Inflammation, Inflamm Disorders, Wound Healing

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Acute inflammation basics

Back 1

characterized by presense of edema and neutrophils in tissue. response to infection (clear pathogen) and tissue necrosis (clear debris).
Immediate response w limited specificity (innate)

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Toll like receptors (a mediator of acute inflamm)

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on cells of innate immune system (macs, dendritic cells).
Activated by PAMPs.
CD14 (a TLR) on macs recognizes LPS on gram- bac.
TLR activation results in upreg of NFkB...a txn factor to activate immne response genes.

also present on cells of adaptive immunity.

Front 3

Arachidonic acid metabolites (mediator of acute inflamm)

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AA is released from phospholipid cell membrane by phospholipase A2...then 5Lipox -> LT, COX-> PG.

LTB4 attracts/activates neutrophils. LTC4,LTD4,LTE4 vasoconstrict, bronchospasm, inc vasc perm.
PGI2, PGD2, PGE2 (pain) vasodilate, inc vasc perm.
Vasodilation at arteriole, inc vasc perm at post cap venule.

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Mast cells (mediator of acute inflamm)

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activated by tissue trauma, complement C3a/C5a, cross linking of cell surface IgE.
Immediate response involves release of preformed histamine granules (vasodilate, inc vasc perm)
Delayed response produces AA metabolites (LT- maintain acute inflamm*).

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Complement (mediator of acute inflamm)

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Classical- C1 binds IgG/IgM.
Alternative- activated by microbial products.
Mannose bindin lectin- MBL binds mannose on microorg
All produce C3 convertase: C3-> C3a + C3b....then
C5 convertase: C5-> C5a + C5b (MAC w C6-C9)
C3a, C5a anaphylatoxins: trigger mast cell degran/hist release.
C5a is chemotactic for neutrophils
C3b is opsonin for phagocytosis.

Front 6

Hageman factor (mediator of acute inflamm)

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inactive proinflamm protein produced in liver.
Activated upon exposure to subendothelial/tissue collagen....
activates coag and fibrinolytic systems, complement, kinin system (cleave high molecular weight kininogen to bradykinn to mediate vasodilation and pain)

Front 7

Acute inflamm chemoattractants, pain mediators

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LTB4, C5a, IL8, bacterial products all attract and activate neutrophils.
PGE2 and bradykinin mediate pain by sensitizing nerve endings.
PGE2 also mediates fever.

Front 8

Pain and fever in acute inflamm

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Pain: bradykinin and PGE2 sensitize sensory nerve endings.
Fever: pyrogens (LPS) cause macrophages to release IL1, TNF....increase COX in hypothalamus...inrease PGE2 which raises temerature set point.

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Neutrophil arrival and function (first 2 steps)

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Margination: vasodilation to slow blood flow in postcap venues....neutrophiles marginate from center of flow to periphery.
Rolling: Selectin 'speed bumps' upregulated on endothelial cells to slow down neutrophils. (Pselectin from weibel palade bodies induced by histamine. E selectin induced by TNF, IL1)....selectins bind sialyl Lewis X on leukocytes...this interaction results in rolling of leukocytes along vessel wall.

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Neutrophil adhesion

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Cellular adhesion molecules upregulated (CAMs) on endothelium by TNF, IL1.
Integrins upregulated on neutrophil by C5a, LTB4.
Interaction of CAM and integrins = adhesion.

Leukocyte adhesion deficiency: AR defect in integrins (CD18 subunit). get delyaed separation of umbilical cord, lots of circulating neutrophils, recurrent bac infections that lack pus.

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Transmigration/chemotaxis and phagocytosis

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Transmigration/Chemotaxis: leukocytes transmigrate across endothelium of postcap venule and move toward attractants. attracted by IL8, LTB4, C5a, bac productes.
Phagocytosis: enhanced by IgG and C3b. pseudopods extend from leukocytes to form phagosomes that merge with lysosomes to get phagolysosomes.

Chediak- Higashi syndrome: syndrome of protein trafficking defect. impaired phagolysosome formation bc no microtubules to mobilize. (albinism, neutropenia, giant cells)

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Destruction of phagocytosed material

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O2 DEPENDENT:
NADPH oxidase: O2-> O2- oxidative burst
Superox dismutase: O2- -> H2O2
Myeloperoxidase: H2O2-> HOCl (bleach)
Chronic granulomatous disease: due to bad NADPH oxidase...get recurrent infections with catalase negative organisms (staph, pseudo cepacia)(catalase destroys H2O2 so cant make HOCl).
Nitroblue tetrazolim test is blue if good NADPH oxidase.
MPO deficiency: cant do H2O2-> HOCl, usually asymptomatic but can get Candida.

Front 13

Resolution

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Neutrophils under apoptosis (get pus) and disappear within 24 hours after resolution of inflamm stimulus.

Front 14

Macrophages in acute inflammation

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Predominate after neutropihls leave. peak at 2-3 days after inflamm begins. derived from monocytes.
Arrive same way neutrophils do.
Phagocytize orgs, kill with lysozyme (O2 independent).
Manage next step in inflamm process...
Resolution/healing: antiinflamm cytokines produced (IL10, TGFb)
Continued acute inflamm: IL8 to recruit more neutrophil.
Abscess: acute inflamm surrounded by fibrosis
Chronic inflamm: macs present Ag to activate CD4 helper Ts to secrete cytokines.

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Chronic inflammation basics

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presence of lymphocytes and plasma cells in tissue. Delayed but more specific than acute...adaptice.

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T lymphocytes basics

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Produced in bone marrow as progenitor cells, develop in thymus where T cell receptor rearranges and progenitors becore CD4/CD8 T cells.
T cells use TCR complex (TCR/CD3) for Ag surveillance.
Activation of T cells requires binding of MHC and B7 on APC binding CD28 (for CD4) or IL2 from Th1 (for CD8).

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CD4 helper T cell activation

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Extracellular antigen is phagocytosed, processed and presented on MHCII by APCs.
B7 on APC binds CD28 of T cell as 2nd activating signal.
Activated CD4 secrete cytokines that help inlflammation...
Th1: secrete IL2 (T cell growth factor,CD8 activator), IFNgamma (macrophage activator)
Th2: secrete IL4(allows B cell isotype switching), IL5 (eosinophil chemotax, maturation of B cells), IL10(inhibit Th1).

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CD8 cytotoxic T cell activation

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Intraacellular antigen processed and presented on MHCI (expressed by all nucleated cells, platelets).
IL2 from CD4 Th1 provides second signal.
Killing occurs via secretion of perforin and granzyme (perforin makes hole for granzyme to enter)...activates apoptosis via caspases. Or FasL binds Fas on target cells to activate apoptosis.

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B lymphocytes

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Immature B cells produced in bone marrow undergo immunoglobulin rearrangements to become naive B cells expressing IgM/D
Activation occurs via...
Ag binding to IgM/D -> IgM/D secreting plasma cell
B cell Ag presentation to CD4 -> CD40 binds CD40L -> T cell secretes IL4/5 for maturation/isotype switching

Front 20

Granulomatous inflammation

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collection of epithelioid histiocytes (macrophaeges w pink cytoplasm) surrounded by giant cells and lymphocytes.
Noncaseating: lack central necrosis- sarcoid, beryllim, crohns, cat scratch.
Caseating: central necrosis. TB, fungus.

Macs present Ag to CD4 -> macs secrete IL12 -> CD4 to Th1 -> Th1 secrete IFNgamma to convert macs to epithelioid histiocytes.

Front 21

DiGeorge syndrome

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developmental failure of 3/4 pharyngeal pouches due to 22q11 microdeletion.
T cell deficiency (no thymus), hypocalcemia (no parathyroid), abnormalities of heart, great vessels, face.

Front 22

Severe combine immunodeficiency

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Defective cell mediated and humoral immunity.
Etiologies...
Cytokine receptor defects: T and B cells cant proliferate and mature.
Adenosine deaminase defic: ADA necessary to deaminate adenosine for excretion, buildup toxic to lymphocytes.
MHCII defic: cant activate CD4.
Need sterile isolation and stem cell transplant

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X linked agammaglobulinemia

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Total lack of immunoglobulin bc disordered Bcell maturation (naive B cells cant mature to plasma cells).
Due to mutated Bruton tyrosine kinase.
Presents after 6 months of life w recurrent bacterial, enterovirus, giardia infections.
Cant use live vaccines.

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Common variable ummunodeficiency

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low immunoglobulin bc B or T cell defects.
Increased risk for bacterial, enteroviral, giardia infections.
Inc risk for autoimmune diseases in lymphoma.

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Hyper IgM syndrome

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Mutated CD40L (T cell) or CD40 (B cell)
T cell cant recieve signal to secrete IL4/5 to help B cell isotype switching.
Risk of recurrent pyogenic infections

Front 26

Wiskott aldrich syndome

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thrombocytopenia, eczema, recurent infections
Mutation in WASP. X linked

Front 27

Complement deficiencies

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C5-9 defic: inc risk for Neisseria infection.
C1 inhibitor defic: hereditary angioedema (periorbital) and mucosal surfaces....overactive complement.

Front 28

SLE

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Ab against host damage tissues (type II) and Ag-Ab hypersensitivity (type III).
Fever, wt loss, butterfly rash, arthritis, renal damage (diffuse proliferative glomerulonephritis), endocardidits (limann sacks). Renal failure/infection most common death.
ANA, antidsDNA (very specific), antihistone in drugs.
Antiphospholipid Ab syndrome: anticardiolipin (false pos syphillus) and lupus antigocag (false high PTT)...results in thrombosis

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Sjogren syndrome

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anti-ribonucleoprotein (Ro, La).
destruction of lacrimal, salivary glands.
Lymphocyte mediated damage (type IV) w fibrosis.
Present w dry eyes and dry mouth, recurrent dental carries. "cant chew cracker, dirt in eyes".
Assoc w RA. Inc risk for B cell lymphoma (unilateral enlargement of parotid late in disease).

Front 30

Scleroderma

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Antitopoisomerase. activation of fibroblasts, deposition of collagen.
Diffuse: esoph most common.
Localized: Calcinosis, Raynaud, Esoph dysmotility, Sclerodactyly, Telangiectasia of skin.

Front 31

Mixed connective tissue disease

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mixed features of SLE, systemic sclerosis, polymyositis
Ab against U1 ribonucleoprotein.

Front 32

Wound regeneration

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replacement of damaged tissue w native tissue.
Labile: tissue posseses stem cells that continously cycle to regenerate tissue (mucosal crypts, basal layer skin, bone marrow CD34).
Stable: tissues with quiescent (G0) cells that reenter cell cycle (liver)
Permanent: lack regenerative potential (heart, muscle, neurons)

Front 33

Wound repair

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replacement of damaged tissue with fibrous scar. occurs when regen stem cells are lost.
Form granulation tissue...
fibroblasts- deposit type III collagen (reticulin)
capillaries- provide nutrients.
myofibroblasts- contract wound.
Eventrually results in scar where type III is replaced by type I via collagenase w zinc.

Front 34

Mechanism of tissue regeneration and repair

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Mediated by paracrine signaling via growth factors from macrophages that target fibroblasts.
TGFalpha: epithelial and fibroblast growth factor
TGFbeta: fibroblast growth factor (inhibit inflamm)
PDGF: endothelium, smooth muscle, fibroblast factor.
FGF: for angiogenesis, skeletal development
VEGF: angiogenesis

Front 35

Normal and abberant wound healing

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Primary intention: wound edges brought together via suture w minimal scar.
Secondary intention: edges not approximated. granulation tissue fills defect. myofibroblasts contract wound.
Delayed heaing occurs in....
infection, Vit C deficiency, Copper defic (cant corsslink lys to stabilize collagen), zine defic (collagenase defic)
Hypertrophic scar: excess type I collagen
Keloid: excess type III collagen.