Lec2-3 Acute and Chronic Inflammation Flashcards
Inflammation basics
- ubiquitous, fast, non-specific rxn of vascularized tissue to local injury
- functions:
- – defend and stop aggression
- – clean up [phagocytosis]
- – repair
Characteristics of acute inflammation
- interstitial edema
- accumulation neutrophils
3 major steps of acute inflammation
- alteration vascular caliber to increase blood flow
- structural change in microvasculature so plasma proteins and neutrophils can leave circulation
- emigration of neutrophils from microcirculation and accumulation in injury site
5 Classic signs of inflammation
Present in acute inflammation
- heat [calor]
- redness [rubor]
- edema [tumor
- pain [dolor]
- loss of function
Characteristics of chronic inflammation
- presence of mononuclear cells
- – lymphocytes, plasma cells, macrophages
- admixed with granulation tissue
Cause of acute inflammation
- microbial infection
- physical agents
- chemicals
- necrotic tissue
- immunologic reactions
4 Vascular events in acute inflammation
- brief vasoconstriction then vasodilation –> increase blood flow
- increased vascular permeability
- interstitial edema
- vascular stasis and congestion
vascular permeability in acute inflammation
endothelial cells become leaky from direct cell injury or via chemical mediators
- get escape protein rich fluid into interstitium
- inflammation associated edema
Endothelial cell contraction
- gap between cells due to endothelial contraction
- common in venules
- fast process, short-lived
- due to vasoactive mediators [histamine, leukotrienes]
Vasodilation or vasoconstriction in acute inflammation
immediately vasoconstriction then vasodilation which leads to greater blood flow to area
- leads to redness [rubor] and heat [calor]
Exudation
fluid, proteins, RBCs and WBCs leave intravascular space because of high extravascular - due to osmotic P (∏i) or high hydrostatic P intravascularly [Pc]
Vascular stasis
slowing of blood in bloodstream, along with vasodilation and fluid exudation allows chemical mediators and inflammatory cells to collect and respond to stimulus
Endothelial cell retraction
- delayed response, long lived
- cytoskeletal and junctional reorganization
- due to cytokine mediators: IL-1, TNF
4 Mech of increase endothelial permeability
- endothelial cell contraction
- endothelial cell retraction
- direct endothelial injury
- neutrophil-mediated endothelial injury
Direct endothelial injury
- endothelial cell necrosis and detachment
- occurs in severe necrotizing injuries [toxins, burns, chemicals]
- occurs in venules, capillaries, arterioles
- causes immediate and long term leakage
Neutrophil-mediated endothelial injury
- mostly in venules, pulmonary capillaries
- due to neutrophil aggregation, adhesion, and emigration across endothelium
- – release ROS and proteolytic enzymes
- – endothelial injury / detachment –> more permeability
- late response, long-lived
3 Steps extravasation
extravasation = leukocytes going to site of injury
- rolling and adhesion of leukoctyes in lumen
- transmigration across endothelium
- Migration through interstitial tissue toward chemotactic stimulus
Selectins
- surface molecules that share similar carbohydrate binding domain
- bind sialyl Lewis-X glycoprotein on cells
- allow attachment and rolling of neutrophils
- stimulated by histamine + cytokine to present on cell surface
3 Types of selectins
P-selectin: platelets, endothelial cells
E-selectin: endothelial cells
L-selectin: leukocytes
Integrins
- expressed in cytokine stimulated endothelial cells
- affinity of integrins increased by chemokines
- – allows firm adhesion of neutrophil to endothelial surface
PECAM
Platelet endothelial cell adhesion molecule
- involved in migration
Diapedesis
Movement of neutrophils through intracellular junctions into interstitium
Neutrophil chemotaxis
- neutrophils migrate along gradient of chemotactic agents in interstitial space
- chemotactic agents bind receptors on neutrophils and produce secondary messengers
- –leads to assembly of contractile elements that allows the cell to move via extension of pseudopods
4 Neutrophil chemotactic agents
- bacterial products
- complement fragments [C5a]
- arachidonic acid metabolites [leukotriene B4]
- chemokines [IL-8]
What does neutrophil do once it reaches site?
- phagocytosis of offending agent
- release lysosomal contents and free radicals to interstitium –> chemical tissue destruction
Steps of phagocytosis
- recognition and attachment
- –opsonins coat antigens and enhance recognition
- —– Fc of IgG and C3b of complement
- engulf phagocytosed particule
- – form phagosome
- – lysosome fuses with phagosome, form phagolysosome
Neutrophil oxygen dependent bactericidal mech
- triggered by activation nicotinamine-adenine dinucleotide phosphatase
- – reduces O2 –> O2- –> H2O2
- myeloperoxidase [MPO] from lysosomal granule converts H2O2 –> HOCL- which kills bacteria
Neutrophil oxygen independent bactericidal mech
- kill bacteria directly by releasing bactericidal permeability-increasesing-proteins, lysozyme, lactoferrin, major basic protein [MBP], eosinophils, argenine-rich defensins
- killed organisms degraded by hydrolases + other lysosomal enzymes
myeloperoxidase
MPO
- from lysosomal granules
- converts H2O2 + Cl- –> HOCL- which is very bactericidal
- part of oxygen dependent mech
Neutrophil induced tissue injury
during phagocytosis neutrophils release products into phagolysosomes but also into extracellular space
- lysosomal enzymes
- free radicals
- products of arachidonic metabolism [prostaglandins and leukotrienes]
amplifies effects of initial inflammatory stimulus
Macrophages in inflammation
clean up everything, migrate away, restore normality of area
Purulent
exudate with prominent neutrophils
suppurative
purulent exudate plus tissue necrosis
abscess
localized collection of pus [tissue necrosis]
fibrinous
exudate that has fibrin due to proteins leaking from vessels with increased permeability and activation of coagulation cascade
ulcer
defect on surface of organ or tissue secondary to sloughing off of inflamed necrotic tissue
4 Possible outcomes of acute inflammation
- complete resolution: restoration to normal
- abscess formation: particularly in infections
- healing by fibrosis [connective tissue replacement] and scarring
- progression to chronic inflammation
Histamine
- mostly from mast cells plus basophils + platelets
- prefomed
- one of first mediators of inflammatory response
- causes vasodilation and increased vascular permeability
Cell derived mediators of inflammation [2 main types]
preformed mediators secreted in granules
- vasoactive amines [histamine, serotonin]
- lysosomal enzymes
newly synthesized mediators
- arachidonic acid metabolites
- —– cyclooxygenases [prostaglandins + thromboxanes]
- —–lipoxygenases [leukotrienes + lipoxins]
- platelet activating factor
- activated oxygen species
- nitric oxide
- cytokines
Serotonin
Preformed, in platelets
What causes mast cells to release histamine
- physical agents [trauma/heat]
- immunologic rxns of binding IgE Ab to mast cell
- complement fragments C3a, C5a [anaphylatoxin]
- neuropeptide [substance P]
- cytokines [IL1-8, IL8]
- histamine releasing factors from leukocytes
Functions of Prostaglandin I2?
Prostacyclin
- vasodilates, inhibits platelet aggregation
Functions of Prostaglandin E2?
Hyperalgesic [makes skin hypersensitive to pain] , vasodilates
Functions of Thromboxane A2?
vasoconstrictor, promotes platelet aggregation
Functions of Leukotrienes C4, D4, E4?
Increase vascular permeability, vasoconstrictor
Functions of leukotriene B4?
powerful chemotactic agent
by leukocytes
Functions of Lipoxin?
Endogenous negative regulators of leukotrienes, inhibit neutrophil chemotaxis, cause vasodilation
Inhibitors of cyclooxygenase?
aspirin
What are cyclooxygenases?
prostaglandins + thromboxanes
Platelet activating factor
- phospholipid-derived
- from mast cells [and other leukocytes + EC]
- Stimulated by IgE mediated rxns
- function: platelet aggregation, broncoconstriction, vasodilation, increase vascular permeability, leukocyte adhesion, chemotaxis
5 Major categories of cytokines
- Regulators of lymphocyte function
- inflammatory cytokines = involved in immunity
- Activate inflammatory cells
- Chemokines
- Cytokines that stimulate hepatopoiesis
What are cytokines?
- proteins that modulate function of other cell types
- Can act on multiple cell types
- Can be multifunctional with opposing actions
- Bind specific receptors on target cells
3 [2 do the same thing] Cytokines that regulate lymphocyte function
IL2 and IL4: favor lymphocyte growth and differentiation
IL1 and transforming growth factor: neg regulation of immune
Inflammatory cytokines
TNF-alpha, IL-beta
Type 1 interferons [IFN-a and b]
IL6
Cytokines that activate inflammatory cells
IFN-gamma, TFN-a, IL-5, IL10, IL12
Chemokines
chemotactic activity for leukocytes
IL-8
Cytokines that stimulate hematopoiesis
mediate immature leukoctye growth and differentiation
- Il3, Il7, GM-CSF, macrophage-CSF, granulocyte-CSP, stem cell factor
IL-1 and TNF
- major inflammatory cytokines
- act on: endothelium, leukocytes, induction of systemic rxns to acute inflammation
- produced in macrophages
What stimulates secretion of IL-F and TNF
Macrophages secrete them when:
- endotoxin, immune complexes, toxins, physical injury
Cachexia
wasting syndrome
- due to overproduction TNF-alpha
- characterized by weight loss and anorexia
Endothelial cell activation by ILF-1/TNF
stimulate:
- Induction adhesion molec and chemical mediators
- production of enzymes associated with matrix remodeling
Hemodynamic effects of septic shock produced by IL-1 and TNF
hypotension
decreased vascular resistance
high HR
low blood pH
Acute inflammation responses by IL-1 and TNF
- fever, loss of appetite, production sleep
- release neutrophils into circulation, release adrenocorticotropic hormone + corticosteroids
3 systems of plasma derived mediators of inflammation
3 interrelated systems
- complement system
- kinin system
- clotting factor [Hageman factor] system
Hageman Factor
Hageman factor = clotting factor XII
- activated by: neg charge substances on cell surface, bacterial lipopolysaccharides
- initiates kinin, clotting, fibrinolytic and complement cascades
- Has chemotactic activity
- Causes neutrophil aggregation
Complement components with inflammatory activity
- C3a and C5a: increase vascular permeability
- C3b/C3bi: opsonin
- C5b-9: membrane attack complex
Functon of C3a in inflammation?
an anaphylatoxin, increase vascular permeability
Function of C5a in inflammation?
An anaphylatoxin, increase vascular permeability, highly chemotactic to most leukocytes
Function of C3b and C3bi in inflammation?
opsonin - aid phagocytosis
Function of C5b-9 in inflammation?
- Form membrane attack complex
- lyse cells, stimulate arachidonic acid metabolism, produce ROS by leukocytes
Kinin system
- generates bradykinin = vasoactive protein
- regulates BP, smooth muscle relaxation/contraction, cell migration, inflammatory cell activation
Bradykinin
- vasoactive protein of kinin system
- formed from plasma kininogens via enzyme kallikrein
- blood vessel dilator, increases vascular permeability, causes pain
What does Kallikrein do?
- enzyme in kinin system
- forms bradykinin from plasma kininogens
- part of autocatalytic loop = activator of hagemen factor so amplifies the effect
Intrinsic clotting pathway
- series of plasma proenzymes that can be activated by hageman factor
- activation of thrombin
- cleavage of fibrin, generation of fibrin clot
- forms fibrinopeptides
Thrombin
- Activated from prothrombin by factor Xa
- Increases leukocyte adhesion to endothelium
Fibrinopeptides
- Formed in rxn fibrinogen –> fibrin activated by thrombin
- induce vascular permeability
- Chemotactic for leukocytes
Chronic inflammation
inflammation of wks or months, active inflammation, tissue destruction and attempts at healing all proceeding simultaneously
3 main causes of chronic inflammation
- progression of acute inflammation
- repeated bouts of acute inflammation
- low grade response does not follow classic acute inflammation [most common]
How does acute inflammation lead to chronic inflammation?
- persistent stimulus
- abnormality in healing
3 Major cause of chronic inflammation?
- low-grade response does not follow classic acute inflammation
- – persistent infection by intracellular microbes of low toxicity [TB, viral]
– prolonged exposure to toxic endogeneous or exogenous substances [ silica and silicosis, plasma lipid and atherosclerosis]
– immune rxns against own tissue [autoimmune]
3 Characteristics chronic inflammation
- tissue infiltration by mononuclear cells
- – macrophages, lymphocytes, plasma cells
- tissue destruction
- – induced by inflammatory cells
- attempts at repair
- – connective tissue replacement, angiogenesis, fibrosis
Lymphocyte
- Single nucleus fills most of cell, looks like stand-alone nucleus
Plasma cell
- Produces Abs against foreign Ag or altered tissue component
- Clock face nucleus with adjacent halo pale area from large golgi
Macrophage
Synonyms: histiocyte, kupffer cell
- from peripheral blood monocytes
- activated by cytokines [interferon gamma, T cells], endotoxins
- secrete toxic substances [ex ROS]
- cause influx other cells [macro + lymphocytes]
- cause fibroblast proliferation + colllagen deposition
- phagocytosis
Mast cell
- found in connective tissue
- express receptors that bind Fc portion of IgE
- in acute response: Ag recognition –> histamine release
- – part of anaphylactic rxn to allergens
- some parasite infections also increase IgE and mast cell activation
Eosinophil
- immune rxn mediated by IgE and parasites
- recruitment of eotaxin [a chemokine]
- granules contain major basic protein [MBP] that is toxic to parasites and epithelial cells
Factors secreted by macrophages
- neutral proteases
- chemotactic factors
- arachidonic acid metabolites
- ROS
- complement components
- coagulatin factors
- growth factors
- cytokines [IL-1 and TNF]
- others [PAF and alpha-IFN]
Granulomatous inflammation
characterized by
- collections of epithelioid macrophages surrounded by collar of mononuclear leukocytes [mostly lymphocyte, some plasma]
- central necrosis may be present
2 types: foregin body, immune
Occurs in TB, sarcoid, leprosy
Epithelioid macrophage
activated macrophage that has epithelial like appearance
Immune Granuloma
Formed by T-cell mediated rxn to Ag that are hard to degrade
- prototype = TB
May have central necrosis [necrotizing granuloma]
- caseous necrosis
Foreign body granuloma
Caused by inert foreign bodies
ex. suture granulomas
3 Outcomes of chronic inflammation
- resolution/regeneration to normal
- – requires removal toxic agent, cells able to regenerate, intact stromal frame
- reapire/organization/healing by connective tissue/fibrosis/scarring
- idenfinitely occuring [ex. rheumatoid arthritis]
Requirements for chronic inflammation to resolve to normal
- removal toxic agent
- cells able to regenerate
- intact stromal framework
How to tell acute vs chronic inflammation [time frame, cell types, pathogenesis, cause, outcomes, treatments]
time frame: acute = short, chronic = long
components: acute = neutrophils, chronic = lymphocytes + macrophages
pathogenesis: acute = vasodilation + vascular permeability, chronic = cytokines/chemokines attract lymphocytes + neovascularization
cause: acute = infection or burn, chronic = prolonged exposure to toxic agent
outcomes: acute = resolution or abscess or scarring or become chronic, chronic = regeneration or scar formation or resolution
What should you look for in histology of tissue undergoing repair?
- granulation tissue
- brining in fibroblasts to form scar
What should you look for in histology of tissue undergoing regeneration?
- mitotic figures
- hyperplasia
Granulation tissue is a sign of what?
repair
- composed of proliferating capillaries + cells [fibroblasts, macrophages, etc] within loose connective tissue
What is etiology of rheumatoid arthritis?
AA amyloids from precursor SAA protein
What histologically shows you there is cirrhosis of the liver?
presence of fibrous septa that subdivide parenchyma into disorganized regenerating nodules
If you see liver nodules, think what condition?
cirrhosis!
predominant cell type in acute inflammation
neutrophils
3 chemotactic agents for neutrophils
- leukotriene B4
- C5a/C3a
- cytokines [IL-8]
2 chemical mediators of systemic acute phase response
TNF-alpha
IL-1
What stimulates selectins?
histamine and cytokines
What 2 cytokine mediators induce endothelial cell retraction?
IL-1
TNF
Is endothelial cell contraction or retraction longer liver? Which happens first?
endothelial cell contract is first
endothelial cell retract lasts longer
Among the 4 mechanisms of increased vascular permeability, which are short/long lived and which are immediate/delayed?
neutrophil mediated endothelial injury: late, long lived
direct endothelial injury: immediate, long term
endothelial cell contraction: immediate, short lived
endothelial cell retraction: late, long liveed
What are the functions of IL-1 and TNF
- systemic acute phase response
Where does endothelial contraction usually occur?
venules
What produces leukotrienes?
lots of cells?
Where does neutrophil mediated endothelial injury occur?
mostly in venules, pulmonary capillaries
What is a function of IL-2 and IL-4?
favor lymphocyte growth and differentiation
What cytokine is associated with cachexia?
TNF-alpha
