inflammation Flashcards
inflammation definition
response to infection or tissue necrosis that allows inflammatory cells, plasma proteins, and fluid to enter the interstitial space with the goal of eliminating the pathogen/clearing debris
features of inflammation
rubor, calor, dolor, tumor, decreased function
steps of inflammation
- recognition of injurious agent
- recruitment of WBCs
- removal of agent
- regulation of response
- repair
characteristics of acute inflammation
- innate immunity
- immediate response
- pyogenic
- neutrophils, antibodies, complement
- associated with extracellular organisms
characteristics of chronic inflammation
- adaptive immunity
- delayed response
- more specific
- lymphocytes, plasma cells, monocytes/macrophages
- associated with intracellular organisms
pro-inflammatory cytokines
IL1 and IL6 => fever
IL8 => attracts neutrophils
TNFa => increased cyclooxygenase
pro-inflammatory mediators (endothelial cell contraction)
prostaglandins, leukotrienes, bradykinins, histamines
prostaglandins
arachidonic acid products that mediate vasodilation and increased vascular permeability, pain, and fever
leukotrienes
arachidonic acid products that attract neutrophils, mediate bronchospasm, and increased vascular permeability
bradykinins (from kallikrein)
mediate vasodilation via NO, increased vascular permeability, and pain
histamines
mediate vasodilation, endothelial cell contraction, and increased vascular permeability
what is the function of the vascular component of inflammation?
vasodilation (for increased blood flow) and increased vascular permeability (via endothelial cell contraction and damage)
what are the cellular components of acute inflammation?
neutrophils:
- drawn towards inflammatory mediators from mast cells and macrophages
- phagocytose and destroy organisms
- release cytokines to draw more neutrophils
monocytes:
- release more cytokines
what are the cellular components of chronic inflammation?
if neutrophils can’t remove the organisms, they produce cytokines to draw:
- lymphocytes
- plasma cells
- monocytes and macrophages
steps of neutrophil recruitment in the blood vessel
- margination
- rolling
- adhesion
- transmigration and chemotaxis
neutrophil margination
vasodilation and increased vascular permeability => slow blood flow => white cells move to periphery of vessel
neutrophil rolling
- histamine, IL1, and TNFa => P-selectin and E-selectin expression on endothelial cells
- sialyl lewis X on neutrophils binds to P-selectin and E-selectin
- selectin-neutrophil binding causes slow rolling of neutrophil on vessel wall
neutrophil adhesion
- C5a and leukotrienes => integrin expression on neutrophils
- TNFa and IK1 => ICAM and VCAM (cellular adhesion molecules) on the endothelium
- integrin - ICAM/VCAM interaction causes adhesion of neutrophil to endothelium
neutrophil transmigration
neutrophils migrate through the endothelium via diapedesis and move towards chemokines (IL8 and C5a) via chemotaxis
what is the cause and presentation of leukocyte adhesion deficiency (LAD)?
caused by: defect in integrins (CD18 subunit)
causes: delayed separation of umbilical cord, recurrent bacterial infections, high neutrophil counts in blood (they can’t escape to tissues)
what are the stages of phagocytosis?
- recognition and attachment
- engulfment
- destruction
what receptors are involved in recognition?
- PRRs for PAMPs: TLRs, NOD, RIG-I, MBL
- receptors for opsonins: complement C3b, IgM, IgG
how does a neutrophil engulf a bacterium?
- C3b (opsonin) binds to bacterial capsule
- Binds to C3b receptors on a neutrophil
- Neutrophil invaginates membrane to form phagosome
how do neutrophils destroy phagocytosed bacteria?
phagosome fuses with lysosome (which contains killing enzymes), forming a phagolysosome
what enzymes are involved in oxygen dependent killing of organisms?
Respiratory burst:
- NADPH oxidase forms superoxidase radical
- superoxide dismutase forms hydrogen peroxide
- myeloperoxidase catalyzes production of hypochlorite (in neutrophils only–most effective killer)
how to catalase + organisms evade immunity?
bacterial catalase breaks down hydrogen peroxide, decreasing the formation of hypochlorite by myeloperoxidase
what are the cause and presentation of chronic granulomatous disease?
cause: defect in NADPH oxidase => can’t product hydrogen peroxide to kill bugs
causes: recurrent infections from catalase + organisms and failure to kill organisms => granulomas
what are the cause and presentation of chediak-higashi?
cause: genetic defect in vesicle formation and trafficking => can’t form phagolysosome
causes: neutropenia with giant granules (lysosomes with built up myeloperoxidase) in neutrophils and monocytes, oculocutaneous albinism, susceptibility to pyogenic infections
how do inflammation/neutrophils damage tissues?
- neutrophils non-specifically release enzymes and free oxygen radicals into the extracellular space
- if a pathogen is not cleared, neutrophils continue to be activated => lots of free oxygen radicals => DNA damage and potential dysplastic/neoplastic change
how is inflammation resolved?
some tissues can regenerate (such as the top layer of the epithelim)
- macrophages release anti-inflammatory molecules (TGFB)
- macrophages recruit fibroblasts and release vascularization factors (forming granulation tissue)
- if tissue architecture was lost: fibroblasts deposit collagen and ECM to form scars
what are the components of granulation tissue?
fluid/empty space, blood vessels, collagen/fibroblasts
what are the two pathways of wound healing and when is each used?
First intention/primary union:
- wound only involves epithelium
- wound edges are approximated
Secondary intention/secondary union
- tissue loss is extensive
- would edges cannot be brought together
what are the steps of healing by first intention?
- hemorrhage and blood clot
- acute inflammation and scab formation
- proliferation: formation of epithelial cell layer under scab and granulation tissue below
- organization: fibroblasts make collagen and inflammation decreases
- scar formation: epidermis is intact but there is a loss of sweat glands and hair follicles and there is fibrous tissue beneath
how is healing by secondary intention different?
- larger clot
- more inflammation
- more granulation tissue
- wound contraction mediated by fibroblasts
what is fibrosis?
parenchymal organ damage caused by excessive collagen/ECM deposition in response to injury => organ disfunction
mediated by TGFB and occurs when tissue cannot regenerate
