Usmle-gen Path p3

8/9/2019 Usmle-gen Path p3

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First Foundations in PathologyPart 3: Growth and Repair

Paul G. Koles, MD

Asst. Prof. Pathology and Surgery

Diretor of Pathology !duation"oonshoft Shool of Mediine at #right State $ni%ersity


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&%er%iew Part 3• 'ontrol of nor(al ell growth and regeneration

• !)traellular (atri) * ell+(atri) interations

• Repair y onneti%e tissue -firosis

• #ound healing


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Repair following infla((ation:

two si(ultaneous proesses• : replacement of

injured/necrotic cells by cells of same

type, often leaving no evidence ofprevious injury

• : replacement

of injured/necrotic cells by connectivetissue, leaving a permanent scar

(microscopic or macroscopic)


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'ontrol of ellular population


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'ell 'ylePHASES of

Cell Cycle:

G1:

S:

G2:

M:

G0:


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'orrelation of 'ell 'yle and /issue /ypes

• 'ontinuously di%iding -laile ells:

– Surface epithelium and excretory ducts of glands (sin,gi / gu mucosa, biliary tract, pancreas)

– !arro" hematopoietic cells

– Stem cells in multiple organs (immature, undifferentiatedcells)

• 0uiesent -stale ells in G1: – #rgan parenchymal cells (liver, idneys)

– !esenchymal cells (fibroblasts, smooth muscle,endothelium, chondrocytes, osteocytes)

• 2ondi%iding per(anent ells -ant re+enter ellyle – $eurons, seletal % cardiac myocytes


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'ontrol of Passage through 'ell 'yle

• : group of proteins thatcontrol cascade of phosphorylationpath"ays at various points in cell cycle

• : surveillancemechanism for ensuring orderly completionof molecular events, sensing problems in&$' replication, &$' repair, and

chromosome segregation f problemsidentified, progression to next phase of cellcycle can be delayed or stopped


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Mehanis(: ontrol of ell yle

Which cyclin ?

Which cyclin?

Cyclin-dependent kinase inhibitors


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'ell Growth: (oleular o%er%iewGrowth Factors or Cytokines

Changes in Gene !pression "#p and down reg#lation$

%ind to

&nitiate

'ro(ote

)es#lting in


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Modes of 4nterellular Signalling


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Surfae Reeptors: 3 lassesReceptors with

intrinsic

************* *************

*************

____________________

(G protein-coupled)

Receptors

without

intrinsic ___________

___________

___________


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'onse5uenes of Reeptor Ati%ation

• 4ntrinsi+6inase ati%ity reeptors:

– rreversible commitment of cell to enter

(proliferati%e response)

• Reeptors without intrinsi 6inase ati%ity

-yto6ine superfa(ily: – 'ctivation cytosolic inases to mediate functional

response (not proliferative)

• G+protein oupled -se%en spanning reeptors:

– #ver *+ receptors identified

– -ind various ligands, producing specific intracellular

response


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Signal /ransdution y /yrosine

Kinase Reeptors

Growth +actors: co(ing soon,

Clinical

application: i+

(#tant ras

protein is

per(anently

+i!ed in actie

G.' +or(/ what

pathologic process (ay

res#lt?


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/ransription Fators• Definition: intraellular proteins that regulate gene

e)pression, therey ontrolling ell growth• Specific domains in transcription factors:

– : permits factor to bind specifically to shortse.uences of &$'

– : allo"s factor to increase transcription of &$'

– :allo"s factor to decrease transcription of &$'

• ranscription factors no"n to be operative in malignantneoplasms:

– Growth pro(oting: +M7' and +8$2

– 'ell yle inhiiting -tu(or suppressor gene: p93


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Growth Fators

• Definition: proteins that bind to cell surface

receptors "ith

generating cascade response that signals

cell to enter S0phase (cell division)

• hese factors can also modulate cell

functions: locomotion, contractility,

differentiation, etc


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Maor growth fators ; effets

FA'/&R

• 123 4 epidermal

• 230a 4 transforming

• 51234vascular endothelial

• 6&234 platelet0derived

• 3234 fibroblast

• 3230*4acidic

• 323074basic

!FF!'/S

• !itogenic for epithelium % fibroblasts

• !itogenic for hepatocytes

• !itogenic for endothelial cells

• !itogenic for monocytes, fibroblasts,

smooth muscle cells8 activatesneutrophils

• 'ngiogenesis, "ound repair (mitogenic

for both fibroblasts and eratinocytes)


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issue 9egeneration

ier +ro( liing donor be+oretransplantation/ o#tlining right

lobe to be #sed +or gra+ting

into recipient

ier o+ donor one week post- partial hepatecto(y/ showing

ar!ed "rowth of left lo#e

(copensatory hyperplasia)

witho#t regrowth o+ right lobe

Why didnt right lobe regrow also?


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!)traellular (atri)


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!)traellular (atri) -!'M =

• Groups of (aro(oleules in !'M:

– Firous strutural proteins: 7 major families

are:

– Adhesi%e glyoproteins

– Gel proteins in intercellular junctions and cell

surfaces: proteoglycans % hyaluronic acid


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!)traellular (atri) -!'M 3

• !acromolecules of 1;! assemble into

t"o types of organi


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'ollagen: su((ary of (aor types

Skin "304$/ bone "504$/ tendons

Genetic deficiency of

type $% in:


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'ollagen synthesis&utrient re'uired

for hydroylation

of alpha chains:

eficiency of this

nutrient causes

poor wound

healin" in

disease called:

$nherited disorders

of colla"en

synthesis* leadin" to

defecti+e fi#ers:


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!lasti Fiers• &efinition: fibers capable of stretching and

recoiling to original si


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Adhesion (oleules <F#nction:

attach cells toEC atrices6

2 glycoprotein

chains held

together by

dis#l+ide bonds6

prod#ced by

+ibroblasts/

endothelial

cells/ 7(onocytes

8a(e?


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Adhesion (oleules =

Most ab#ndant

glycoprotein in

base(ent

(e(branes6 it

spans basal la(ina

and binds to bothcell s#r+aces and

CM co(ponents:


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Adhesion (oleules 3.rans(e(brane

glycoproteins with

alpha and beta chainsthat bind to

+ibronectin/ la(inin/

7 collagen .his

+a(ily o+ s#r+acereceptors (ediate

attach(ent o+ cell

(e(branes to CM:

.hese also (ediate

adhesion o+ which cell

type to endotheli#(?


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Su((ary: interations ell+!'M a.or EC structural protein:

/i"0 1-23* Patholo"ic 4asis of isease* 5th ed* Else+ier 6778


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&%er%iew: Repair after inury

AC9E A& CHR;&$C $&/


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Firosis -firoplasia

• 3our components:

– : formation ne" blood

vessels – of fibroblasts into

damaged tissue

– of extracellular matrix

– #rgani


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Se5uene of e%ents in repair

=> hrs: proliferation of fibroblasts % endothelial cells

#ithin 3+9 days:

8ew

capillaries

'roli+eration

o+ yo#ng

+ibroblasts

ittle

(at#re

collagen

bl#e-staining collagen

"trichro(e stain$

Peranent result

(wee!s later)


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Angiogenesis

• Definition: pre0existing vessels send outcapillary sprouts to form ne" vessels

• f. %asulogenesis: the primitive vascular

net"or established during embryogenesis• 'linial i(portane:

– 9epair post0inflammation

– 3ormation collateral circulation (post0!) – Support gro"th of neoplasms (therapeutic

implications)


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Angiogenesis: = (ehanis(s


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!'M proteins affeting angiogenesis

• 4ntegrins: formation and maintenance ne" vv• Matri) proteins "hich destabili


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Firosis -firoplasia

•1migration and proliferation of fibroblasts atinjury site, triggered by multiple gro"th

factors produced by cells in granulation

tissue, most important of "hich is:

• 1;! deposition by fibroblasts: fibrillar

collagen synthesis enhanced by gro"th

factors and cytoines, thus converting

&nto a


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/issue re(odeling

• ;onversion granulation tissue into scar

involves changes in composition of 1;!

• : en


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#ound ?ealingealing by +irst intention ealing by second intention


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Su((ary: phases of wound healing

=ound tensile stren"th: 27> of noral at 5 days?

57-@7> of noral at 1 onths


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Fators influening wound healing

• @oal Fators

– : most important single cause of delay

– !echanical: too early motion can delay

– Foreign odies: may impede or cause abscess

– @oation: speed of healing proportional to richness ofblood supply:

face > trun > extremities

– /ype of wound: pri(ary intention heals faster than

seondary intention


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Fators influening wound healing

• Syste(i fators:

– : first of t"o most important

factors !ost important deficiencies (7):

– : second of t"o most

important factors 'rterial or venous

insufficiency commonly delays healing

– : iatrogenic delay of healingby blunting the normal inflammatory/repair

response


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Pathologi o(pliations of healing

: exaggeration normalcontraction of "ound, resulting in deformity(palms, soles, anterior thorax) ;ommonafter burns

&eficient granulation tissue/ scar formation: – : rupture of "ound, usually

due to increased mechanical pressure orinappropriate movement

– : usually due to arterialinsufficiency caused by atherosclerosis8 venousstasis also can contribute


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Pathologi o(pliations, =

• 1xcessive formation of repair components:

– 1xcessive granulation tissue – &esmoid tumor (aggressive fibromatosis)

• -est vie"ed as lo" grade neoplasm "ith stubborn tendency forrecurrences

3ibrosis: Summary


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3ibrosis: Summary


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&%er%iew: infla((ation * repair


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'onlusion

• 6hysicians stand in "onder at the ama

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Usmle-gen Path p3

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