-
Platelet contents
- Integrin membrane receptors, p-selectin
- arachidonic acid (Thromboxane A2)
- alpha granules
- electron dense bodies
-
Alpha granules in platelets (7)
- fibrinogen
- fibronectin
- factor V
- factor VIII
- thrombospondin
- PDGF
- TGF-B
-
Electron dense bodies in platelets (5)
- ADP
- Ca2+
- Histamine
- serotonin
- epinephrine
-
Platelet Aggregators (6)
- ADP and Thromboxane A2
- Thrombin
- Collagen
- Epinephrine
- Immune complexes
- platelet activating factor
-
Platelet adhesion steps
- von Willebrand's factor binds subendothelial collagen
- platelets bind von Willebrand's factor via gpIb surface integrins
-
Promote platelet aggregation producing primary hemostatic plug
ADP and Thromboxane A2
-
Promotes further platelet aggregation and polymerizes fibrin
Thrombin
-
This links platelets with adjacent platelets during aggregation
Fibrinogen binding
-
Endothelial pro-coagulant factors (5)
- von Willebrand's factor - synthesize it
- Tissue factor - express in response to cytokines and endotoxin
- binding sites for activated clotting factors
- platelet activating factor
- tissue type plasminogen activating factor - inhibits fibrinolysis
-
Endothelial cell anti-coagulant factors
- cover thrombogenic subendothelial collagen
- NO & PGI2 - inhibit platelet aggregation
- Antithrombins
- plasminogen inhibitors (and activators)
-
Blood anticoagulant factors
- Antithrombins
- Proteins C & S
-
Processes of thrombosis inhibition (3)
- Heparin-like surface molecules activate antithrombin - thrombin inactivated
- Thrombomodulin binds thrombin and activates proteins C & S - cleave factors V & VIII
- NO & PFI2 inhibit platelet aggregation
-
Where is plasminogen located?
Plasma and platelet membranes
-
Steps of plasminogen-plasmin system (3)
- Plasminogen binds fibrin
- cleaved by plasminogen activators to form plasmin
- plasmin digests polymerized fibrin
-
Plasminogen activators (2)
- tissue type plasminogen activator (endothelial cells)
- urokinase like plasminogen activator (plasma)
-
Released during arteriolar constriction
epinephrine
-
causes vasodilation of venules
histamine
-
Relaxes vascular smooth muscle
-
Chemical mediators of vascular permeability (6)
- vasoactive amines (5-HT, serotonin, histamine)
- kinins
- complement
- arachidonic acid mediators (prostaglandins)
- cytokines
- platelet activating factor
-
Inflammatory exudate that is thin and watery
serous
-
inflammatory exudate containing mucus
catarrhal
-
exudate containing abundant fibrin
fibrinous
-
Sequence of WBC Emigration
- Neutrophils within 1 hr
- Macrophages after 12 - 48 hrs
- Lymphocytes - slow to enter
-
Suppurative inflammation is dominated by
neutrophils
-
purulent inflammation of connective tissues
cellulitis
-
fluctuant pocket of pus in subcutis
phlegmon
-
purulent inflammation of fascia
fasciitis
-
local collection of pus
abscess
-
accumulation of pus in body cavity
empyema
-
How long do neutrophils last in the circulation?
8 hrs
-
First line of defense
neutrophils
-
Neutrophils have what kind of metabolism
glycolytic (anaerobic)
-
Neutrophils release (3)
- enzymes
- antimicrobial molecules
- pro-inflammatory mediators
-
Neutrophil granule contents (among others) (13)
- cd18/11b - integrin adhesion molecule
- complement receptor 1
- CD14 (endotoxin receptor)
- Gelatinase
- cytochrome B
- lysozyme
- collagenase
- elastase
- lactoferrin
- myeloperoxidase
- defensins
- acid hydrolases
- cathepsins
-
4 main types of proteases
- Serine
- Metallo-
- Cysteine
- Aspartic
-
Protease important in wound healing and cancer metastasis
Metallo
-
Inhibits all 4 protease classes
Alpha 2 macroglobulin
-
Inhibit serine proteases
serpins
-
antiplasmin, plasminogen activator inhibitor, antithrombin III are examples of
serpins
-
TIMPs stands for
Tissue inhibitors of matrix metalloproteinases
-
Avian, reptile and rabbit equivalent of the neutrophil
heterophils
-
Eosinophilic inflammation occurs when?
- allergic/hypersensitivity reactions
- fungal infections
- parasitic infections
-
Eosinophil granules do what?
inactivate mast cell derived mediators
-
Eosinophil granules contain (3)
- major basic protein
- arylsulfatase
- enzymes
-
Mast cell granules stain metachromatically with
toluidine blue
-
Mast cell granules contain
- histamine
- proteolytic enzymes
- anticoagulants (heparin & chondroitin sulfate)
- chemotactic factors for EOS & Neutrophils
-
These are the circulating counterpart of mast cells (only in blood)
basophils
-
Types of mature monocytes (6)
- alveolar
- pulmonary intravascular
- microglia
- kuppfer
- epithelioid
- multinucleate giant cell
-
Macrophage metabolism
oxidative respiration (cannot function in dead tissue)
-
Monocytes/Macrophages produce (6)
- Lysosomal proteases & hydrolases
- reactive oxygen species
- complement components
- arachidonic acid mediators
- cytokines
- growth factors
-
Chronic inflammatory process with immune component
lymphocytic inflammation
-
These mediate vascular changes in inflammation
platelets
-
Platelets secrete (5)
- histamine
- thromboxane A2
- p-selectin
- growth factors
- enzymes
-
Endothelial cells & fibroblasts secrete
- cytokines
- growth factors
- proteases
-
Fibroblasts secrete
ECM components
-
What cells regulate clotting?
endothelial cells
-
Major players in inflammation
- Platelets
- endothelial cells
- fibroblasts
- neutrophils, monocytes/macrophages, mast cells, etc.
-
Sequence of events in leukocyte efflux from vasculature (5)
- Margination - slow blood flow
- Rolling - selectins
- Adhesion & Pavementing
- Transmigration - integrins
- Migration in tissue - integrins/chemotaxins
-
These are involved in recirculation of lymphocytes to lymphnodes
Addressins
-
Chemotactic molecules (5)
- c5a
- bacterial products
- leukotrienes
- fibrin degredation products
- WBC products (IL-8)
-
Phagocytic events (4)
- opsonization
- attachment
- ingestion
- killing & degradation
-
These coat particles to be opsonized (4)
- C3b
- Immunoglobulin (antibodies)
- lysozyme
- fibronectin
-
hernia in non-natural opening
eventration
-
Steps in Killing/Digestion during phagocytosis
- phagosome & lysosome fuse - degranulation
- phagolysosome becomes acidified
- respiratory burst
-
components of oxygen-independent killing of a microbe within a phagolysosome (6)
- Acidic phagolysosomal environment
- BPI - phospholipase activated membrane degradation Bactericidal permeability increasing molecule
- Defensins - cationic cytotoxic peptides
- Lysozyme - hydrolyzes bacterial coat
- Lactoferrin - sequesters iron
- Nramp-1 – Pumps Fe out of the phagosome
-
The first step in Oxygen-dependent killing of a microbe in a phagolysosome
NADPH oxidase reduces oxygen to superoxide
-
After the superoxide is formed within the phagolysosome, subsequent reactions form these oxygen based radicals (4)
- hydrogen peroxide
- hydroxyl radical
- singlet oxygen
- secondary reactive nitrogen oxides
-
Myeloperoxidase-halide system forms
hypohalous acids
-
Myeloperoxidase-independent systems rely on
oxygen based radicals
-
Neutrophil-mediated tissue damage is caused by (3)
- lysosomal suicide
- frustrated phagocytosis
- regurgitation while feeding
-
Example of frustrated phagocytosis of neutrophils
degranulation against immune complex deposited in glomerular basement membrane
-
Regurgitation while feeding is a result of what
asynchronous phagolysosome fusion
-
Hallmark of chronic inflammation is
neovascularization & fibrosis with macrophages
-
Macrophage accumulation during chronic inflammation is due to
- continued recruitment
- local proliferation (mitosis in tissues)
- immobilization at site
-
Macrophages are continually recruited during chronic inflammation by (4)
- C5a
- chemokines
- growth factors
- fibrin degradation products
-
Immobilization of macrophages is done by what factor?
Migration Inhibition Factor
-
A granuloma consists of
- epithelioid macrophages
- lymphoid cells
- peripheral fibrosis
-
Two types of granulomas
- foreign body
- immune granuloma
-
Two mechanisms of healing and repair
- parenchymal regeneration
- replacement by fibrous tissue
-
Fibrosis occurs when (3)
- stromal framework destroyed
- permanent cell population destroyed
- exudate cannot be reabsorbed
-
Two factors affecting healing
- stromal integrity
- regenerative capacity of tissue
-
Populations of cells that are constantly being replaced are called
labile
-
Populations of cells that undergo mitosis are called
stable
-
Growth factors involved in wound healing (6)
- epidermal
- Platelet derived
- transforming
- fibroblast
- macrophage-derived -wound contraction
- Vascular endothelial GF - angiogenic
-
Three phases of granulation tissue formation
- Inflammatory phase
- Proliferative phase
- remodeling phase
-
Cells of granulation tissue (3)
- macrophages
- fibroblasts
- endothelial cells
-
What do macrophages do in granulation tissue?
- remove exudate
- secrete fibrogenic & angiogenic factors
-
Zones of granulation tissue (4) and features of each
- Zone of necrotic debris - fibrin, neutrophils, blood clots
- Zone of capillary sprouts + arches - macrophages
- Zone of capillary proliferation - proliferating towards surface, fibroblasts
- Zone of Mature connective tissue - fibroblasts
-
Phases of wound healing (6)
- 1. Inflammation
- 2. Cell migration
- 3. Matrix deposition
- 4. Vascular proliferation
- 5. Collagen synthesis
- 6. Remodeling
-
Adverse outcomes of healing (5)
- Adhesion
- Ankylosis
- Stricture
- contracture
- critical tissue replaced by scar tissue
-
Reduction of lumen size during healing is called
stricture
-
Fixation of a joint during healing
ankylosis
-
A fibrous adhesion is composed of
- collagen
- fibroblasts
- blood vessels
-
These adhesions can be broken
fibrinous adhesions
-
Plasma derived mediators of inflammation (3)
- Hageman Factor - clotting factor
- Complement components
- Kininogens - become kinins and increase vascular permeability
-
Activated in first step of intrinsic coagulation cascade by negatively charged surfaces
Hageman factor
-
Hageman factor initiates generation of these 4 processes
- Clotting
- fibrinolysis
- kinin generation
- complement cascade
-
Actions of kinins
- vasodilation
- increased vascular permeability
- pain
-
Cell-derived mediators of inflammation
- Histamine & serotonin (preformed)
- Arachidonic acid derivatives (newly synthesized)
-
Histamine and Serotonin are stored in granules of these cells (3)
- mast cells
- basophils
- platelets
-
Arachidonic acid is formed by
phospholipases acting on cell membranes
-
Arachidonic acid can be converted into (2)
- Cyclooxygenase
- Lipoxygenase
-
This form of cyclooxygenase is constitutively expressed
Cox 1
-
Steroids inhibit
phospholipase
-
What does Prostacyclin do?
- vasodilation
- inhibits platelet aggregation
-
What does Thromboxane A2 do?
- causes vasoconstriction
- promotes platelet aggregation
-
Cyclooxygenase products (3)
- Prostacyclin
- Thromboxane A2
- Prostaglandins (vasodilation)
-
Lipoxin formation requires
contact between pmn & platelet in presence of a clot
-
Lipoxins resolve injury and promote healing by (2)
- decreasing pmn adhesion & chemotaxis
- promote monocyte adhesion
-
lipid, derived from most inflammatory cells, produces all cardinal signs of inflammation
Platelet Activating Factor
-
Reactive Oxygen Species is produced by
activated phagocytes
-
What does ROS do? (3)
- Damage
- activates neutrophils
- increases vascular permeablility
-
Cytokine classes (5)
- regulate lymphocytes
- natural immunity
- activate inflammatory cells
- stimulate hematopoiesis
- chemokines
-
Chemokine really important for recruiting neutrophils
IL-8
-
Causal classifications of Shock
- Hypovolemic
- Neurogenic
- Cardiogenic
- septic
-
Phases of shock
- 1. Nonprogressive
- 2. Reversible
- 3. Irreversible
-
What happens during the nonprogressive stage of shock
- baroreceptor reflexes
- catecholamine release
- RAAS
- ADH release
- Resulting in: tachycardia, peripheral vasoconstriction, decreased urine output
-
What happens in the reversible stage of shock
- Hypoxemia leads to acidosis which blunts vasomotor responses
- Arterioles dilate, blood pools in microcirculation resulting in worsened hypotension
- widespread cell injury and DIC
- Organs begin to fail, myocardial contractility decreases
- Confusion
-
Cytokine storms beginning with LPS binding
- LPS binds TLR
- TNF release
- IL-1 release
- Il-6/8 release
- NO, PAF release
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