Inflammation and Repair

Acute Inflammation

9/14/2010 6:36:00 PM

Acute Inflammation (AI) y

Signs

for Infection:

o

ubor R ubor

(R edness) edness)

o

Calor

o

Tumor

(Heat) (Swelling)

**all 3 are histamine mediated to cause vasodilation except that ubor R ubor

and

Calor

are arterioles and Tumor increases permeability

of venules of venules to let fluid in interstitial space (edema) o

Dolar

Caused

 o y

Loss

(pain) by PGE2 and bradykinin

of Function

Causes: o

Infection, Immune

eactions, R eactions,

Necrosis, trauma, radiation,

burns, punctures Steps:

Vascular

y

Vasoconstriction (few seconds)

y

Vasodilation of arterioles o

Increases blood flow and hydrostatic pressure Histamine, NO, PGI2, serotonin

 y

Increase Permeability of Venules o

Endothelial cells contract together to leave gaps Leaks

 o

Caused

y

Swelling

y

educed R educed o

out fluid?

by Histamine,

Serotonin, C3a, C5a, LTC4-D4-E4

Blood Flow

Decrease

in hydrostatic pressure by outflo w of fluid into

interstital tissue Steps: Cellular y

NEUTROPHILS o

y

aggregate, neutrophils in periphery

E-Selectin o

y

R BC

primary leukocytes in acute inflammation

makes neutophils roll along endothelium

Deficiency

in selectin

 LAD

2

Adhesion o

Half the neutrophils are in circulating pool, half are in marginal pool 

Beta2

Intergrins (CD11a:CD18) help

with

adhesion

Deficiency



y

in

CD11a:CD18  LAD

type 1

Activated by C5a and leukotriene

B4

(LTB4) Enhanced by endotoxins

o

(neutropenia) y

Inactivated by Catecholamines, corticosteroids and lithium



ICAM and VCAM binds to integrin on surface of  neutofiles Mediated by Interleukin 1 and



Tumor Necrosis

Factor **neutrophils important in umbilical cord seperation o

If umbilical cord does not come off by a month then its problem Also severe gingivitis and poor

wound

healing means no

neutrophils y

Diapedesis o

Neutrophils rolls along the endothelium and dissolves thru to enter the interstial fluid 

It helps dilute the bacterial toxin and provins IgG and C3b to help with phagocytosis

y

Chemostasis o

y

helps neutrophil find infection

Mediators

 C5a

and

LTB4

and Interluekin 8

Phagocytosis o

Opsonization 

Opsonin (IgG & C3b) attach to bacteria



Neutrophil attaches to bacteria *Bruton¶s agammaglobulinema Is a opsonization defect

o

Ingestion 

Neutrophils engulf bacteria into vacuoles 

Lysosomes

empty hydrolytic enzymes into

vacuoles producing phagolysosomes *Chediak

Higashi

phagolysosomes o

Killing

sydrome cannot produce



MPO (O2 dependent myeloperoxidase)

Only

in

neutrophils and monocytes (not macrophages) 

Produces superoxide O2y

NADPH oxidase converts oxygen to superoxide o



R eleases

Superoxide

respiratory burst

dismutase converts superoxide to

hydrogen peroxide 

MPO combines HOCL-



with

H2O2 and

Chloride

to make

kills bacteria

**Chronic Granulomatous Disease 

X Linked

**MPO 

or AutoR ecessive

y

Deficiency of NADPH oxidase

y

No O2- and H2O2 produced

y

No respiratory burst

Deficiency

AutoR ecessive y

O2- and H2O2 produced

y

There

is a respiratory burst

**G6PDH defiency



no NADPH Oxidase

**Diabetes Mellitus 

TYPES y

Defects

in phagocytosis and chemotaxis

OF AI Purulent (suppurative) inflammation o

Proliferation of pus forming organisms 

S.

Aureus (most common cause 

Contains y

coagulase

Cleves o

y

fibrinogen to fibrin (blood

Traps

Clots)

bacteria

Fibrinous Inflammation o

Due to increased vessel permeability with deposition of  fibrin 

y

Serous o

Often occurs on pericardium, peritoneum and pleura

Inflammation

Thin

Watery Exudate



Insuffinct amount of fibrinogen to produce fibrin 

y

Examples blisters

Pseudomembranous Inflammation o

Bacterial toxin (clostridium difficle) causes damaged to mucousal lining 



pseudomembranous colitis

Produces shaggy membrane composed of necrotic tissue

IMMUNOGLOBIN M Transudate  y

Can

clear fluid, protein less produce pitting edema

Exudate ±> protein full, cell rich (neutrophil) y

Produces swelling of tissue but no pitting edma o

Ex pus

Fever Occurs Acte Phase y

R eaction 

mediated by IL6

Endocirne ± secretion of  C

R eactive

protein,

Associated Protein y

Autonomic ± Increased pulse and BP

y

Behavorial ± chills, rigor,anorexia, malaise

Bacterial infection Parasite Viral







neutrophilia

eosinophilia

lymphocytosis

Serum

Amyloid

Cell

Mediators

9/14/2010 6:36:00 PM

Vasodilation y

Histamine, nitric oxide, PGI2, serotonin

Vasoconstriction y

Thromboxane

A2

Increased Vessel Permeability y

Histamine, bradykinin,

y

Bradykinin, PGE2

y

PGE2, IL1, TNF, IL6

LTC4-D4-E4, C3a

& C5a,

Serotonin

Pain Fever Chemotaxis y

C5a, LTB4,

IL8, IgG

Prostatagladins comes from macrophages, endothelial cells, and platelets and

COX y

Makes o

TXA2

TXA2 

via PGH2 helps

with

clotting

Leukotrines y

Comes

from Aracadoninc Acid via lipoxygenase mediated

hydroxylation o

Inhibited by zileuton

Bradykinin y

Product of kinin system activated by activated Factor 12

Chemokines y

Activates neutrophil chemotaxis o

Comes

from endothelial cells

Complement y

Syn

from liver

o

C3a,C5as

and so on

o

Increase vascular permeability

o

Stimulates

mast cells

Interluekins y

Comes

from macrophages, moncytes, dendritic cells and endothelial

cells o

IL1 

Fever, Leukocyte adhenion, coagulation

Histamine y

Comes

from mast cells

Nitric Oxide y

Comes

from macrophages, platelets and enterochromaffin cells,

endothelial cells Serotonin y

Comes

from platelets, mast cells

y

Increases vascular permeability

Chronic

Inflammation

9/14/2010 6:36:00 PM

Inflammation that is prolonged y

Causes: o

Infections ex.

Hep

C

Most common



y

TB, Leprosy,

o

Autoimmune

o

Sterile

 R heumatic

Agents

 Silica,

Arth.

Systemic Lupus

Uric Acid,

Silicone

in breast implants

Morphology o

Cell

involved



Monoctyes



Macrophages (key cells)



Lymphocytes



Plasma



Eosinophils

o

Necrosis 

o

Destruction of Parenchyma 

o

Loss

not as prominent

of tissue function



repaired via fibrosis

Formation of Granulation Tissue (Scar Tissue) 

Needs Fibronectin 

Fibroblast makes the collagen on the bv to help form new blood vessels Needs

y

Vascular Endothelial

Growth

Factor (VEGF) and Fibroblast Growth Factor (FGF) o

Important for angiogenesis

Increase in serum IgG y

Granuloma inflammation o

Aggregates of modified macrophages 

Surrounded 

o

Immune Granuloma (TB)

Non caseating 

Central 

o

May have central area of caseation in

Based on pathogenesis 

o

by lymphocytes and fibrosis

Mechanism

area has not gone under necrosis,

See

giant cells and lymphocytes

TB



CD4 

cells activated and produce IFN Gamma IFN Gamma acts on macrophage and macrophage becomes epitheloid cell and becomes a

wall

R epair

9/14/2010 6:36:00 PM

Tissue R epair: y

Two

Factors

o

Parenchymal

o

R epair

Parenchymal y

Cell

Depends o

by

Cell R egeneration

Connective

tissue

R egeneration

on

Labile

Cell

ability to reproduce

(stem) and

Stable

(don¶t replicate unless needed)

(fibroblast, hepatocytes, kidney cells) can replicate o

Permanent (cardiac, and striated muscle) are replaced by scar tissue

o

Cell Cycle 

G1 is the most variable phase in cell cycle 

Controlled y

by

and

Cyclin D

Cyclin d binds to Cdk4 causing the cell to enter



Cdk4

R epressed

S

by

phase R etinoblastoma

y

Keeps

y

Cdk4 binds to

(R B)

cell in G1 phase R B

to allow cell to go into

S

phase 

TP53 y

Inhibits

y

Make sure that o

Cdk4 DNA

damaged is repaired

If damage is too much BAX is activated 

Inhibits BCL2 (antiapotosis) 

R elease

cytochome c and

apotosis occurs o

R estoration

and R epair

needs preservation of basement membrane

ECM

by connective tissue

**macrophages play major role in healing process y

Occurs

y

Steps o

when

injury is severe or persistant

in repair R equires

neutrophil transmigration to liquefy injury tissue and

macrophages to remove the debris o

R equires

formation of granulation tissue

 o

Accumatulates in ECM and produces scar

Needs

Type

3

Collagen

(major component of connective

tissue) o

Collagen Synthesis

First intention: clean

wound,

edges are close together, less time to heal, less

fibrosis, epithelila regereration occurs Second

intention: big defect, edges are messed up

Factors that impair y

Persistant infection o

Most common cause of impaired 

y

Healing

Staph

Aureus



wound

healing

most common pathogen

Metabolic disorders o

Ex.

Diabetes



Mellitus

Causes

decreased blood flow and increase glucose in

tissue y

Nutrition defiencies o

Protein

o

Vit

o

Copper 

C  Scurvy



causes Ehlers

Stretchy 

o

Danlos

skin

Cant

make cross links

Zinc 

Needed for removal and remodeling by activating metalloproteinase, degrades excess extracellular matrix

o

Glucocorticoids 

Interferes

with

collagen formation, prevents healing

process 

R epair y

Used to prevent over scarring ( Keloids)

in other tissue Liver o

Mild Injury (Hep A) 

R egeneration 

o

Severe 

of hepatoctyes

Will restore to normal if cytoskeleton is intact

Injury (Hep

C)

Increased fibrosis

will

occur and lead to cirrhosis



R egenerative

nodules that develop lack sinusoids

and portal triad y

Lung o

Type 

2 Pneuoctyes repair the cell Synthesizes 

y

Astroctyes and Microglial cells

Periphreal Nerve o

y

Schwann Cells

Heart o

Cardiac 

Keloid  y

occurs if type 2 is damaged to much

Brain o

y

R DS

surfactant

muscle is permanent

R eplaced

by scar tissue

usually in African Americans Excess of synthesis of type 3 collagen

Proud Flesh y

Excessive granulation tissue o

May block epithelial regeenreation

Hypertrophic scarring y

Type

1 collagen

Contracture y

Permanent tighting of skin, muscle, tendon, ligaments and prevents normal body movment