2 Inflammation and Repair

8/11/2019 2 Inflammation and Repair

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2 Inflammation and Repair

Acute Inflammation

Transient and early response to injury that involves release of chemical

mediators, causing stereotypic vessel and leukocyte responses

AcuteInflammation

Transient and early response to injury that involves release of chemical

mediators, causing stereotypic vessel and leukocyte responses

Cardinalsigns ofinflammation

1. Rubor (redness) and calor (heat)

o istamine!mediated vasodilation of arterioles". Tumor (s#elling)

o istamine!mediated increase in permeability of venules

$. %olor (pain)

o &rostaglandin (&') "sensities specialied nerve endings to the

effects of bradykinin and other pain mediators.

*timuli foracuteinflammation

1. +nfections (e.g., bacterial or viral infection)

". +mmune reactions (e.g., reaction to a bee sting)$. ther stimuli

o Tissue necrosis (e.g., acute myocardial infarction), trauma, radiation,

burns

*e-uentialvascularevents

1. asoconstriction of arterioleso /eurogenic refle0 that lasts only seconds

". asodilation of arterioles

a. istamine and other vasodilators (e.g., nitric o0ide) rela0 vascular

smooth muscle, causing increased blood flo#.b. +ncreased blood flo# increases hydrostatic pressure.

". +ncreased permeability of venulesa. istamine and other mediators contract endothelial cells producing

endothelial gaps.b. transudate (protein and cell!poor fluid) moves into the interstitial

tissue.$. *#elling of tissue (edema)

o /et outflo# of fluid surpasses lymphatic ability to remove fluid.


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$. Reduced blood flo#

o decrease in hydrostatic pressure is caused by outflo# of fluid into

the interstitial tissue.

*e-uentialcellularevents

Chronic granulomatous disease (C'%), an 2!linked recessivedisorder, is characteried by deficient /%& o0idase in the cellmembranes of neutrophils and monocytes. The reduced productionofresults in an absent respiratory burst. Catalase!positive organismsthat produce ""(e.g., Staphylococcus aureus) are ingested but

notkilled, because the catalase degrades "". 3yelopero0idase ispresent, but Cl4is notsynthesied because of the absence of"". Catalase!negative organisms (e.g., Streptococcusspecies)are ingested and killed #hen myelopero0idase combines ""#ithCl!to form Cl4. The classic screening test for C'% is the nitrobluetetraolium test (/5T). +n this test, leukocytes are incubated #ith acolorless /5T dye, #hich is converted to a blue color if therespiratory burst is intact. This test has been replaced by other moresensitive tests.

3yelopero0idase (3&) deficiency, an autosomal recessivedisorder, differs from C'% in that bothand ""are produced (normal respiratory burst). The absence of3& prevents synthesis of Cl4.

The events described #ill emphasie neutrophil events in acute inflammation

due to a bacterial infection (e.g., Staphylococcus aureus).

1. /eutrophils are the primary leukocytes in acute inflammation". 3argination

a. R5Cs aggregate into rouleau0 (6stacks of coins6) in venules.b. /eutrophils are pushed from the central a0ial column to the periphery

(margination).$. Rolling

a. %ue to activation of selectin adhesion molecules on the surface of

neutrophils and endothelial cellsb. /eutrophils loosely bind to selectins and 6roll6 along the endothelium.7. dhesion

a. dhesion molecules firmly bind neutrophils to endothelial cells.b. /eutrophil adhesion molecules

i. 8"!+ntegrins (C%11a9C%1:)ii. dhesion molecule activation is mediated by C;a and

leukotriene 57(


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i. +ntercellular adhesion molecule (+C3) and vascular celladhesion molecule (C3) bind to integrins on the surface ofneutrophils.

ii. +C3 and C3 activation is mediated by interleukin 1 (+

d.

nly present in neutrophils and monocytes (not

macrophages)


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&roduction of supero0ide free radicals

/%& o0idase converts molecular "to

, #hich releases energy called therespiratory, or o0idative, burst.

&roduction of pero0ide ("") *upero0ide dismutase converts

to "", #hich is neutralied by glutathionepero0idase.

&roduction of bleach (Cl4)

3& combines ""#ith chloride (Cl!) to

form hypochlorous free radicals (Cl4),#hich kill bacteria.

Chronic granulomatous disease and 3& deficiency

are e0amples of diseases that have a defect in the"!dependent 3& system.

%eficiency of /%& (e.g., glucose!?!phosphate

dehydrogenase deficiency) produces a microbicidaldefect.

ii. "!independent system Refers to bacterial killing from substances located in

leukocyte granules

0amples!lactoferrin (binds iron necessary for

bacterial reproduction) and major basic protein(eosinophil product that is cytoto0ic to helminths)

Chemicalmediators

Table 2-1. Sources and Functions of Chemical Mediators

Mediator Source(s Function(s

Arachidonic AcidMetabolites

&rostaglandins 3acrophages, endothelial cells,platelets&'"9 major precursor of &'sand thrombo0anes

&'"9 vasodilation, pain, fever&'+"9 vasodilation inhibition of plateletaggregation

Thrombo0ane " &lateletsConverted from &'"bythrombo0ane synthase

asoconstriction, platelet aggregation,bronchoconstriction

endothelial cells+nitiate &'"synthesis in anteriorhypothalamus, leading to production offever


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ctivate endothelial cell adhesion molecules+ncrease liver synthesis of acute!phasereactants, such as ferritin, coagulationfactors (e.g., fibrinogen), and C!reactiveprotein+ncrease release of neutrophils from bonemarro#

+

+

$istamine 3ast cells (primary cell),platelets, enterochromaffin cells

asodilation, increased vessel permeability

%itric &'ide (%& 3acrophages, endothelial cells=ree radical gas releasedduring conversion of arginine tocitrulline by / synthase

asodilation, bactericidal

Serotonin 3ast cells, platelets asodi lation, increased vessel permeability

+


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a.


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granulomas)b. 3orphology

i. &ale, #hite nodule #ith or#ithout central caseation

ii. Esually #ell!circumscribed

iii. Cell types pithelioid cells

(activatedmacrophages),mononuclear(round cell)infiltrate (C%7helper T cells, orTcells of the T1type)

3ultinucleated

giant cells formedby fusion ofepithelioid cells

/uclei

usuallylocated attheperiphery

iv. &athogenesis of atuberculous granuloma

!& 2-1 S)*+)%C) &F F&RMATI&% &F A T+!)RC+,&+SRA%+,&MA

The tubercle bacillus Mycobacterium tuberculosisundergoes phagocytosis by alveolar macrophages(processing of bacterial antigen).

3acrophages present antigen to C%7 T cells in association

#ith class ++ antigen sites.

3acrophages release interleukin (+

interferon (activates macrophages to kill tubercle bacillusepithelioid cells), and migration inhibitory factor (causesmacrophages to accumulate).


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in tissuerepair

1. &arenchymal cell regeneration

". Repair by connective tissue (fibrosis)

&arenchymalcellregeneration

Table 2-2. Factors Inoled in Tissue Repair

Factor Function(sro/th Factors

ascular endothelial cell gro#thfactor ('=)

*timulates angiogenesis

5asic fibroblast gro#th factor(5='=)

*timulates angiogenesis

pidermal gro#th factor ('=) *timulates keratinocyte migration*timulates granulation tissue formation

&latelet!derived gro#th factor(&%'=)

*timulates proliferation of smooth muscle, fibroblasts,endothelial cells

$ormones

+nsulin gro#th factor!1 (+'=!1) *timulates synthesis of collagen&romotes keratinocyte migration

Interleu#ins (I,

+

from the liver

1. %epends on the ability of cells to replicatea.


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22 3ost critical phase of the cell cycle

222 Control proteins include cyclin!dependent kinase 7 (Cdk7)

and cyclin % 'ro#th factors activate nuclear transcribing proto!

oncogenes to produce cyclin % and Cdk7.

Cyclin % binds to Cdk7, forming a comple0 causingthe cell to enter the * phase.

2222 RB(retinoblastoma) suppressor gene

R5 protein product arrests the cell in the '1phase.

Cdk7 phosphorylates the R5 protein causing the cell

to enter the * phase.2v2 TP53suppressor gene

T&;$ protein product arrests the cell in the '1phase

by inhibiting Cdk7. &revents R5 protein phosphorylation and, if

necessary, provides time for repair of %/ inthe cell

+n the event that there is e0cessive %/ damage,the BAgene is activated.

BAgene inhibits the BC!"antiapoptosis

gene (Chapter 1) causing release ofcytochrome cfrom the mitochondria andapoptosis of the cell.

". Restoration to normala. Re-uires preservation of the basement membraneb. Re-uires a relatively intact e0tracellular matri0 (C3 i.e., collagen,

adhesive proteins)


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type +++ collagen begins but does notbridge the incision site.3acrophages replace neutrophils.

%ays 7!?9 granulation tissue formation peaks, and collagen

bridges the incision site.

Heek "9 collagen compresses blood vessels in fibrous

tissue, resulting in reduced blood flo#. Tensile strength is1GI.

3onth 19 collagenase remodeling of the #ound occurs, #ith

replacement of type +++ collagen by type + collagen. Tensilestrength increases, reaching :GI #ithin $ months. *cartissue is devoid of adne0al structures (e.g., hair, s#eatglands) and inflammatory cells.

Secondar" Intention

Typically, these #ounds heal differently from primary

intention9

3ore intense inflammatory reaction than primary healing

+ncreased amount of granulation tissue formation than inprimary healing

Hound contraction caused by increased numbers of

myofibroblasts

1. ccurs #hen injury is severe or persistento Tissue in a third!degree burn cannotbe restored to normal o#ing to

loss of skin, basement membrane, and connective tissueinfrastructure.

". *teps in repair

a. Re-uires neutrophil transmigration to li-uefy injured tissue and then

macrophage transmigration to remove the debrisb. Re-uires formation of granulation tissue

ccumulates in the C3 and eventually produces dense

fibrotic tissue (scar)c. Re-uires the initial production of type +++ collagen

22 Collagen is the major fibrous component of connective tissue.

222 +t is a triple heli0 of cross!linked J!chains.


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22 Hound remains open

222 Esed for gaping or infected #ounds

=actorsthatimpairhealing

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1. &ersistent infectiona. 3ost common cause of impaired #ound healingb. Staphylococcus aureusis the most common pathogen.

". 3etabolic disorders

o 0ample!diabetes mellitus increases susceptibility to infection by

decreasing blood flo# to tissue and increasing tissue levels ofglucose.

2. /utritional deficiencies

a. %ecreased protein (e.g., malnutrition)b. itamin C deficiency

%ecreased hydro0ylation of proline and lysine causes

decreased tensile strength in collagen o#ing to loss oflinkage sites bet#een J!chains.

c. Trace metal deficiency

22 Copper deficiency leads to decreased cross!linking of J!

chains in collagen.222 Kinc deficiency leads to defects in removal of type +++ collagen

in #ound remodeling.". 'lucocorticoids

a. +nterfere #ith collagen formation and decrease tensile strength

b. ccasionally used along #ith antibiotics to prevent scar formation(e.g., bacterial meningitis)

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@eloids, the raised scars caused by e0cessive synthesis of type +++collagen, are common in frican mericans and may occur as the

result of third!degree burns. 3icroscopically, keloids appear asirregular, thick collagen bundles that e0tend beyond the confines ofthe original injury

Repairin othertissues

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1.


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triads.ii. +ncreased fibrosis occurs around regenerative nodules.

&otential for cirrhosis

".


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&eripheral blood neutrophil pools

3arginating pool9 adherent to the endothelium (account for ;GI ofperipheral blood pool)

Circulating pool9 measured in complete blood cell count (C5C)

Causes neutrophilic leukocytosis

+nfections (e.g., acute appendicitis)

*terile inflammation #ith necrosis (e.g., acute myocardial infarction)

%rugs inhibiting neutrophil adhesion molecules9 corticosteroids,catecholamines, lithium

3onocytes andmacrophages

@ey cells in chronic inflammationReceptors for +g' and C$b3onocytes become macrophages9 fi0ed (e.g., macrophages in red pulp),#andering (e.g., alveolar macrophages)=unctions9 phagocytosis, process antigen, enhance host immunologicresponse (secrete cytokines like +

5 cells and T cells &eripheral blood lymphocyte count9 T cells ?G!LGI, 5 cells 1G!"GI of thetotal5 cell function9 become plasma cells #hen antigenically stimulatedT cell functions9 cellular immunity (type + *R), cytokines regulate 5 cells,defense against intracellular pathogens (e.g., tuberculosis)Causes of 5MT lymphocytosis9 viral infections

&lasma cells ntibody!producing cells derived from 5 cells3orphology9 #ell!developed rough endoplasmic reticulum (site of proteinsynthesis) bright blue cytoplasm under Hright!'iemsa stain nucleuseccentrically located and has perinuclear clearing

3ast cells andbasophils

Release mediators in acute inflammation and allergic reactions (type + *R)Receptors for +garly release reaction9 release of preformed mediators (i.e., histamine,chemotactic factors, proteases)

%efined as greater than 1GI band (stab) neutrophils or thepresence of earlier precursors (e.g., metamyelocytes)

b. To0ic granulation &rominence of aurophilic granules (primary lysosomes) in

neutrophils


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c. +ncrease in serum +g3

i. &eaks in L to 1G daysii. +sotype s#itching (N heavy chain replaced by F heavy chain)

in plasma cells to produce +g' peaks in 1" to 17 days.

". Chronic inflammation (e.g., tuberculosis)

b. bsolute monocytosisc. +ncrease in serum +g'

$. summaries cells involved in inflammation.7. &eripheral blood effects of corticosteroid therapy

d. bsolute neutrophilic leukocytosis

+nhibits activation of neutrophil adhesion moleculesb. 5 cells and T cells &eripheral blood lymphocyte count9 T cells ?G!LGI, 5 cells 1G!"GI of thetotal

5 cell function9 become plasma cells #hen antigenically stimulatedT cell functions9 cellular immunity (type + *R), cytokines regulate 5 cells,defense against intracellular pathogens (e.g., tuberculosis)Causes of 5MT lymphocytosis9 viral infections


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&lasma cells ntibody!producing cells derived from 5 cells3orphology9 #ell!developed rough endoplasmic reticulum (site of proteinsynthesis) bright blue cytoplasm under Hright!'iemsa stain nucleuseccentrically located and has perinuclear clearing

3ast cells andbasophils

Release mediators in acute inflammation and allergic reactions (type + *R)Receptors for +g

arly release reaction9 release of preformed mediators (i.e., histamine,chemotactic factors, proteases)

%efined as greater than 1GI band (stab) neutrophils or thepresence of earlier precursors (e.g., metamyelocytes)

b. To0ic granulation &rominence of aurophilic granules (primary lysosomes) in

neutrophilsc. +ncrease in serum +g3

i. &eaks in L to 1G daysii. +sotype s#itching (N heavy chain replaced by F heavy chain)

in plasma cells to produce +g' peaks in 1" to 17 days.

". Chronic inflammation (e.g., tuberculosis)

b. bsolute monocytosisc. +ncrease in serum +g'

$. summaries cells involved in inflammation.7. &eripheral blood effects of corticosteroid therapy

d. bsolute neutrophilic leukocytosis

+nhibits activation of neutrophil adhesion moleculesb.


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ii. *ignal for apoptosis of lymphocytese. osinopenia

*e-uesters eosinophils in lymph nodes

rythrocytesedimentationrate (*R)

*R is the rate (mmMhour) of settling of R5Cs in a vertical tube.

1. *R is increased in acute and chronic inflammation (e.g., rheumatoidarthritis).

". &lasma factor or R5C factors that promote rouleau0 formation increase the*R.

a. +ncrease in fibrinogen (acute!phase reactant) in plasma decreasesnegative charge in R5Cs, promoting rouleau0 formation.

b. nemia promotes rouleau0 formation.

bnormally shaped R5Cs (e.g., sickle cells) do notproduce

rouleau0.

C!reactiveprotein(CR&)

1. cute!phase reactant". Clinical usefulness

a. *ensitive indicator of necrosis associated #ith acute inflammation

CR& is increased in inflammatory (disrupted) atheroscleroticpla-ues and bacterial infections.

b. 0cellent monitor of disease activity (e.g., rheumatoid arthritis)

*erum protein electrophoresis in inflammationClinical correlation9 &roteins in serum are separated into individualfractions by serum protein electrophoresis (*&). Charged proteinsplaced in a buffered electrolyte solution #ill migrate to#ard one orthe other electrode #hen a current is run through the solution.&roteins #ith the most negative charges (e.g., albumin) migrate tothe positive pole, or anode, and those #ith the most positivecharges (e.g., F!globulins) remain at the negatively charged pole, or

cathode. 5eginning at the anode, proteins separate into five majorpeaks on cellulose acetate!albumin, follo#ed by J1!, J"!, 8!, and F!globulins. The F!globulins in decreasing order of concentration are+g', +g, and +g3 (+g% and +g are in very lo# concentration).

1. cute inflammationa. *light decrease in serum albumin

i. Catabolic effect of inflammationii. mino acids are used by the liver to synthesie acute phase

reactants.b. /ormal F!globulin peak

*erum +g3 is increased in acute inflammation ho#ever, itdoes notalter the configuration of the F!globulin peak.

22 Chronic inflammation (see


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a. 'reater decrease in serum albumin than in acute inflammationb. +ncrease in F!globulins due to increase in +g'

%iffuse increase in the F!globulin peak is due to many clonesof benign plasma cells producing +g' (i.e., polyclonalgammopathy).

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