Inflammation Flashcards
2 key mechanisms of cellular injury
- hypoxia
- ischemia
4 cellular adaptations to injury
- hyperplasia
- hypertrophy
- atrophy
- metaplasia
hyperplasia
- increase in # of cells in organ or tissue
- often related to increase in demand for fxn
- may be associated with increase in cell size
- normal- uterus
- compensatory - liver repair
- pathalogic-graves
Autoimmune antibodies associated with Graves
HLAB8, HLADR3
Graves Pathogenesis
ab bind to TSH receptor –> increase TH hormone –> hyperplasia –> hyperthyroidism
Hypertrophy
- increase in cell size due to increased protein synthesis (not cell swelling)
- increased demand for function
Atrophy
- decrease in cell size
- decreased workload, decreased blood supply, inadequate nutrition, loss of endocrin, denervation
Spinal Muscular Atrophy (SMA) Pathogenesis
mutation in SMN1 gene –> LOF –>neuronal death –> atrophy of muscle
Metaplasia
- reversible change in differentiation program of tissue stem cells to different cell type
- e.g. columnar to squamous metaplasia of respiratory tract in response to cigarettes
Why is ischemia more rapidly injurious than hypoxia?
loss of both oxygen and nutrients
Factors of irreversible cell injur
- severe mitochondrial swelling –> free radical production and release
- extensive membrane damage –> Ca influx –> enzyme activation –> digestion of cell
Anti-oxidant mediators
- superoxide dismutase
- catalase
- glutathione peroxidase
Free radical effects on cell
- DNA –> breaks, modifications
- proteins –> misfolding, cross-linking
- lipid peroxidation –> unstable, chain-reactive
CCL4 mediated cellular injury - MOA
CCL4 –> converted to CCL3 radical by P450 –> lipid peroxidation –> diminished protein synthesis in ER –> reduced export from ER –> fat retention –> autocatalyzed peroxidation –> Ca influx –> death
Necrosis
morphologic changes due to degradative actions of enzymes on lethally inured cell
- coagulative
- liquefactive
- caseous
Coagulative necrosis-features
- acidophilic (pink) cytoplasm
- nuclei disappearance
- preservation of cell architecture
- hyperemic border
Coagulative necrosis is indicative of what process?
Irreversible ischemic injury
Liquefactive necrosis-features
- hydrolytic enzymes predominate
- rapid softening
- loss of architecture
- abscess formation
- brain and pus
Abscess
focal localized collection of bacteria and pus with fibrotic border w/liquefactive necrosis
Caseous necrosis-features
- incomplete liquefication of celular architecture
- cheesy
- granulomatous inflammatory wall
- mycobacteria
Apoptosis
regulated programmed cell death to eliminate unwanted cells
Apoptosis-features
- cells shrink
- chromatin condenses
- blebs form
- phagocytosis
- plasma membrane remains intact
- no inflammation
Apoptosis triggers
- withdrawal of growth factors
- receptor-ligand interactions (FAS)
- CTL mediated
2 main features of acute inflammation
- fluid exudation
- neutrophil emigration
2 main features of chronic inflammation
- scarring/fibrosis
- macrophages and lymphocytes
Vascular effects in acute inflammation
- vasodilation
- incrased permeability
- stasis
- leukocyte margination
Four key mediators that induce endothelial cell contraction in blood vessels to increase permeability
- histamine
- bradykinin
- leukotrienes
- VEGF
Edema
accumulation of fluid extravascular compartment or interstitial tissues (stains pink)
Exudates have a higher _______ than transudates
specific gravity due to protein/cell content
Serous inflammation-morphology
- watery, protein poor fluid
- bright pink
- few cells
Fibrinous inflmmation-morphology
- fibroblasts and vessels
- linings of body cavities
Suppurative inflammation-morphology
- neutrophils
- edema fluid
- necrotic cells
- central necrosis with scarring
Ulcer
site of inflammation where epithelial surface has become necrotic and eroded/sloughed
3 Key cellular events in inflammation
- leukocyte emigration
- chemotaxis
- leukocyte activation
Leukocyte rolling and activation
- rolling mediated by selectins –> bind w/low affinity to leukocytes
- integrins finally bind strongly
- leukocytes spread out on endothelial surface
- trnasmigration via PECAM-1/CD31
Key mediator of leukocyte transmigration
PECAM-1/CD31
Ways leukocytes kill ingested pathogens
- HOCL- myeloperoxidase radical
- bactericidal permeability increasing protein
- lysozyme
- major basic protein - parasites
Which complement molecules are anaphylatoxins?
C3a and C5a
Which complement molecule activates leukocytes via chemotaxis?
C5a
Which complement molecule is an opsonin?
C3b
Histamine
- found in mast, basophils, platelets
- released by truama, heat, IgE, C3a, C5a
- vasodilation and venular endothelial contraction
Roles of TNFalpha and IL1 in inflammation
- endothelial activation
- systemic acute phase reactions
- hypotension
- aggregation and activation of neutrophils, protease release, tissue damage
NO
- produced by macrophages and endothelial cells in inflammation
- vasodilator, antagonizes platelets, microcidal
*
Neutral proteases
- contained in neutrophil/monocyte lysosomal granules
- e.g. elastase, collagenase
- antiproteases like a-1 antitrypsin reduce tissue damage –> deficiency = emphysema
*
Chronic inflammation
- can coexist with acute
- can be caused by acute or start off chronic
- accumulation of APCs (macrophages, lymphocytes, plasma cells) –> lymphocytic infiltrate
- angiogenesis and feibrosis
Granulomatous inflammation
- characterized by epithelioid histiocyte cells -activated macrophages that are squamous (abundant pink cytoplasm)
- multinucleated giant cells (langhans)
- wall off injury
- tb
- leprosy
- syphilis
- cat scratch
- parasitic
- fungal
- silicosis
- foreign bodies (sutures
- sarcoidosis
- crohn’s
Granulation tissue
Fever generation in acute inflammation
- pyrogens
- exogenous: lps
- endogenous: IL1, TNF
ESR
acute phase proteins (fibrinogen and Ig) in plasma neutralize neg. charges on RBCs–> no more repulsion –> staacking –> sinking in test tube
A normal ESR rules out
inflammatory conditions.
Wound healing
repair of damaged tissue by replacement and/or regeneration
Regeneration
restoration of lost tissue structures via cell division
- division of parnchymal cells in normal stroma (post-CCL4 exposure)
- compensatory division of parenchymal cells (after hepatectomy)
- stem cell division
Replacement
filling of wound with less specialized connective tissue
Which tissues regenerate readily?
GI epithelium, epidermis, bone marrow
Which tissues regnerate on a normally limited but inducible basis?
liver, kidney, vascular endothelia
Healing by primary union
straight wound, well apposed edges, clean –> minimal scar
Healing by secondary union
Irregular wound, unapposed edges, dirty –> significant scarring
______ cells release PDGF, resulting in ______.
- activated platelets and macrophages
- proliferation of fibroblasts and vascular endothelial cells
______ cells release FGF, resulting in ______.
- macrophages and fibroblasts
- angiogenesis
______ cells release KGF, resulting in ______.
- fibroblasts
- growth of keratinocytes
______ cells release VEGF, resulting in ______.
- endothelial cells, fibroblasts, macrophages in hypoxic environment
- endothelial cell proliferation, angiogenesis, vessel permeability
______ cells release TGF beta, resulting in ______.
- platelets, macrophages, fibroblasts, keratinocytes
- A LOT
Wound healing day 0
- Clot
- entry of acute inflammatory cells
- chemokine and growth factor release
Wound healing day 2
epithelialization
Wound healing day 7
granulation tissue
Wound healing day 14
disordered collagenization (type 3)
Wound healing 1 year
organized scar-type 1 collagen
What cell cycle inhibitor may limit full wound healing and is a key mediator of proliferative arrest in senescent cells?
p21
