Lecture 3+4: Acute and Chronic Inflammation Flashcards
Inflammation
-from infections or bad stimuli
-eliminates harmful agents and necrotic cells
-initiates healing
-may injure normal tissues
Inflammation damaging normal tissue scenarios
-response too strong (severe infection)
-prolonged reponse (persistent or recurrent infection)
-inappropriate response (self antigens in autoimmune disease)
pharmacological approaches to inflammation
-glucocorticoids
-NSAIDs
-antihistamines
-leukotriene antagonists
-biologics targeting cytokine signaling
leukocytes
white blood cells
phagocytes
-neutrophils, mast cells
-macrophages, monocytes, dendritic cells
Granulocytes
-neutrophils
-eosinophils
-basophils
-mast cells
lymphocytes
-B cells
-T cells
-NK cells
Acute inflammation
cell types
cytokines
-rapid onset
-short duration
-exudation
-accumulation of NEUTROPHILS
-TNF and IL-1 and chemokines
exudation
accumulation of fluid and plasma proteins
Chronic inflammation
cell type
cytokines
-insidious and longer (months to years)
-tissue destroyed by inflammatory cells
-scarring
-influx of LYMPHOCYTES and MACROPHAGES
-IFN-y by T cells and IL-12 by macrophages (synergistic stimulation)
scarring
vascular proliferation and fibrosis
Acute Inflammatory response
- Phagocytes recognize threat then release chemical mediators of inflammation
- mediators cause vasodilation and increase permeability
- leukocytes diffuse to site
- Phagocytosis by leukocytes
- Luekocyte sends signals that suppress inflammation (lipoxins)
- Damage tissue is repaired (cell proliferation)
Signs of acute inflammation
-heat
-redness
-swelling
-pain
-loss of function
Major components of inflammation
-vascular stage
-cellular stage
vascular stage of inflammation
-vasodilation
-increased permeability
cellular stage of inflammation
-leukocyte recruitment
-phagocytosis
Vasodilation
-decrease in fluid velocity
-increased viscosity due to fluid loss to tissues
-margination
margination
-increased leukocyte settling along the inner surface of blood vessels
Increase in vascular permeability
-Gaps due to endothelial contraction (histamine, leukotrienes, bradykinin)
-increased fluid flow through endothelial cells (transcytosis)
-direct endothelial *traumatic) injury
-leukocyte-dependent endothelial cell damage due to release of toxic mediators by leukocytes
-leakage from new blood vessels that form at site of injury
Vascular changes
-transudate
-exudate
-edema
transudate
-small holes
-plasma with little protein
-no cells
exudate
-bigger holes
-protein rich fluid
-numerous cells
edema
-accumulation of fluid and swelling at site of inflammation
Leukocyte recruitment
-margination
-rolling (selectins)
-adhesion (integrins)
-transmigration
-chemotaxis
Chemotaxis
-bacterial products (LPS)
-chemokines
-complement system
-leukotriene B4
Phagocytosis steps
- recognition (direct or indirect)
2, engulfment - Killing
Direct recognition in phagocytosis
-by pattern recognition receptors
-toll-like receptors (LPS, flagella)
-mannose receptors
Indirect recognition in phagocytosis
-by opsonins (IgG, C3b, collectins)
-opsonization
-specific receptors recognize opsonins
opsonization
coat foreign body and dead cells
Engulfment step of phagocytosis
-receptor-mediated ENDOcytosis
-psuedopods form PHAGOSOME around foreign body
Intracellular killing phase of phagocytosis
-phagolysosome
-lysosomal degradation
-oxidative burst
Histamine
-first mediator of inflammation released upon acute inflammation, but transient
-binds H1 receptors
=vasodilation and increased permeability
antihistamine drugs
H1 receptor antagonists
Platelet activating factor (PAF)
-mediator of inflammtion
-generated from phospholipids by phospholypase A2
-induces platelet aggregation
-100-10000 times more potent than histamine
Eicosanoids
-derived from polyunsat FAs like arachidonic acid
-COX pathway (prostaglandins and thromboxane)
-Lipoxygenase pathway (leukotrienes)
prostaglandins
-complex inflammatory response
-fever and pain
thromboxane
-vasoCONSTRICTION
-platelet aggregation
-INHIBITED by NSAIDs
NSAIDs inhibt
thromboxane part of COX pathway
leukotrienes
-similar to histamine
-more potent and longer
-significant in allergic reactions
Plasma proteins
- clotting system: thrombin and fibrinopeptides
- complement system: C3a, C5a, C3b
- kinin system: bradykinin
thrombin
activates leukocytes
fibrinopeptides
-increase permeability
-chemotactic
-produced from digestion of fibrinogen bu thrombin
Anaphylatoxins
-C3a and C5a
-vasodilation
-increase permeability
C5a
-activates leukocytes
-chemotactic
C3b
-acts as opsonin
Bradykinin
-vasodilation
-increased permeability
-causes PAIN
-formed by cleavage of kininogens by protease killikreins
Cytokines
-secretion is transient and tightly regulated
-pleiotropic and redundant functions
-TNF-a and IL-1
-chemokines
TNF-a and IL-1
-major cytokines of inflammation
-come from activated macrophages
-generate cellular and systemic responses
Chemokines
-chemotactic cytokines
-recruit cells
-generate persistant chemotactic gradient
Nitric Oxide (NO)
-short lived (sec) locally acting
-synthesized by inducible nitric oxide synthase (iNOS) which is induced by inflammatory cytokines and mediators
-vasodilation
-antimicrobial in activated macrophages
Reactive Oxygen Species (ROS)
-short lived
-from NADH oxidase pathway
-superoxide, hydrogen peroxide, hydroxyl radical
-released extracellularly by neutrophils and macrophages after stimulation
-may cause tissue injury
Injury by Lysosomal proteases
-release of lysosomal contents into EXTRAcellular space
-matrix degradation and tissue injury
causes of injury by lysosomal protease
-premature degranulation of lysosomes
-phagocytosis attempts of large, flat surfaces (frustrated phagocytosis)
-damage of leukocytes (urate crystals in gout)
Antiproteases
-inhibit lysosomal proteases
-a2-macroglobulin, a1-antitrypsin
-exist in serum and extracellular matrix
Vasodilation and increased vascular permeability is caused by:
-histamine
-PAF
-C3a and C5a
-Bradykinin
-leukotrienes (LTC, LTD, LTE)
-prostaglandins
-Nitric oxide
Chemotaxis caused by:
-C5a
-Leukotriene B (LTB)
-bacterial products (LPS)
-chemokines
Fever caused by:
-IL-1
-IL-6
-TNF-a
-prostaglandins
Pain caused by:
-prostaglandins
-bradykinin
tissue damage caused by:
-lysosomal enzymes
-ROS
-nitric oxide
Abscess
-localized area of inflammation
-pus that may be surrounded by neutrophils
-excessive neutrophil infiltrates or certain bacterial/fungal pyogenic infections
Ulceration
-site of inflammation where epithelial surface has become necrotic and eroded
-may occur as result of tramatic injury to epithelial surface (peptic) or vascular compromise (foot ulcers from diabetes)
Chronic inflammation
-weeks to years
-inflammation, injury, and healing occur at same time
-may progress from unresolved acute inflammation
Characteristics of chronic inflammation
-infiltration with mononuclear cells: macrophages, lymphocytes, plasma cells
-tissue destruction
-repair involving new vessel proliferation (angiogenesis) and fibrosis
Causes of chronic inflammation
-viral infection intracellular
-persistant infection (delayed hypersensitivity)
-prolonged exposure to toxins
-autoimmune disease
Epithelioid macrophages
-activated by cytokines, bacterial products, mediators, dead cells, etc
-release products that may cause tissue damage
-macrophage accumulation persists
Macrophages release:
-proteases
-complement, coagulation factors
-ROS and NO
-eicosanoids
-cytokines
-growth factors = fibrosis
Lymphocytes
-reciprocal of macrophage
1. activation by macrophage presenting antigen
2. activated lymphocytes release mediators (IFN-y)
3. IFN-y activates macrophages
4. activated macrophages release cytokines (IL-12)
5. IL-12 activates lymphocytes
Cells in chronic inflammation
-macrophages and lymphocytes stimulate each until the antigen is gone
-also plasma, eosinophils, and mast cells
Granulomatous Inflammation
-form of chronic inflammation
-formation of granuloma
-caused by hard to control agents
-foreign bodies
-micros that cause TB, syphilis, sarcoidosis, deep fungal infections, brucellosis
Foreign body giant cells (granuloma)
-multinucleated cells formed by macrophages
-encapsulate and isolate offending agents
