Block 1 Acute Inflammation Flashcards
Inflammatory response components
Vascular: increased flow, vessel structure changes for plasma protein & leukos to leave circulation
Cellular: emigration and accumulation of WBCs, activation of cells, cytokines, etc.
Stimuli of acute inflam
Infection, trauma, tissue necrosis (ischemia, phys/chem injury), foreign body, immune reaction (AI, hypersens rxn)
Toll-like receptor
In PM, endosomes; sense microbial products, recognize bacterial DNA and viral dsRNA, activate TFs (inflam mediators, interferons, lympho activation)
Inflammasome
Recognizes products of dead cells (uric acid, extracell ATP, crystals), activates caspase-1 to activate IL-1b -> recruit leukos
Cryoporin-associated periodic fever syndromes (CAPS)
Gain of function mutation in cryoporin (inflammasome component)
Signs of acute inflammation
Rubor, calor, tumor, dolor, loss of function
Causes of increased vascular permeability
Contraction of venule endothelial cells (histamine, bradykinin, LKT, substance P) for 15-30 min Cytoskeleton changes (TNF, IL-1) 4-6 hours for 24 hrs or more Endothelial injury (trauma, microbe, neutro) -> delayed, prolonged leakage
Trancytosis
Fluid, protein through endothelial cells in venules via vesiculovacuolar organelle (channels ^ by VEGF)
Transudate
Serous ultrafiltrate of plasma with little cellular material, low protein, low specific gravity; can cause effusion; ex: blister, serositis
Exudate
Fibrinous fluid due to endothelial gaps in venules, contains cellular material, some protein, high specific gravity; converted to scar tissue in organization; ex: friction rub, adhesions
Pus/purulent/suppurative
Exudate with abundant neutros, bacterial infection (Staph); abscess is localized collection of purulent inflammatory tissue
Extravasation of WBCs
Margination, rolling, adhesion, transmigration (diapedesis), migration (chemotaxis)
Selectins
For rolling; E on endothelium, P on endothelium and platelets, L on leuko
Ligand: sialylated oligosaccharides with mucin-like glycoprotein backbone
Integrins
For adhesion: LFA-1, Mac-1 bind ICAM-1
VLA-4 binds VCAM-1
Leukocyte adhesion deficiency 1 and 2
1: Defect in B2 chain (LFA-1 and Mac-1) -> repeat bact infxn, poor healing, severe form needs bone marrow transplant
2: sialyl-Lewis X-ligand absence (for E- and P-selectins) -> lack fucosyl transferase enzyme, small stature, cog impairment, bact infxn
Transmigration proteins
PECAM-1/CD31 on endothelium and WBCs
Leukos invade BM with collagenases, adhere to ECM with integrins and CD44
Polys in 6-24 hr, mononuc in 24-48 hr
Chemotaxis chemoattractants
Exogenous: bact products (peptide with terminal N-formyl-methionine)
Endogenous: complement (C5a), AA pathway (LTB4), cytokines (IL-8)
Movement by actin polymerization
Causes of leuko activation
Microbes, ag/ab complexes, necrosis products, cytokines (INF-y)
Leukocyte activation responses
Increased cytosolic Ca2+, enzyme activation, AA metabolite production, cytokine secretion, degran of lysosomal enzymes, oxidative burst, modulation of adhesion molecules
Phagocytosis recognition, attachment, result
Mannose/scav receptors for LDL, opsonization by IgG (FcR on WBCs), C3b (CR1,3), plasma lectins/collectins (C1q)
Formation of phagocytic vacuole + lysosome = phagolysosome
Phagocytosis killing mechanisms
Resp burst (H2O2)
Myeloperoxidase -> HOCl
NO -> peroxynitrite (free rad)
Neutrophil granules (enzymes/elastase, defensins, lysozyme, MBP)
Chronic granulomatous disease of childhood
Deficiency of NAPDH oxidase = impaired phagocytosis and resp burst
Myeloperoxidase deficiency
Candida infections
Chediak-Higashi syndrome
AR defect in LYST (lyso transfer to phago vacuole) -> infection susceptibility, albinism due to abnormal melanocytes, giant granules in leukocytes
NETs (neutro extracellular traps)
Extracellular framework of nuclear chromatin & embedded granule proteins, response to bact/fungi & inflam mediators -> physical barrier, high conc antimicrobials -> death of neutro (nuc ag in AI?)
Histamine
Preformed in mast cells, basos, platelets
Trauma, ab (IgE), C3a/5a, IL-1,8
Binds H1-R -> dilation arterioles, increased venule perm
Inact by histaminase
Serotonin
Preformed in platelets, enterochromaffin cells, neurons -> vasoconstriction
Steroids
Inhibit phospholipase -> no AA, LKT, LX, PG, TX
COX-1,2 inhibitors
Inhibit COX = no PG, TX but AA, LKT, LX allowed
Platelet activating factor
Platelets, basos, neutros, mast, MF, endothelium; vasodilation, bronchoconstriction, increased vasc perm, increased WBC adhesion, chemotaxis, degran, ox burst
Nitric oxide
Endothelium, MF, neutros; vasodilation, inhibits WBC recruitment, mast cell induced infam, derivatives = microbicidal
TNF and IL-1
MF, mast -> endothelium, WBCs, fibros, marrow
Systemic acute phase rxn with IL-6
TNF: lipid, protein mobilization, dec appetite, cachexia
IL-1: mutation upregulates genes for caspases = more IL-1 (fam Med fever), activated by urate crystals (gout)
IL-17
From T-lymphs to promote neutro recruitment
ROS
Endothelium damage = ^ perm, protease activation, injury to RBC, parenchyma, inactivated by SD, CAT, GSH peroxidase, ceruloplasmin, transferrin
Leukocyte granules
Specific: lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, alkaline phosphatase
Azuro: myeloperoxidase, lysozyme, defensin, acid hydrolase, elastase, cathepsin G, collagenases
Seurm proteases that counteract leukocyte granular contents
a1-antitrypsin (inh neutro elastase) & a2 macroglobulin
Substance P
Neuropeptide from sensory nerves, WBCs; fibromyalgia
Complement pathways: C3 cleavage
Classical: ag/ab fixation
Alt: microbial surface molecuels
Lectin: plasma mannose-binding lectin binds microbes
Complement factors
C3a, C5a: anaphylatoxins
C5a: WBC adh, chemotaxis, activation
C3b: opsonin for phagocytosis
C5-9: MAC for cell lysis
Hageman factor (XIIa)
Clotting, fibrinolysis, kinin, complement system trigger
Thrombin (IIa)
Coagulation protease, binds PARs -> mobilize P-sel, chemo, cytokines, inc adh molecules, induces complement and AA pathway
Kinins
Vasoactive peptides from plasma proteins (kininogens) by proteases (kallikreins - autocatalytic activator of Hageman)
Bradykinin: inc vasc perm, dilates vessels, pain
Acute inflammation lab tests
Elevated WBC with left shift (15-20k, mostly neutrophils, toxic granulations), elevated erythrocyte sedimentation rate, SPEP elevated alpha-1,2 fractions, increased CRP
SPEP
Serum protein electrophoresis
Normal WBC count
7-9k per uL
ESR & what does elevated mean?
Erythrocyte sedimentation rate
More rapid sed with inc fibrinogen
>100 mm/hr = AI, neoplastic, infection
Normal values for ESR
Male: age/2
Female: (age + 10)/2
SPEP alpha-1,2 fractions
a1: antitrypsin, TBG, transcortin
a2: haptoglobin, ceruloplasmin, a2 macroglobulin
CRP
C-reactive protein: acute phase reactant, increase x1000 in acute inflam, opsonin or fixes complement, non-specific, helpful in acute appendicitis, ? useful assessment cardiac risk
Histopathology of acute, chronic inflammation
Acute: stasis, vascular congestion, fluid/protein exudate = edema, margination, emigration neutros
Chronic: mononuclear cells, angiogenesis, tissue destruction via proteases/ROS, fibrosis
5 R’s of acute inflammation
Recognize injurious agent Recruit leukos Remove agent Regulate response Resolution
