-
Inflammation phases:
- Injury-
- leads to exposed collagen, platelet-activating factor release, tissue factor release from endothelium.
- Platelets bind-
- release important growth factors (platelet-derived growth factor PDGF) and cytokines (IL-1 and TNF-alpha)
- Macrophages-
- dominant role in wound healing, release important growth factors (PDGF) and cytokines (IL-1 and TNF-alpha)
-
See image on pg 60 (and commentary below)
Establishment of a provisional wound matrix:
- 1) platelets bind to the exposed wound matrix through interaction of beta-1 and beta-3 integrins and collagen, laminin, and fibronectin receptors
- 2) after wounding, the coagulation cascade is activated, generating thrombin, which activates platelet glycoprotein gpIIb/IIIa and increases platelet aggregation.
- 3) A provisional wound matrix is formed, made up of platelets, fibrin, fibrinogen, and fibronectin. The activated platelets in the wound generate transforming growth factor beta (TGF-beta), PDGF, and thrombin.
- 4) TGF-beta is strongly chemotactic for neutrophils, macrophages, and fibrobrasts, recruiting these cells into the provisional wound matrix, where they are also subsequently activated by TGF-beta.
- 5) Increasting concentrations of TGF-beta results in macrophage activation, producing increased amounts of tumor necrosis factor-alpha (TGF-alpha) and interleukin-1 (IL-1). TGF-beta also stimulates fibroblast production of extracellular matrix proteins. These reactions further enhance migration of macrophages and fibroblasts into the wound, facilitating repair.
-
Growth and Activating Factors (on following slides)
-
PDGF
- 1) similar effects as TGF-beta
- 2) chemotactic and activates inflammatory cells (PMN and macrophages)
- 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
- 4) angiogenesis
- 5) epithelialization
- 6) chemotactic for smooth muscle cells
- 7) has been shown to accelerate wound healing
-
EGF (epidermal growth factor)
- 1) acts on similar receptors as TGF-beta
- 2) less potent
- 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
- 4) angiogenesis- V-EGF stimulates angiogenesis and is involved in tumor metastasis
- 5) epithelialization
-
FGF (fibroblast growth factor)
- 1) chemotactic and activates fibroblasts --> collagen and ECM proteins
- 2) angiogenesis
- 3) epithelialization
-
PAF (platelet-activating factor)
- 1) not stored
- 2) generated by phospholipase in endothelium and other cells
- 3) stimulates many types of inflammatory cells chemotactic; increases adhesion molecules
-
Chemotactic factors:
For inflammatory cells:
For fibroblasts:
- For inflammatory cells:
- 1- TGF-beta
- 2- PDGF
- 3- PAF
- 4- IL-8
- 5- LTB-4
- 6- C5a and C3a
- For Fibroblasts:
- 1- TGF-beta
- 2- PDGF
- 3- EGF
- 4- FGF
-
Angiogenesis factors:
- 1) TGF-alpha
- 2) TGF-beta
- 3) EGF
- 4) FGF
- 5) IL-8
- 6) hypoxia
-
Epithelialization factors:
- 1) TGF-alpha
- 2) TGF-beta
- 3) EGF
- 4) FGF
- 5) PDGF
-
How long do PMNs stay in tissues? How long in blood?
last 1-2 days in tissues (7 days in blood)
-
How long do platelets last?
platelets last 7-10 days
-
Lymphocytes
1) involved in chronic inflammation (T cells) and antibody production (B-cells)
-
Cell Types in Type I hypersensitivity reactions: (following slides)
-
Eosinophils
- 1) have IgE receptors that bind to allergen
- 2) release major basic protein, which stimulates basophils and mast cells to release histamine
- 3) eosinophils increased in parasitic infections
-
Basophils
- 1) have IgE receptor
- 2) main source of histamine in blood
- 3) not found in tissues
-
Mast cells
- 1) primary cell type in type I hypersensitivity reactions2) main source of histamine in tissues other than stomach
-
Histamine
- 1) vasodilation
- 2) tissue edema
- 3) postcapillary leakage
- 4) primary effectors in type I hypersensitivity reactions (allergic reactions)
-
Bradykinin
- 1) vasodilation
- 2) increased permeability
- 3) pain
- 4) contraction of pulmonary arterioles
-
Angiotensin-converting enzyme (ACE)
inactivates bradykinin
-
Nitric Oxide
- 1) has arginine precursor
- 2) Activates guanylate cyclase and increases cGMP, resulting in vascular smooth muscle dilation
- 3) is also called endothelium-derived relaxing factor (EDRF)
-
Endothelin
vascular smooth muscle constriction
-
Important Cytokines (to follow)
-
What are the main initial cyokines involved in injury/infection:
TNF-alpha and IL-1
-
TNF-alpha (tumor necrosis factor-alpha)
- 1) macrophages- largest producers of TNF
- 2) increases adhesion molecules
- 3) overall, a procoagulant
- 4) causes cachexia in patients with cancer
- 5) activates neutrophils and macrophages--> more cytokine production, cell recruitment
- 6) can cause myocardial depression
- 7) fever, hypothermia, tachycardia, increased cardiac output, decreased SVRI --> high concentration can cause circulatory collapse and multisystem organ failure
-
IL-1
- 1) main source also macrophages
- 2) effects similar to TNF and synergizes TNF
- 3) Responsible for fever (PGE2 mediated in hypothalamus)
- 1- raises thermal set point, causing fever
- 2- NSAIDs- decrease fever, reducing PGE2 synthesis
- 4) alveolar macrophages- cause fever with atelectasis by releasing IL-1
- 5) IL-1 also increases IL-6 production
-
IL-6
- 1) increased hepatic acute phase proteins (C-reactive protein, amyloid A)
- 2) lymphocyte activation
-
Interferons
- 1) released by lymphocytes in response to viral infection or other stimulants
- 2) activate macrophages, natural killer cells, and cytotoxic T cells
- 3) inhibit viral replication
-
Hepatic acute phase response proteins
- 1) IL-6 is most postent stimulus
- 2) Increased:
- 1- C-reactive protein (an opsonin, activates complement)
- 2- amyloid A and P
- 3- fibrinogen
- 4- haptoglobin
- 5- ceruloplasmin
- 6- alpha-1 antitrypsin
- 7- alpha-1 antichymotrypsin
- 8- C3 (complement)
- 3) Decreased:
- 1- albumin
- 2- transferrin
-
Cell Adhesion Molecules (upcomming slides)
-
Selectins
L-selectins, located on leukocytes, bind to E- (endothelial) and P-(platelets) selectins; rolling adhesion
-
Beta-2 integrins -
Beta-2 integrins (CD11/18 molecules)- on leukocytes, bind ICAMS etc. anchoring adhesion
-
ICAM, VCAM, PECAM, ELCAM
on endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets. These are also involved in transendothelial migration
-
Image at bottom of pg 62: Leukocyte recruitement
- 1) circulating leukocytes express integrins in a low-affinity conformation
- 2) exposure to activated endothelium leads to rolling, which is mediated by L-selectin and P-selectin on the neutrophil and E-selectin on the endothelium
- 3) leukocye exposure to cytokines released by macrophages phagocytosing pathogens induces a high affinity integrin conformation. Tight leukocyte-endothelial adhesion involves integrin engagement with counter-ligand expressed on endothelium
- 4) subsequent exposure to chemokines leads to diapedesis, which is further mediated by the family of beta-1 and beta-2 integrins
-
Complement:
- Classic pathway (IgG or IgM)- antigen-antibody complex activates
- 1- factors C1, C2, and C4- foudn only in the classic pathway
- Alternative pathway- endotoxin, bacteria, other stimuli activate
- 1- factors B, D, and P (properdine) found only in the alternate pathway
C3- common to and is the convergence point for both pathways
Mg- required for both pathways
- Anaphylatoxins- C3a, C4a, C5a;
- 1- increases vascular permeability
- 2- smooth muscle contraction (bronchi)
- 3- activate mast cells and basophils
-
Image on pg 63: Complement pathways:
- Alternative pathway:
- 1) C3 is cleaved to C3b
- 2) C3b binds and cleaves B to Bb to form C3 convertase (C3bBb)
- 3) another C3b binds C3 convertase to form C5 convertase (C3bBbC3b)
- Classical pathway:
- 1) C1 binds immunoglobulin
- 2) C1 binds and cleaves C4 and C2 to C4b and C2a to form C3 convertase (C4b2a)
- 3) C4b2a binds another C3b to generate C5 convertase (C4b2aC3b)
- Late pathway:
- 1) C5 convertase cleaves C5 to form C5b, which integrates into the plasmalemma
- 2) C6-8 are recruited forming the C5b-8 complex
- 3) C5b-8 recruits numerous C9 subunits, which form a pore in the pathogen cell wall
-
Prostaglandins (following slides)
-
PGI2 and PGE2
- 1) vasodilation
- 2) bronchodilation
- 3) increased permeability
- 4) inhibit platelets
-
PGD2
- 1) vasocilation
- 2) bronchoconstriction
- 3) increased permeability
-
NSAIDS:
1) inhibit cyclooxygenase (reversible)
-
Aspirin
- 1) inhibits cyclooxygenase (irreversible)
- 2) inhibits platelet adhesion by decreasing TXA2
-
Steroids:
inhibit phospholipase, which converts phospholipids to arachidonic acid--> inhibits inflammation
-
Leukotrienes:
LTC4, LTD4, LTE4-
LTB4-
LTC4, LTD4, LTE4- slow reacting substances of anaphylaxis; bronchocontriction, vasoconstriction followed by increased permeability (wheal and flare)
LTB4- chemotactic
-
Picture on Pg 64: Eicosanoid production
-
Catecholamines (following slides)
-
When do catecholamines peak after injury?
24-48 hours
-
Where are norepinephrine and epinephrine released from?
1) norepinephrine released from sympathetic postganglionic neurons
2) epinephrine and norepinephrine released from adrenal medulla (neural response to injury)
-
Neuroendocrine responses to injury:
- Afferent nerves from site of injury stimulate:
- 1- CRF
- 2- ACTH
- 3- ADH
- 4- growth hormone
- 5- epinephrine
- 6- norepinephrine release
-
What role does thyroid hormone play in injury:
thyroid hormone does not play a major role in injury
-
CXC chemokines:
- 1) Chemotaxis, angiogenesis, wound healing
- 2) IL-8 and platelet factor 4 are CXC chemokines
- 3) C=cysteine X--> another amino acid
-
Pg 65 (see two figures): oxidants generated in inflammation and Cellular Defenses against antioxidants
-
What are the RBC antioxidant properties:
RBCs have some antioxidant properties (superoxide dismutase and catalase)
-
Reperfusion injury: whats the primary mediator?
PMNs are the primary mediator
-
Chronic granulomatous disease:
- 1) NADPH-oxidase system enzyme defect in PMNs
- 2) results in decreased superoxide radical (O2-) formation
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