Pathophysiology: Wounds and Wound Healing

What two processes can tissue repair happen through?

regeneration and connective tissue deposition (scar formation); tissue stem cells/progenitor replace tissues in the epidermis, regeneration by proliferation of differentiated cells seen in the liver

regeneration

restores normal cells/tissues to replace lost structures

connective tissue deposition (scar formation)

happens if tissue cannot regenerate or have complete restitution of tissue; a connective tissue scar is produced which provides structural stability so neighboring tissue can work properly; organization

organization

fibrosis developing in a space with inflammatory exudate, such as in organizing pneumonia of the lung

Regeneration of injured cells/tissues involves _____ __________

cell proliferation

Cell proliferation is driven by _______ _______

growth factors

Cell proliferation is dependent on the integrity of the _____ and development of tissue ______ cells

ECM, stem

Stem cells can have multiple cell __________ and have ___________ properties

lineages, self-renewal

Forms of stem cells

embryonic, adult

Where are adult stem cells prevalent in?

bone marrow, GI, skin

Three types of cells/tissues in cell proliferation

labile, stable, permanent

Labile tissue

continuously dividing, cells continuously lost and replaced by maturation of stem cells and proliferation of mature cells, best at regeneration

stable tissue

cell largely quiescent but can divide in response to injury or loss of tissue mass, limited capacity to regenerate (except for liver)

permanent tissue

terminally differentiated and non-proliferative, majority of neurons and cardiac and skeletal muscle, repair dominated by scar formation, not able to regenerate

Cell proliferation is driven by signals provided by _______ _______ and from the __________ _________

growth factors (GF), extracellular matrix (ECM)

Activated ____________ are the most important source in regeneration of tissue

activated macrophages

Tissue regeneration mechanisms

proliferation of residual cells as well as maturation of tissue stem cells, residual tissue must be structurally intact to restore normal tissue, basement membrane must be intact with skin and mucosal surfaces

Extracellular matrix (ECM)

protein network outside the cell that influences cell function, forms the network in which cells live, serves as reservoir for growth factors and factors that regulate cell proliferation

Two basic forms of ECM

interstitial matrix and basement membrane

ECM is composed of what three things?

fibrous structural proteins (collagen and elastins), adhesive glycoproteins (fibronectin, laminin), water hydrated gels (proteoglycans and hylauronan)

________ is the most abundant protein in the body

collagen

What is the structure of collagen?

three chains twisted into a rope like triple helix structure

What two groups is collagen divided into?

fibrillar and nonfibrillar

fibrillar collagen

forms linear fibrils

What types fall under fibrillar collagen?

type I, II, III, V

Type I

most common, provides tensile strength to tendons, skin, and cornea

Type II

found in cartilage, intervertebral discs

Type III

thinner and seen in distensible organs, initially deposited in healing and then replaced by type I

Type V

more of a support role

Nonfibrillar collagen

forms sheets

What types fall under nonfibrillar collagen?

Type IV, VII, IX

Type IV

found in basement membranes (laminen as well)

Type VII

anchors to maintain structure of stratified squamous epithelium

Type IX

regulates collagen diameter/interactions in cartilage

Defects in collagen production may arise from what (3)?

blueprint errors (faulty product), assembly line errors (weak product), shipping/installment errors (unstable product in tissues)

Defects in collagen synthesis can affect what organ systems?

bones, joints, skin, arteries, heart valves, eyes (cornea)

Defects in collagen synthesis can cause what clinical disorders (4)?

Ehlers Danlos syndrome, Chondrodysplasias, Osteogenesis imperfecta, Scurvy

Ehlers-Danlos syndrome

defect in the synthesis or structure of the fibrillar collagen tissue itself, 13 types with varying severity and presentations

Clinical features of Ehlers-Danlos syndrome are extremely ________

variable

What are some clinical features of Ehlers-Danlos syndrome in the skin?

skin is hyperextensible and thin (atrophic), easily torn and wound healing/scarring often a problem

What are some clinical features of Ehlers-Danlos syndrome in the ligaments and joints?

joint hypermobility/laxity, arthritis, chronic joint pain, recurrent dislocations, scoliosis

What are some clinical features of Ehlers-Danlos syndrome in the cardiovascular system?

mitral valve prolapse, arterial vessel rupture (aorta)

What are some clinical features of Ehlers-Danlos syndrome in the eye?

range from myopia to retinal detachment

Chondrodysplasias

group of inherited skeletal disorders that can cause dwarfism, wide range of severity, subtypes can affect type II or type X collagen or lead to insufficient growth plate signaling (achondroplasia)

What is the most common type of chondrodysplasias?

achondroplasia

Osteogenesis imperfecta

group of disorders due to genetic defects involved in the production of type I collagen, most common inherited disorder of the connective tissue (too little bone), brittle bone disease with multiple fractures and bone deformities but also eye, ear, joint, skin and teeth manifestations, blue sclera, DDX of child abuse

Scurvy

deficiency of vitamin C leads to decreased hydroxylation of procollagen causing reduced cross linking of collagen, impaired formation of mature connective tissue, vitamin C only obtained in diet

What symptoms would you see in Scurvy?

bleeding gums, loss of teeth, difficulty fighting infections, impaired bone growth in children leading to bowing of long bones, impaired wound healing

Elastin

complex polymer that allows tissue to be elastic and stretch

Central core of elastin is surrounded by ______ largely consisting of ________, a glycoprotein

microfibrils, fibrillin

Fibrillin provides a scaffold on which tropoelastin is deposited to form _____ _______

elastin fibers

Fibrillin is important in the control of _______ bioavailability

TFG-beta

Marfan syndrome

most cases are inherited (autosomal dominant) due to sporadic mutations, genetic mutation from FBN1 gene, clinical features due to abnormal elastin fibers and excessive activation of transforming growth factor- beta

What are clinical features of marfan syndrome?

patients are tall with long thin extremities and phalanges, may have chest wall abnormalities, loose joints, arachnodactyly, dislocation of the ocular lens, scoliosis, cardiovascular abnormalities such as mitral valve prolapse, aortic root abnormalities, ascending thoracic aorta dilation, aortic dissection

Acquired elastin tissue defects

aging, solar elastosis (aka actinic elastosis), digestion by enzymes (tissue breakdown)

Goal of connective tissue deposition repair

restore tissue to original state

Often connective tissue deposition is required producing a ______

scar

If insult persists, ________ and _______ occur simultaneously

damage, repair

When damage and repair occur simultaneously, this is referred to as _______

fibrosis

What does fibrosis usually denote?

an abnormal deposition of connective tissue

erosion

lesion does not extend through the epithelial layer, superficial wound

ulceration

lesion extends through the epithelial layer

laceration

irregular wound through epithelial layer

incision

a regular wound (I.e. surgery)

abrasion

superficial epidermis torn off by friction or force, scrape

Phases of wound healing (4)

hemostasis, inflammation, proliferation/granulation, maturation and remodeling

hemostasis

immediately after injury see vasoconstriction, clotting cascade activation, platelet plug formation, deposition of fibrin, stops bleeding, provides scaffolding for fibrin

inflammation

components of acute inflammation occur in response to the injury lasting 6-48 hours, eliminates any offending agents and clears out debris, release chemotactic factors for inflammatory cells

proliferation/granulation

cells types (epithelial, endothelial, fibroblasts) migrate to area, covers the wound (epithelial cells), forms new blood vessels via angiogenesis (endothelial cells/pericytes), and lays down ECM (fibroblasts), leads to formation of granulation tissue, provides a proper environment for wound healing to occur/continue

Maturation and remodeling

ongoing deposition of connective tissue (ECM) by fibroblasts replacing the granulation tissue, contraction of the wound edges, and ongoing remodeling

Numerous _______ _______ influence the phases of wound healing and

growth factors

How do macrophages play a central role in regeneration of tissue (3)?

clearing offending agents and dead tissue, providing cell growth factors for proliferation of various cells, secreting cytokines that stimulate fibroblast proliferation and connective tissue synthesis and deposition

Where do most macrophages in wound healing come from?

alternate (M2) activation pathway

VEGF plays a role in _________

angiogenesis

What is most important for stimulating connective tissue production healing but can lead to fibrosis?

Transformative growth factor-beta (TGF-b)

Enzymes responsible for remodeling

Matrix metalloproteinases (MMP)

What do platelets play a key role in?

hemostasis, inflammation, wound healing

How do platelets play a key role in wound healing?

mitogens stimulate fibrogenesis, serotonin stimulates collagen production and cross linking, prostaglandins

Overview of repair by connective tissue deposition (essay!)

insult with formation of blood clot (hemostasis), induction of inflammatory processes, cell proliferation which includes angiogenesis and granulation tissue formation (proliferation of fibroblasts, epithelialization, synthesis of ECM proteins and collagen deposition with scar formation), tissue modeling and maturation (wound contraction-myofibroblasts, granulation tissue replaced by ECM proteins and balance between ECM synthesis and degradation by enzymes, wound strength)

Early response in cutaneous wound healing

hemostasis gives a dried scab, fibroblast proliferation, inflammatory cells and blood supply are necessary for healing

Angiogenesis

formation of new blood vessels from preexisting vesselsgr

Most important growth factor in angiogenesis

VEGF

What does VEGF do?

increase permeability and vasodilation

What do notch signals and VEGF coordinate?

sprouting of new vessels

Immature vessels formed tend to be _______

leaky

Granulation tissue is the hallmark of ________

healing

Granulation tissue is a product of ____________

angiogenesis

What is granulation tissue composed of?

fibroblasts, loose connective tissue, endothelial cells, WBCs

What are you looking for in granulation tissue?

pink, soft, granular, cobblestone appearance

What is granulation tissue a response to?

angiogenic factors produced by inflammatory cells abd platelets

What does epithelialization depend on?

basal cell proliferation

Epithelialization process

adjacent cells stimulated to leapfrog over one another to cover a mixture of fibrin and fibronectin, forms a bridge, basement membrane important to orient where epithelial cells go

What surface is preferable in epithelialization?

moist surface through nonadherent dressing or scab

Scar formation is connective tissue produced by ________

fibroblasts

What is the most important cytokine for the synthesis and deposition of connective tissue proteins?

Transforming Growth Factor Beta (TGF-B)

Open wounds close by movement of the wound edges toward the ______

middle

Wound contraction is performed by contractile fibers of __________ that are derived from _______

myofibroblasts, fibroblasts

When does connective tissue modeling begin?

after 3 weeks and continues for months to years

connective tissue remodeling is the balance between ______ synthesis and _________

ECM, degradation via MMPs

Connective tissue remodeling removes excess _________

collagen