adhesion?
Chemokines activate LFA-1 (conformational change) which now binds to ICAM on endothelial cells
What mediators play a role in leukocyte transmigration?
Endothelial cells have ICAM and PECAM (both cells) binding to LFA-1
Collagenases are used to break down BM
Neutrophils are involved in acute inflammaiton for the first 6-24 hours and then monotcytes replace from 24-48 hours
Examples of exogenous chemoattractants?
bacterial peptides with N-formyl methionine, lipids
Examples of endogenous chemoattractants?
Complement components (C5a), leukotrienes, cytokines
Phagocytosis and the three distinct steps?
- 1. Recognition of particle to be ingested
- 2. Engulfmenet into a vacuole
- 3. Killing followed by degradation
What are the macrophages recognizing for attachment in phagocytosis?
Mannose carbs, LPS, have receptors for opsonins like C3b, C3Bi, C1q, Fc portion of IgG and IgM when bound
Describe the killing and degradation process of phagocytosis?
Activation of NADPH oxidase converts oxygen to superoxide anion converted to hydrogen peroxide (MPO) in prescense of Cl converts to HOCL.
Lactoferrin is an oxygen independent pathway for killing.
How are the inflammation and kinin system connected?
Kallikrein makes Bradykinin that leads to vasodilation, vascular permeability, smooth muscle contraction
Kallijrein has chemotactic activity and converts c5 to c5a an opsonin
Inflammation and the clotting system relation?
Hageman factor begins the clotting cascade.
Thrombin causes leukocyte adhesion, fibrblast prolif
Factor XIIa inc vascular permeability and leukocyte extravasation
Il-1 and TNF cause acute phase reactions in inflammation like?
Fever, inc sleep, dec appetite, inc acute-phase proteins, shock, neutrophilia
How is NO made?
Regularly by eNOS requiring inc of calcium in cell
Can be induced (iNOS) in activated macrophages by TNF-alpha and INF-gamma (no Ca required)
Functions of NO?
- 1. vasodilator (potent)
- 2. dec platelet aggregation
- 3. block neutrophil rolling and adhesion on venules
- 4. reduces neutrophil recruitment
- 5. antimicrobial producing different ROIs
When does connective tissue replacement commonly occur in acute inflammation?
In pyogenic infections
Some predisposing factors for chronic inflammation?
- 1. persistent infecitons
- 2. prolonged exposure to exo or endogenous toxic agents
- 3. autoimmunity
Repair in chronic inflammation is caused by?
Angiogenesis and fibrosis
What is the half life of a monocyte?
1 day compared to
activated macrophages that life months to years
What mediators activate macrophages?
IFN-gamma secreted by T cells and NK cells
Macrophages can proliferate locally....
in atheromatous plaques
What mediators promote lymphocyte recruitment?
IL-1, IFN, and chemokines
Granulamotous inflammation consists of?
macrophages transformed into epithelium like cells, surrounded by a collar of lymphocytes and plasma cells
Two types of granulomas:
- 1. Foreign body
- 2. Immune: TB
Epithelioid cells fuse to form?
Giant cells (20 or more small nuclei)
If peripherally arragned: Langhans-type giant cell
If haphazardly placed: Foreign body-type giant cells
True or false, foreign body granuloma have specific immune response?
What do pyrogens do?
Increase temp (acute phase) LPS stimulates Il-1 and TNF release upregulating COX which increases prostaglandins.
PGE2 stim cAMP in hypothalamus reseting temp set point
leads to heat shock proteins which enhance lymphocyte response to antigens
What are some acute phase proteins?
C reactive protein, fibrinogen, serum amyloid protein A
CRP and fibrinogen induced by IL-6
SAA induced by IL-1 and TNF
What is the role of acute phase proteins?
Act as opsonins
Bind to chromatin to clear necrotic nuclei
Inc fibrinogen causes rouleaux in erythrocytes (stacking due to discoid shape)
Long term effects of acute phase proteins?
SAA causes amyloidosis
CRP sustained inc causes MI
What causes DIC?
High levels of LPS and subsequent levels of IL-1 and TNF.
TNF and LPS combo induce TF expression which intiates coagulation
this also inhibits tissue factor pathway inhibitor
How do we have cardiac failure in inflammation?
Too much inflammatory mediators cause inc NO production leads to loss of perfusion pressure resulting in heodynamic shock
How do inflammatory cytokines affect glucose levels in blood?
impair function of liver to move glycogen ro glucose, impaired gluconeogenesis
What causes SEPSIS or septic shock?
Triad: DIC, hypoglycemia, and cardiac failure
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