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232 Cards in this Set
- Front
- Back
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most important vasoactive amine
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histamine
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where is histamine found?
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prefomed mediator in granules of mast cells, basophils and platelets
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effects of histamine
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arteriolar dilation (relaxation of smooth muscle)
increased vascular permeability, especially in venules (contraction of endothelial cells) |
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serotonin
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vasoactive amine
platelets are the main source (also enterochromaffin cells) vasoconstriction increased vascular permeability plately aggregation |
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platelet-activating factor (PAF)
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synthesized by activated PMNs, platelets, mast cells, basophils and endothelial cells
many potent pro-inflammatory and pro-coagulatory effects |
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effects of PAF
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on WBCs: chemotaxis, activation, oxidative burst
at LOW concentrations: vasodilation and increased venular permeability at HIGH concentrations: vasocontriction and bronchoconstriction platelet activation and aggregation |
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chemokines
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small proteins which attract WBCs to the site of inflamamtion, and lead to their activation
also involved in regultion of immune responses, hematopoiesis and angiogenesis produced by WBCs, tissue cells, endothelial cells at site of inflammation |
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alpha-chemokines
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C-X-C
act primarily on PMNs eg: IL-8 |
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beta chemokines (C-C)
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act primarily on monocytes, eosinophils, basophils and lymphocytes
eg: MCP-1 |
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C chemokines
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produced by T cells
targets lymphocytes eg: lymphotactin |
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C-XXX-C chemokine
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produced by activated endothelial cells
promotes adhesion and chemotaxis of monocytes and T cells |
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acute phase proteins (APPs)
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marked changes in concentration due to inflammatory response
many are synthesized in liver stimulated by IL-1, IL-6 and TNF |
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positive APPs
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show increase in plasma concnetration
C3, C4, CRP, fibrinogen, serum amyloid A |
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negative APPs
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show decrease in plasma concentration
albumin, transferrin, factor XII |
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clinical signs associated with APPs
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acute-phase responses:
fever, malaise, loss of appetitie, changes in HR and BP |
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Plasma proteins (Hageman factor-dependent pathways)
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tangled web of 4 plasma-derived protease cascades:
coagulation cascade fibrinolysis system (plasmin-mediated) complement cascade kinin system |
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coagulation cascade within Hageman factor dependent pathways
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leads to production of fibrin
thrombin - protease which cleaves soluble fibrinogen --> insoluble fibrin |
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thrombin's role in WBC recruitment
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binds to protease-activated receptors (PARs) on platelets, endothelial cells, smooth muscle cells, etc.
activation of these cells --> WBC recruitment |
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fibrinolysis
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plasmin: breakdown of fibrin helps to sustain exudation of WBCs and chemical mediators to tissue site of inflammation
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critical step of complement cascade
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cleavage of C3 is the critical step
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important complement componenets of inflammation
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C3a: anaphylatoxin - triggers histamine release from mast cells, basophils and platelets
C3b - opsonin - binds C3b receptors on phagocytes to enhance phagocytosis C5a - chemotaxin - attracts and activates WBCs C5bC6C7C8C9 - membrane attack complex (MAC) - cell lysis |
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kinin system
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group of polypeptides derived from plasma kininogens by enzymes called kallkdreins
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most important kinin
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bradykinin
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effects of bradykinin
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vasodilation (of venules) or vasoconstriction (smooth muscle contraction in arterioles)
smooth muscle contraction in bronchioles increased vascular permeability major mediator of pain response of acute inflammation |
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tachykinins
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vasoative neuropeptides, eg: substance P
produced by sensory afferent nerve fibers |
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arachidonic acid metabolites are derived from...
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membrane phospholipids
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derivation of arachnidionic acid metabolites from membrane phospholipids
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mb lipids rapidly rearranged when cells are injured or when mbs bind certain inflammatory mediators
phospholipases activated by binding of pro-inflammatory mediators to specific mb receptors arachidonic acid (20C FA) derived drom dietary lipids or linoleic acid |
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what "frees" arachidonic acid from its esterified state in membrane phospholipids?
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action of phospholipases
espcially PLA2 |
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which cells of the body produce arachidonic metabolites?
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all of them
types and amounts vary with cell type |
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eicosanoids
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arachidonic acid metabolites
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do eicosanoids affect normal processes as well as pathological processes?
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yes
why COX inhibitors have bad side effects |
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3 enzymes in cyclooxygenase pathway
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COX-1, -2, -3
thromboxane A2 prostaglandins (& prostacyclin) |
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COX-1
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consitutive (continuously expressed)
for day-to-day physiologic needs of cells (expressed in almost all tissues) especially important in hemostasis and protection of GI tract |
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COX-2
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produced primarily for "unusual" circumstances, like inflammation
induced by exogenous and endogenous inflammatory stimuli produced locally by WBCs, endothelial cells, fibroblasts |
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COX-3
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aka: COX-1b
produced constitutively in cerebral cortex acetaminophen shown to inhibit COX-3 in dogs (basis for pain relief?) |
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thromboxane A2
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produced primarily by platelets
pro-coagulatory effects (vasoconstriction, platelet activation) |
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prostacyclin
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PGI2
produced primarily by endothelial cells anti-coagulatory effects (vasodilation, inhibit platelet aggregation) |
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prostaglandinds
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PGD2, PGE2, PGF2
vasoconstriction or vasodilation (depending on metabolite and tissue site) increased vascular permeability pain (PGE2) |
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agens in lipoxyengase pathway
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lipoxins
5-HETE leukotriene B4 (LTB4) LTC4, LTD4, LTE4 |
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lipoxins
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secreted primarily by platelets
primarily anti-inflammatory - inhibit WBC chemotaxis and adhesion to endothelial |
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5-HETE
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chemotactic for PMNs
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LTB4
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potent mediator of PMN and monocyte/macrophage chemotaxis and activation
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LTC4, LTD4, LTE4
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vasoconstriction, increased vascular permeability, WBC chemotaxis
bronchospasm - more potent in this than histamine (important in asthma) |
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antiinflammatory therapies involving eiconisoids
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cyclo-oxygenase inhibitors
lipoxygenase inhibitors glycocorticoids increase dietary intake of fish oil |
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COX inhibitors
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eg: aspirin, NSIADS
COX-2 inhibitors: less toxic side effects |
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lipoxyngase inhibitors
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useful in treatment of asthma
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glucocorticoids
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down regulate expression of genes encoding for COX-2 and PLA2
upregulate genes encoding for lipocortin, which inhibits release of arachidonic acid from mb phospholipids |
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why does increasing dietary fish oil help with anti-inflammation
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fish oil FAs are poor substrates for conversion to active arachidonic acid metabolites
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nitric oxide (NO)
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produced primarily by endothelial cells, monocytes/macrophages, specific population of neurons in brain
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what is common to cells producing NO?
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contain enzyme nictric oxide synthase (NOS)
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"constitutive" forms of NOS
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endothelial cells: eNOS
neurons: nNOS involved in cell-cell communication |
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"inducible" forms of NOS
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produced or increased in amount when needed (eg: during inflammation)
eNOS: endothelial cells iNOS: produced primarily by monocytes/macrophages |
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effects of NO in inflammation
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vasodilation
decreases platelet aggregation and adhesion slow WBC recruitment NO is a free radical - destructive to many microbes |
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definition of cytokine
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secreted protein which modulates functions of other cell bodies
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interleukins
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various pro- and anti-inflammatory effects in all phases of the inflammatory response
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TNF
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tumor necrosis factor
induce apoptosis of target cells, including neoplastic cells produced mainly by activated macrophages, along with IL-1 |
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interferons (IFN)-alpha, -beta, -delta
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IFN-alpha = anti-viral
IFN-delta = potent activator of macrophages |
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growth factors
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influence growth, proliferation, diferrentitation, and locomotion of cells
essential roles in healing (regeneration and repair) |
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endotoxin
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LPS from cell wall of G- bacteria
potent activator of macrophages --> attraction, activation of other WBCs direct injury to microvasculature --> increased vascular permeability activates PMNs --> increase release of toxic ROS --> increased iNOS --> widespread vasodilation (septic shock) |
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vascular enodthelial cells
morphology |
long, thin, spindle-shaped cells in resting state
may become plump and rounded during inflammation b/c of contaction, activation or injury ( = "reactive" endothelial cells) |
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active involvement of vascular endothelial cells during inflammation
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intreactions with WBC adhesion molecules (E-selectin, P-selectin, PECAM-1, ICAM-1)
respond to chemical mediators (contract in resposne to histamine --> increase vascular permeability) synthesize and release mediators of their own (PGI2, NO) --> vasodilation, inhibition of platelet aggregation --> sustain blood flow role in angiogenesis |
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granules released by platelets
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dense granules - ADP, serotonin
alpha granules - fibrinogen lysosomes - proteases and hydrolases membrane mediators - thromboxane A2, PGs, LTs |
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serotonin role in inflammation
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increased vascular permeability
vasoconstriction |
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fibrinogen role in inflammation
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fibrin - hemostasis, WBC migration, helaing
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major source of fibrinogen during acute inflammation
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hepatocytes
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role of thromboxane A2 in inflammation
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platelet aggregation, vasoconstriction --> slow blood flow
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where are mast cells most numerous?
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in CTs at sites of exposure to external environment (skin, mucosa)
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are mast cells tissue cells or circulating cells?
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tissue cells
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mast cell morphology
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round or oval cells with round nucleus
granules stain basophilic in H&E granules stain purple/red with metachromatic stains such as toluidine blue or Giemsa |
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Granule contents
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histamine
heparin serotonin |
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H-1 receptors
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target cells w/ H-1 receptors are involved in pro-inflammatory events
vascular endothelium --> contraction --> increased permeability relaxation of vascular smooth muscle --> vasodilation |
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H-2 receptors
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target cells w/ H-2 receptors are involved in anti-inflammatory or regulatory events
eg: T cells modulate mucosal mast cell activity and inhibit degranulation |
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heparin
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found in mast cell granules
anticoagulant: prevents polymerization of fibrinogen to fibrin --> sustains exudation |
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serotonin
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found in mast cell granules
causes increased vascular permeability and vasoconstriction |
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membrane mediators of mast cells
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LTs (LTC4)
PGs (PGD2) PAF (platelet activating factor) |
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cytoplasmic factors found in mast cells
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chemokines:
eotaxin - eosinophil chemotaxis, activation and proliferation eosinophils are often nurerous in tissues containing many mast cells C-C chemokine for macrophages others: proteases, substance P |
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processes in which mast cells function
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acute inflammation
immediate type (type 1) and delayed type (type IV) hypersensitivity reactions parasitic diseases neoplastic diseases |
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mast cell functions in acute inflammation
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readily activated by physical agents, C3a/C5a, substance P
pro-inflammatory effects: active hyperemia, inflammatory edema bridge btw vascular and cellular events |
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mast cell function in hypersensitivity reactions
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membrane receptors that bind Fc portion of IgE --> allergic reactions
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PMN morphology in tissues
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pale eosinophilic cytoplasm
granules invisible recognized by multi-lobed nucleus |
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why are most PMNs in exudates difficult to identify?
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they're dead
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lifespan of PMNs in tissue
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less than 4 days
undergo apoptosis after phagocytosis and then ingested by macrophages lost by migration into lumina (eg: intestine, airways, body cavities) and destroyed enzymatically |
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PMN granule types
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azurophil (primary) granules
specific (secondary) granules |
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azurophil granules
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myeloperoxidase - O2-dependent microbial killing
lysozyme - O2-dependent microbial killing defensins - anti-bacterial peptides (eg: lactoferrin) cationic proteins acid hydrolases elastase, collagenase |
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specific granules
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callagenases, gelatinases, metalloproteinases
--> degradation of ECM components to aid cell movement through tissue lysozyme lactoferrin |
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PMN phagocytosis is most effective against which microbe type?
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bacteria
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steps in PMN phagocytosis
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recognition and binding of particle to be phagocytized (opsonization)
engulfment (using pseudopods and phagocytic vacuole) microbial killing degradation of killed microbes by acid hydrolases |
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PMN-mediated microbial killing
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fusion of phaosome with lysosome --> phagolysosome
fusion of phagolysosome with primary granule --> aerobic killing (ROS) NADPH oxidase catalyzes reaction with oxygen --> ROS MPO catalyzes reaction of ROS and HOCl --> more effective microbicide oxyten independent killing uses bacteriacidal proteins in granules |
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can PMNs multiply in tissues?
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no
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PMN-mediated tissue injury
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lysosomal enzymes, ROIs and eiconasoids released extracullularly can cause endothelial injury and tissue damage
amplification of inflammatory response |
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defects in PMN function
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defects in WBC adhesion
defects in phagolysosome function defects in microbicidal activity |
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PMN defects in WBC adhesion
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inherited WBC adhesion deficiency, types 1 and 2 (LAD 1, LAD 2)
recurrent bacterial infections |
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PMN defects in phagolysome function
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Chediak-Higashi syndrome
autosomal recessive inheritance giant granules - ineffective microbial killing - poor transfer of lysosomal contents to phagocytic vacuole |
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PMN defects in microbicidal activity
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eg: chronic granulomatous disease
group of disease characterized by inherited defects in genes for NADPH oxidase recurrent bacterial infections |
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PMN exudates
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suppurative or purulent
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pustule
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focal accumulation of pus in the epidermis
subset of abscesses |
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empyema
definition types |
general term for pus in body cavity
pyothorax pyoperitoneum pyopericardium |
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lymphocytes
morphology in tissues |
similar to morphology in peripheral blood
round, intensely basophilic nucleus and thin rim of cytoplasm |
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2 major lymphocyte functions in tissues
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innate immunity
adaptive immunity |
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lymphocyte-macrophage interactions
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macrophages display Ag's to T cell and produce cytokines that stimulate T cell responses
activated T cell produce cytokines that activate macrophages (eg: IFN-gamma, TNF-alpha, IL-2) |
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plasma cells
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terminally differentiated B cells
occurs when cell encounters its specific Ag at site of infection |
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plasma cells
morphology in tissues |
round, eccentric nucleus with "clockface" chromatin pattern
pale basophilic cytoplasm paranuclear clear zone, representing golgi complex |
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function of plasma cells
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antibody synthesis
Ag neutralization Abs also function as opsonins for phagocytosis |
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macrophage origin
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bone marrow --> monocytes (longer half-life than PMNs)
monocytes --> macrophages in tissues (Mf's are long lived) macrophages proliferate in tissues |
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inflammatory macrophages
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monocytes that are recruited into tissue sites of inflammation and become macrophages
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resident macrophages
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"fixed macrophages"
Kupffer cells dendritic cells alveolar Mf's histiocytes (CT) osteoclasts microglia, etc |
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macrophage
morphology |
large
round, polygonal or spindle-shaped oval, sometimes indented, pale basophlic nucleus abundant eosinophilic cytoplasm |
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morphologic variants of macrophages
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epithilioid cells
multinucleate giant cells |
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epithelioid cells
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resemble epithelial cells
diminished phagocytic capacity extracellular secretion of lyosomal enyzmes their presence implies an immune-mediated component to the inflammatory response |
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multinucleate giant cells
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formed by fusion of macrophages
retain phagocytic capacity Mphage response to difficult-to-digest material: higher microorganizms, eg: protozoa, fungi, parasites, etc. large, praticular foregin matter |
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processes in which macrophages function
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chronic inflammation
tissue repair immune responses (adaptive immunity) neoplastic diseases |
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macrophage role in chronic inflammation
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more versatile phagocytes than PMNs
monokine production - inflammatory mediators and WBC recruitors |
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macrophage role in tissue repair
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macrophage is the director of the repair process
phagocytosis of tissue and cellular debris stimulate fibroblast migration, proliferation and collagen synthesis stimulate endothelial cell migration and proliferation in process of angiogenesis influences on tissue remodeling (secretion of proteinases) |
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macrophage role in immune responses (adaptive immunity)
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Ag processing and presentation to lymphocytes
regulate proliferation and activation of lymphocytes |
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mononuclear cell exudates
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nonsuppuprative
granulomatous granuloma pyogranulomatus |
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nonsuppurative mononuclear cell exudates
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dominated by lymphocytes, plasma cells and macrophages
aka: lymphocytic exudate |
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granulomatous mononuclear cell exudates
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dominated by macrophages
macrophages usu. predominant cell types in inflammatory reactions caused by higher, difficult-to-phagocytized microorganisms (eg: M. tuberculosis) no characteristic gross appearance - lack of fluid exudate, a hollow organ may have thicker wall than normal |
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granuloma mononuclear cell exudates
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focal nodular aggregate of marophages
usually a peripheral collar of lymphocytes and plasma cells |
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pyogranulomatous mononuclear cell exudates
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macrophages dominate, but PMNs present in significant numbers
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esoinophils
morphology in tissues |
eosinophilic granules in cytoplasm
bi-lobed or multi-lobed nucleus |
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eosinophils
location in tissues |
resident cells, in low numbers, in CT at sites of exposure to ext. environment (like mast cells): skin, mucosal surfaces
recruited from blood to sites of inflammation can persist in tissue for days, so inflammatory rxns w/ numerous eosinophils may be acute or chronic |
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eosinophils functions in tissues
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acute inflammation
immediate hypersensitivity reactions parasitic diseases autoimmune diseases neoplastic diseases |
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eosinophil function in acute inflammation
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modulation of mast cell activity
phagocytosis eosinophil cationic protein (ECP) - proinflammatory effects proteinases degrade ECM |
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eosinophil granule constituents that modulate mast cell activity
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histaminase - inactivates histamine
arylsulfatase B - inacativates LTC4, LTD4, LTE4 phopholipase D: inactivates PAF |
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eosinophil-mediated phagocytosis
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less avid, but more versatile, than PMNs
eosinophil peroxidase is involved in killing |
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eosinophil cationic protein (ECP)
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pro-inflammatory effects:
kinin activation plasminogen activation |
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role of eosinophil in parasitic diseases
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major basic protein (MBP):
toxid to many helminth parasites also causes histamine release from mast cells and basophils may contribute to tissue damage ECP also has anti-parasitic effects |
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eosinophilic exudates
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no characteristic gross appearance
usu. no fluid exudate histologically eosinophilic |
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basophils
origin |
from common bone marrow precursor cell as mast cell, but basolphils differentiate along different cell lines
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basophils
morphology in tissues |
recruited to tissue sites of inflammation, but present in v. low numbers
difficult to recognize in histologic sections basophilic granules, multi-lobed nucleus |
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processes in which basophils are involved
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actue inflammation
immediate and delayed tyupe hypersensitivity reactions parasitic disease |
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role of basophils in acute inflammation
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effects similar to those of mast cells, but basophil's contribution is minimal b/c of such low numbers
have histamine, substance P and IgE receptors |
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3 variations in proliferative capactiy of cells
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"labile" or renewable cells
"stable" or quiescent cells permanent cells |
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"labile" or renewable cells
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continuous turnover, ability to multiply throughout life
remain in cell cycle "loop" eg: hematopoietic cells, lymphocytes in lymphoid tissues, epidermis, mucosal epithelium |
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"stabile" or queiscent cells
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do not contineu to multiply throughout life, but retain capacity to do so in response to appropriate stimuli
when quescent, exist in Go phase of cell cycle eg: renal tubular epithlium, hepatocytes, glandular epithlium, mesenchymal cells, vascular endothelial cells |
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examples of mesenchymal cells
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fibroblasts
chondrobalsts osteoblasts smooth muscle cells (all stable/quiescent cells) |
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permanent cells
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lose capacity to divide when completely differentiated (terminally differentiated)
cannot reenter cell cyle will not be replaced by same cell type if they die eg: neurons, cardiac muscle |
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size of cell populations in tissue or organ determined by which factors?
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rates of cell proliferation
rates of cell differentation rates of PCD contributions of stem cells |
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embryonic stem cells
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pluripotent cells, found in embryos, which can give rise to all cell types and tissues of the body
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adult stem cells
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have a more restricted differentiation capacity than embryonic stem cells
tissue stem cells hematopoietic stem cells bone marrow stromal cells multipotent adult progenitor cells |
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tissue stem cells
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type of adult stem cells
located in tissues, not bone marrow differentiate into mature cells of the organs in which they reside eg: satellite cells in skeletal muscle |
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hematopoietic stem cells
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type of adult stem cells
located in bone marrow can differentiate into any of the blood cell lines can be recruited to other tissues - may differentiate into cells of that tissue - may influence cells of that tissue to replicate (eg: promoting tissue repair) |
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growth factors influence what 3 things?
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cell proliferation
cell differentiation cell migration |
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do GFs generally act distally or locally?
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locally
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important GFs and GF families
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epidermal GFs (eg: EFF and TGF-alpha)
heaptocyte GF VEGFs - angiogenesis PGDFs fibroblast GFs - angiogenesis, wound repair, hematopoiesis TGF-beta |
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TGF-beta rols
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inhibits growth of most epithelial cell types and WBCs
generally stimulates proliferation of fibroblasts and smooth mm cells stimulates fibroblast migration, proudction of collagen strong anti-inflammatory effect on WBCs |
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function of proto-oncogenes
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regulation of cell proliferation
genes encode for GFs, GF receptors, signal transduction proteins |
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what proteins regulate cell cycle check points?
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cyclins
cyclin-dependent kinases (CDKs) |
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how are checkpoints regulated by cyclins and CDKs
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cyclins are phase-specific (G1 cyclins, G2 cyclins)
cyclins bind to CDKs, which phosphorylate and activate proteins critical for phase transition CDK inhibitors "deactivate cyclin-CDK complexes |
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what happens at G1/S checkpoint?
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integrity of DNA is checked before replication
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What happens at G2/M checkpoint?
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integrity of replication DNA is checked, to ensure cell can cneter mitosis successfully
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Chalones
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peptides secreted by mature cells that inhibit cell growth and proliferation
act locally generally inhibit cells in G1 phase |
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functions of ECM
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structural support for parenchymal cells - basement membranes and interstitial matrix
reservoirs for GFs cell-cell interactions and adhesion |
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biochemical components of the ECM
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fibrous structural proteins (collagens, elastin)
adhesive glycoproteins (CAMs) proteoglaycans and hyaluronic acid |
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where are adhesive glycoprotiens
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cell membranes
cytoplasm ECM |
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fibronectin
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binds collagen, fibrin, proteoglycans and cell surface receptors
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laminin
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most abundant glycoprotein in basement membranes
binds ECM and cell surface receptors |
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proteoglycans
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core protein and glycoaminoglycan (GAG) side chains
include heparan sulfate, chondroitin sulfate, dermatan sulfate roles in regulation of CT structure and permeability may also influence cell growth and differentiation |
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regeneration of tissue
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repair by parenchymal replacement
replacement of dead/damaged cells by new cells identical to those that were lost |
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regeneration occurs only with which cell types?
involves which processes? |
occurs with labile and stable cells
involves hyperplasia and hypertrophy |
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effective tissue regeneration occurs only if...
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the structural framework of the tissue is maintained:
implies relatively mild injury structural framework includes supporting CT, epithelial basement membranes |
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healing =
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reapire by scarring, fibrosis, or CT replacement
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major players in healing
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macrophages
fibroblasts endothelial cells |
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where does healing occur?
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in tissues with regenerative capacity if supporting framework is destroyed
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only option for repair of myocardium
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healing
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phases of healing
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inflammatory phase
proliferative phase remodeling phase |
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inflammatory phase of healing
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vascular and cellular events of inflammation
24-48 hours after injury, endothelial cells and fibroblasts are called in by collagenase and other proteases from granulocytes macrophages phagocytose necrotic debris and infectious agents macrophages direct healing process via secretory functions |
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secretory function by which macrophages direct healing process
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cytokines that stimulate neovascularization
cytokines that attract and activate fibroblasts cytokines that stimulate ECM synthesis and degradation |
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aspects of proliferative phase of healing
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angiogenesis
fibrobast migration, proliefration, collagen/ECM syntheis collagen synthesis synthesis of ECM components |
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angiogenesis
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part of proliferative phase of healing
formation of new blood vessels by recruitment of endothelial progenitor cells from bone marrow branching and extension of pre-existing adjacent blood vessels |
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purposes of angiogenesis
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re-establish blood supply in devitalized tissue
provide nutrients for fibroblast proliferation and ECM synthesis recruitment of more WBCs from blood |
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function of fibroblast migration, proliferation and collagen/ECM synthesis
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laying down of collagen restores structural integrity and provides tensile strength to damaged tissue
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if significant quantity of fibrous tissue is produced in healing process...
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there may be some compromise in functional capacity
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proliferation of fibroblasts beings where?
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at the periphery of an area of tissue injury in an attempt to isolate the injurious agent or limit the spread of tissue damage
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"granulation tissue"
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highly vascular, immature fibrous CT
often edematosis, b/c of the leakiness of new blood vessels velvety, bright pink or red most mature tissue is at base of defect or at periphery of area of healing |
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fibrin and fibronectin serve as a scaffold for what?
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fibroblast migration
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differences in proliferative phase processes over time
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as phase progresses, less endothelial and fibroblast proliferation, and more ECM deposition
collage and ECM syntehsis begins w/in 3-5 days of injury and continues for several weeks, depending on size of wound |
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collagen synthesis in healing
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part of proliferative phase
trype III collagen is abundant in young granulation tissue as healing tissue matures, type III is replaced by type I collagen |
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what component of ECM is abundant during inflammatory phase of healing?
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hyaluronic acid
makes healing tissue relatively rluid and allows cell movement through the matrix |
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____ _content increases in new ECM as hyaluronic content wanes
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chondroitin sulfate
increases resilience of healing tissue stimulates fibroblast proliferation and type III collagen synthesis |
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remodeling phase of healing
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involves collagen synthesis and degradation, and the sequential appearance of various ECM components
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what happens to ECM over remodeling phase of healing
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matrix becomes less fluid, more organized, and more resilient, with increaed tensile strength
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time for remodeling phase of healing
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up to a year, depending on size of wound
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GFs and cytokines that regulate fibroblast migration and ECM syntehsis also modulate...
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synthesis and activation of metalloproteinases
metalloproteinases degrade ECM components |
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matrix metalloproteinases
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MMPs
Zn-dependent for activity produced by fibroblasts, Mphase, PMNs, synovial cells inhibited by TIMPs, so collagen and ECM synthesis is controlled |
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TIMP
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tissue inhibitors of MMPs
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continued changes in ECM in remodeling phase of healing
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dermatan sulfate is predominant GAG --> stimulates type I collagen synthesis
healing tissue becomes les vascular over time --> tissue gets less pink and more white (scar formation) wound contraction |
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wound contraction
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helps close wound
most important in wounds w/ significant tissue loss beings in proliferative phase and continues into remodeling phase movement toward center of defect contraction is due to myofibroblasts |
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myofibrobasts
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fibroblasts with smooth muscle-like properties
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harmful side effects of wound contraction
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if contraction impinges on vital structures (eg: nerves)
or causes strictures in hollow organs (eg: intestine) |
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contracture
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excessive wound contraction
common on palms of hands, soles of feelt and anterior thorax and on skin healing from severe burns |
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healing by first intention, aka:
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primary union
or Closed Wound Healilng |
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Healing by first intention involves...
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wounds iwth minimal tissue loss and limited cell death -
wound edges can be apposed eg: sutured surgical incision rapid repair |
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describe rapid repair in healing by first intention
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small volume of clotted blood and fibin in incisional space - dries on surface to form scab
PMNs appear w/in 24 hours epithelial cells migrate from wound edges, beheath scap to bridge gap by day 3, Mphages predominant phagocyte fibroblasts and endothelial cells form granulation tissue btw days 2 and 5 reepithlialization complete w/in 5-7 days edama/inflammation subside by day 7 |
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following rapid repair, how long does remodeling of fibrous tissue take?
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several weeks
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healing by second intention, aka:
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Secondary Union
or Open Wound Healing |
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Healing by second intention involves...
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wounds with significant tissue loss
wound edges cannot be apposed volume of blood, fibrin and tissue debris which fills the wound initially is significant if wound involves the skin, bacterial contramination is common less rapid healing than first intention |
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less rapid healing than first intention healing because
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a large volume of exudate must be removed - inflammatory reaction is more intense
re-epithelialization must cover a longer distance significant fibroblast and endothelial cell proliefation (i.e.: granulation tissue formation) is required to fill the defect |
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why is scar larger from second than from first intention healing?
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significant granulation tissue formation in second intention healing
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local factors influencing healing
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infection - creates addition tissue injury and inflammation
presence of foreign bodies - persistent inflammation excessive tissue debris - increases workload for phagocytes, wound may require "debridement" removal of necrotic tissue movement - creates persistant trauma --> persistent inflammation wound location - wounds in richly vascularized areas, like the face, heal faster than would in less well vacularized areas, like the foot |
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dehiscence
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breakdown and rupture of a closed wound
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systemic factors influencing healing
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nutrition - protein deficiency, vitamin C deficiency --> inhibit collagen synthesis
metabolic or circulatory diseases - DM --> microangiopathy --> delayed healing -arteriosclerosis |
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genetic factors influencing healing
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keloids
exuberant granultion tissue desmoids or "aggressive fibromatoses" |
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keloids
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genetic factor in healing
scar tissue grows beyond boundaries of original wound predisposition in some African-Americans |
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exuberant granulation tissue
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excessive granulation tissue which protrudes above the skin surface and impedes re-epithelialization
must be removed by cautery or excision |
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desmoids
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aggressive fibromatoses
excessive prolieration of fibroblasts and ECM wqhich may recur even after surgical excision borders on neoplasia |
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Two groups of new and emerging diseases
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Group I: pathogens newly recognized in the past decades (includes H. pylori, Hep C, Lyme borreliosis)
Group II: re-emerging pathogens (includes mumps virus, prion diseases) |
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examples of emerging zoonotic diseases
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avan influenze, bonvine spongiform encephalopathy, Nipah virus
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CDC lists infectious agents that pose the greates danger based on what four factors?
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how efficiently they can be transmitted
how readily they reproduce and can be disseminated how readily they can be defended against how likely they are to alarm the public |
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Category A infectious agents
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highest risk
easily disseminated or transmitted person-to-person result in high mortality rates might cause public panic and social disruption require special action for public health preparedness eg: anthrax, botulism, plague, smallpox |
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Category B infectious agents
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intermediate risk
moderatly easty to disseminate result in moderate morbility rates and low mortality rates require specific enhancements of CDC's diagnostic capacity and enhanced disease surveillance eg: Brucella spp., food safety threates (Salmonella, etc.), water safety threats (cholera, etc.) |
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Categeroy C infectious agents
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third highest priority
emerging pathogens that could be engineered for mass dissemination in the fugure potential for high M/M raes and major public health impact eg: hantavirus and Nipah virus |
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Types of infectious agents
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prions
viruses bacteriophages, plasmids, transposons bacteria fungia protozoa helminths |
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prions
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protease-resistant form of normal host protein
Sc or Res superscript denotes abnormal prion protein conformational change in normal protein --> protease resistance cause "transmissible spongiform encephalopathies" |
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examples of transmissible spongiform encephalopathies (TSEs)
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eg: kuru, Creutzfeld-Jacob disease (CJD)
eg: bovine spongiform encephalopahy (BSE, mad cow ds) |
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bacteriophages, plasmids, transposons
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all are mobile genetic elements that infect bacteria
indirectly cause ds by encoding virulence factors can convert nonpathogenic to pathogenic bacteria |
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smallest free living organisms nown
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mycoplasmas
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two examples of obligate intracellular parasitic bacteria
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chalmydiae
rickettsiae |
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what do chlamydiae, rickettsieae and mycoplasmas have in common?
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bacteria which lack cetain structures or funciton of other bacteria
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fungi
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eukaryotic, with chitin-containing cell walls
grow as budding yests or filamentous hyphae |
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dimorphism of some fungal pathogens
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hyphal forms at room or envrionmental temp
yeast forms at body temp |
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two important systemic fungal pathogens
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Coccidioides
Histoplasma |
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protozoa
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single-celled eukaryotes
esp improtant pathogens in developing countries can replicate in or out of host cells commonly affect UG tract, blood or GI tract blood-borne protozoa transmitted by insect vectors (eg. malaraia Plamodium) |
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Helminths
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parasitic worms
complex life cycles w/ sexual and asexual phases |
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helminth definitive host
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host in which the parasite completes sexual phase of its cycle - female lays eggs
definitive host contains adult worms and sheds eggs/larvae disease is often associated with response to eggs/larvae |
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ectoparasites
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insects or arachnids that attach to and live on or in the skin
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inflammatory responses to infection
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pattern of response depends on interaction btw microbe and host
pyogenic bacteria --> intense PMN response (eg: Staph and Strept) agents diffiult to phagocytize induce granulomatous inflamm or granulmoa formation (eg: M. tuberculosis) PMN phase of inflammation is breif in many viral infections --> mononuclear inflamm cells predominate |
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Suppurative inflammation
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aka: polymorphonuclear inflammation
reaction to acute tissue damage (i.e.: to necrosis) or pyogenic bacteria predominant WBC: PMN exudate: suppurative or purulent |
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mononuclear or granulomatous inflammation
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mononuclear cells: lymphocytes, plasma cells, macrophages
typically seen with CHRONIC inflammation lymphocytes usu. predominate in viral infxns of brain plasma cells usu. predominate in syphilis Mphages typically predominate in infections by higher microbes --> granumomatous inflammation |
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cyopathic-cytoproliferative inflammation
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cell damage or necrosis or cell proliferation with little inflammation
characteristic of some viral infections - herpes --> cell damage - papillomavirus --> cell proliferation (hyperplasia or dysplasia) |
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necrotizing inflammation
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extensive tissue damage with minimal inflammation
usu. acute infections by highly potent organisms (eg: C. perfringens infection of muscle or bowel) |
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chronic inflammation with scarring
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end result of infection is complete healing or extensive scarring
scarring response may permanently affect tissue or organ function |
