Lecture 11: Wound Healing and Surgical Inflammation

surgery =

creation of a wound

disruption of tissue homeostasis —> inflammation

normal surgical inflammation is

acute

mild-moderate

• dependent on procedure and body system

local

short duration

• reduced with primary wound closure

and self-limited

abnormal surgical inflammation

prolonged (chronic)

severe

signs of infection

systemic signs

• underlying pathology

phases of wound healing

what is the body’s goal during bleeding?

hemostasis, to stop bleeding while maintaining perfusion

Hemostasis involves:

endothelial cell disruption

• immediate vasoconstriction

• exposure of vWF —> platelet activation and aggregation

• coagulation cascade

hemostasis —> inflammation, how?

endothelial cells release vasodilators —> vasodilation

—> increased blood flow )- redness & heat

mediated by: histamine, NO, LTs, PGs, complement

hemostasis —> inflammation

post-capillary venule leakiness

increases inflammatory cell and inflammatory mediator infiltration

protein leakage

hemostasis —> inflammation

protein leakage

• decreased osmotic pressure

• increased blood viscosity

• increased interstitial pressure

= edema formation (swelling)

edema

• facilitates delivery of soluble factors and cells

• PAIN & loss of function

vascular congestion

• fluid loss to edema

• hemoconcentration

• reduced velocity of blood flow

inflammation is also called:

debridement phase

2 phases of debridement phase

early —> neutrophil recruitment

late —> monocyte transformation

functions of inflammation:

• prepares the body for next phases of wound healing

• removes dead tissue and foreign material

severity of truama —> intensity of inflammation —>

extent of scar tissue formed

leukocytes during inflammation are recruited from:

from circulation by chemoattractants (from coagulation)

initiate: Rolling, Activation, Tight Adhesion, and Transmigration of cells through microvascular endothelium

neutrophil diapedesis is encouraged by what during inflammation?

increased capillary permeability

diapedesis:

the passage of blood cells through intact capillary walls

when do neutrophils join the party during inflammation?

1-2 days after injury

neutrophil jobs

they are the first line of defense against contaminated wounds

they destroy debris

they phagocytose bacteria

the latter 2 jobs process ends when wound is cleaned up

what ends the early phase of inflammation?

when neutrophils destroy debris and phagocytose bacteria

macrophages during inflammation, how do they get there?

monocytes migrate from vasculature and become macrophages

what do macrophages do?

• pro-inflammatory functions

• stimulate proliferation of dermal, endodermal, and epithelial tissues

• help with remodeling phase

macs jobs help to orchestrate all the phases of wound healing!

how do we reach resolution of inflammation?

each of the pathways needs to be halted or reversed

apoptosis of cells

doesn’t always work!

• can lead to chronic, suppurative inflammation and a non-healing wound

• excessive granulation tissue (proud flesh in horses)

which phase of wound healing is the most easily manipulated by clinicians?

the inflammatory phase

what can clinicians do to modulate the inflammatory phase?

1) proper surgical debridement

2) good hemostasis

3) adequate drainage

4) medications

• NSAID's

• Steroids

how do steroids and COX 1 and 2 inhibitor affect inflammation

proliferation phase includes

fibroplasia

• necessary for other processes

angiogenesis

epithelialization

fibroplasia, what is it?

formation of granulation tissue by fibroblasts

• scaffold

• temporary barrier infection

granulation tissue

fibroplasia is made by 3 elements:

1) macrophages - debride, produce cytokines and growth factors that stimulate angiogenesis and fibroplasia

2) fibroblasts - proliferate and make new extracellular matrix

3) blood vessels - carry O2 and nutrients for cell metabolism and growth

when do you start to see granulation tissue?

around day 5!

fibroplasia in detail

• fibroblasts are directed by macrophages via cytokines and growth factors

  • produce ECM - initially more type III collagen (immature)

  • later more type I collagen (mature)

time of increasing wound strength with fibroplasia:

rapid gain 7 - 14 days

• corresponds to time of suture removal

angiogenesis is:

the formation of new capillaries from pre-existing vessels

what is angiogenesis regulated by:

macrophages and endothelium

• VEGF

• other misc. angiogenesis growth factors

increases tissue hypoxia —> increases vessel ingrowth

what happens during epithelialization and how fast does it happen?

epithelium covers wound

• reform barrier of infection

• centripetal

• 0.1 - 0.2 mm/day

what happens during maturation?

continued epithelialization

• thickening of epidermis

wound contraction

• fibroblasts differentiate into myofibroblasts under influence of GF and cytokines

• myofibroblasts contain a-smooth muscle actin

what happens during remodeling?

converstion of granulation tissue into scar tissue

what is involved in remodeling?

matrix metalloproteinases (MMPs)

• collagenases

• gelatinases

• stromelysins

these are the demolition team!

how long does remodeling take?

up to 1 - 2 years, depending on size of wound

what is good about remodeling?

progressive increase in tensile strength of wound

when does healing stop?

when wound edges meet

• ideal

when tension surrounding skin > force of myofibroblasts

• not ideal

reduced #s of myofibroblasts

• not ideal

granulation tissue is proliferative

• epithelial cells can’t climb!!!

healing by first intention

healing by second intention

dysfunction in the inflammatory response - shock

“the rude unhinging of the machinery of life” Samuel D Gross, 1872

• cascade of events that begins when cells/tissue are O2 deprived from inadequate perfusion

• can lead to SIRS and MOD

• will discuss. ore 3rd year…

SIRS

Systemic Inflammatory Response Syndrome

causes of SIRS

normal?

many causes - one syndrome

• infectious

• non-infectious

generally considered excessive response

• “cytokine storm”

• leukocyte dysfunction

• delayed resolution of inflammation

examples of inciting factors of SIRS

Clinical definition of SIRS

must meet any 2 with underlying pathologic cause:

• hyper- or hyothermia

• tachycardia

• tachypnea

• leukocytosis or leukopenia

• depression

  • neutrophils ± left shift

hyperthemia (fever), what’s going on behind the scenes?

IL-1, IL-6, TNF-a, PGE2

• act on hypothalamus

• increases body’s thermostat —> fever

hypothermia can lead to

shock

• hypoperfusion

• central blood sequestration

BAD sign

mechanism behind tachycardia

mechanism behind tachypnea

CBC alterations during shock

primarily from change in neutrophils

1st: leukopenia (<48 hours)

• initial - endothelial “stickiness”

• increased use

2nd: leukocytosis (>48 hours)

• release from sequestered areas

• bone marrow, spleen

3rd: left shift (variable)

• immature neutrophils

• supply < demand

mechanisms behind depression

• cytokines

• eicosanoids

what happens during the stress response?

• IL-1 and TNF-a —> increases Adrenocorticotropic

• REDUCE*** healing

  • anti-inflammatory

  • reduce activity/production of growth factors

stress leukograpm is:

• variable by species

• due to endogenous (or exogenous) corticosteroids

• neutrophilia (usually mature, no bands)

• lymphopenia

• monocytosis - more common in dogs

• eosinopenia

Multiple Organ Dysfunction Syndrome (FYI) MODS

progression or sequela of SIRS