Pathophys Inflammation & Healing

What is the cascade of events after tissue injury

acute inflammation —> chemical mediators which lead to either vasodilation, increased permeability, chemotaxis, and irritation of nerve endings

healing begins, and either chronic inflammation occurs or healing occurs

What are the chemical mediators

Histamine, kinins, prostaglandins

Vasodilation and increased bloodflow

Hot and red

Increased capillary permeability

Edema, pain

Chemotaxis

WBC floods to area

What happens after capillaries experience increase capillary permeability?

clot and fibrin mesh walls off area

What happens when WBC flood to the area

Phagocytosis occurs to remove cell debris

What happens to the tissue when chronic inflammation occurs

Scarring

Types of healing

Regeneration= replacement by same type of cell

Resolution= damaged cells make a recovery

Define inflammation

Automatic response to an injured cell that which

1. neutralizes harmful agents

2. removes any dead tissue

3. prepares the injured tissue for healing

Is inflammation normal? What types of active inflammation are there

Yes it is normal. Acute or chronic, localized (to a specific area) or systemic (throughout the whole body)

What are inappropriate inflammation types?

• Inappropriately activated

• unresponsive

• exagerrated

Inappropriately activated inflammation

Triggered by wrong target (either self body, or harmless environmental agents)

Unresponsive

Inflammation that does not go away even after threat has subsided

Exagerrated

Immune response disproportionate to threat, and creates a life threatening intensity that destroys healthy cells as well as the invader

What are some visible signs of acute inflammation

• Redness (aka erythema or hyperemia)

• Heat

• Swelling, localized edema

  • pain

Local response occur within…

minutes

systemic responses ocur within…

days

what are the steps postceeding local responses

vascular stage and cellular stage

what are the steps postceeding systemic responses

white blood cell and acute phase response

What is the difference between localized vs systemic inflammation

Localized

• Neutralizes whatever substance is invading

• Localizes WBCs to the damaged area to clear out invading pathogens alonside damaged cells

• separating/walling off the area that is damaged to prevent further spread of pathogen

Systemic response

• send out more WBCs throughout the body to hunt down any invading pathogens that escaped the walling off earlier

  • conserve energy therefore shutting down certain functions in order to fight off the injury/infection

Neutrophils are

Neutrophils are the most common type of white blood cell in the human body, acting as rapid first responders of the innate immune system to fight off bacterial and fungal infections

they act within minutes

Monocytes are

Monocytes are a type of white blood cell that act as a rapid-response defense and clean-up crew for your immune system.

They act within days.

Vascular stage comprises

• vasoactive chemicals = pain

  • vasodilation = redness and heat

  • increased vascular permeability= swelling

Cellular stage comprises

Neutrophil and monocyte recruitment, leaving blood and leaking into damaged tissues

What are cytokines

Short life span proteins that communicate between cells during inflammation

• Circulating immune cells, platelets, and mast cells release these cytokines

Tissues have cytokine receptors!

What 2 enzymes are responsible for chemical conversion into cytokines?

• Cyclooxygenase COX

  • Lipoxygenase LOX

What do cytokine receptors do

• propel and coordinate both localized and systemic inflammation steps

• recruit more WBCs to the site of infection/injury

• Regulate WBC actions along with platelet activity

  • start the healing process via promoting new vessel growth

Histamine

Is an inflammatory cytokine (protein)

• mast cells within tissue and platelets have pre-formed histamine stored in their veiscles

• as a response to tissue damage, histamine is released

  • also a vasoactive chemical, affecting the diameter of a vessel along with its permeability

Hyperemia

arterioles and venules dilate which increase blood flow to injured area to deliver WBCs and antibodies = RED AND HOT

Swelling

Capillaries become more permeable

• hydrostatic pressure is greater than osmotic reabsorption back into blood (next to vessels having holes) = net fluid gain into the tissue, leading to swelling and edema

• this dilutes toxins and clears debris from the inflamed site and moves debris and toxins into lymphatics for elimination

Platelets and WBCs

• Platelets acitvated during injury, clotting any bleeding and close any entry portals

• WBCs and plasma like fluid fall out of the vasculature (exudaet) and localize to the injury site

  • goal is to destroy infective organisms (neutrophils in first hours, monocytes by day 3)

  • remove damaged cells

  • release even more cytokines and inflammatory mediators

  • recruit more WBCs if needed

    • control further inflammation response

Walling off

Platelets and neutrophils create a physical mesh around the injury site

Prevents/delays patogen, toxin, destructive infalmmatory mediator spread

If the wall is large or prolonged, it can create more problems W

Why can a prolonged or large wall cause problems?

• obstruct blood/lymphatic flow = more inflammation and tissue death

• abscess= pus filled encapsulation of bacterial pathogens; wall won’t allow more WBCs to enter the site leading to perpetual localized inflammation

  • Granulomas= pathogen that can’t be killed or removed, but surrounded by WBCs meaning the pathogen is still there and can reactivate at any time

Systemic manifestation of accute inflammation

• localized acute phase occurs within first 3 days of an injury

  • destroy the infection/resolve damage and proceed to normal healing

  • OR the pathogen/damage persists and may have escaped the localized site

• Body needs more inflammatory response= buildup of cytokines spread to peripheral organs to mount systemic inflammatory response

WBCs release cytokines tha affect what?

The brain

• distrupted thermoregulation eg fever or shivering

• decreased cognitive function eg fatigue, malaise, appetite, depression, sleepiness

Bone marrow

• induces more WBC synthesis

Skeletal muscle

• cytokine actions cause muscle catabolism leading to amino acid release and muscle wasting

Liver

• Cytokines induce synthesis of specific liver proteins (hepatic response)

What is the hepatic response to inflammation?

Increased production of;

• clotting factors and fibrinogen: facilitate clotting, helping with walling off

C-reactive protein (CRP)

• this protein binds to pathogens/damaged cells for phagocytosis

• Moderate inflammatory responses

What do hepatic lab tests tell us in the face of inflammation?

WBC differential

Fibrinogen

CPR

What are mast cells

A mast cell is a type of white blood cell that lives in your body’s tissues and acts as an early responder to protect you from infections

Chronic inflammation

• if acute inflammation is inadequate in containing the threat (ie within 5 days) then the inflammatory response enters a chronic phase which may then last for a very long time

• macrophages accumulate in the damaged area and keep releasing cytokines and inflammatory mediators

  • will often restructure to contain the damage/threat, thereby causing tissue remodelling

New tissue in chronic inflammation

• don’t have the same properties of original tissue, leading to physical structure change and/or functional problems

• If someone repeatedly hurts the injury site before healing actually completes

  • DNA replication and cell division continuous; more likely for errors in the DNA leading to dysplasia

Pharmacological treatment of inflammation

• used for acute inflammation when red/hot/swelling/pain is affecting daily life OR
  
  

  • Used for chronic inflammation to limit the repeated damage

Anti inflammatories target production of cytokines

Antihistamine

Nonsteroidal anti inflammatories

Corticosteroids

Antihistamine

Diphenydramine (Benadryl)

Nonsteroidal anti-inflammatories (NSAID)

• Inhibits the enzymes COX and LOX which make cytokines

  • i.e Ibuprofen (Advil), acetaminophen (tylenol)

Corticosteroids

Steroids inhibit the genes which make pro-inflammatory cytokines or the COX enzyme

i.e., prenisone, hydrocortisone

what is tissue healing

• replacing injured tissue by newly formed tissue that is living

  • New tissue might be correct (no scarring) or fibrous (scarring)

The 3 types of headling:

• regenerative

• normal scarring

• pathological scarring (i.e., keloid, discolouration, abnormal tissue replacement)

Two ways to heal without scarring resolution or regeneration

1. Resolution= original damaged cells reversibly injured and recover. Tissues return to normal in a short period of time i.e., muscle strain

2. Regeneraiton= replacement of injured cells by division of remaining viable cells of the same type. Caveat is the tissue cell must be able to regenerate

   1. the supporting framework must be intact (stroma)

   2. returns injured tissues to their normal structure and function without scarring

Explain regenerative capacity

Only cells capable of cell division constribute to regeneration

• continuously dividing cells

• quiescent (aka stable cells like hepatocytes) are dormant cells that can reenter the cell cycle given the right signal

Permanent tissue are cells that are not capable of cell division

• once destryoed permanent cells are replaced by fiborus scar tissue that lacks function of the original tissue

Examples of permanent cells

neurons (brain and nerve cells), cardiac muscle cells, skeletal muscle cells

cells that are constantly dividing

• epidermis

• GI epithelia

• endometrium

• bronchial epithelia

  • bone marrrow

quiescent cells

liver

kidney

re-enter cell cycle due to limited or extensive injury

Cells that can not regenerate

• neurons

• cardiac muscle

• skeletal muscle

can only scar (fibrous repair only)

What is the purpose of scar tissue

Temporary scar

• granulation then collagenous scar to immediately close off portal of entry and buy time for regeneration

Permanent scar

• Extensive damage (esp into stromal layer) and/or when cells cannot regenerate

They provide support and protection for remaining tissue, though not the original function

What are the 3 phases of wound healing

1. inflammatory phase

2. proliferative phase

3. remodeling phase

Cells involved during wound healing

• WBCs (neutrophils and macrophages)

• Fibroblasts

• Myofibroblasts

• Angioblast

Fibroblasts are

cells that produce the extracellular matrix (collagen, proteoglycans, fibronectins)

What are myofibroblasts

• hybrid between smooth muscle and fibroblasts

• contract to pull edges of the area of injury together

Myofibroblasts are specialized healing cells that act like tiny muscles, gripping the edges of a wound and contracting to physically pull the skin back together

Angioblasts are

• precursors to blood vessel cells

• stimulate blood vessel growth at the margins of the wound

List the phases of a healing skin wound

1. Immediate: Bleeding starts, and mast cells trigger an inflammatory response.

2. Hours later: A scab forms and clotting isolates the region, while phagocytic cells remove debris and cells of the stratum germinativum begin migrating along the edges.

3. One week: The scab is undermined as epidermal cells migrate over a meshwork produced by fibroblast activity, while phagocytic activity ends and the fibrin clot disintegrates.

4. Weeks later: The scab is shed and the epidermis is complete

Inflammatory phase of the healing process

Blood clotting and inflammation starts it all, leaving chemicals to bring in the main players of inflammation and wound healing

• inflammation lasts up to 4 days

Proliferative phase of the healing process

Begins in 2-4 days and can last several weeks. Includes:

1. Angiogenesis

2. fibrogenesis

3. epithelialization

4. scar tissue formation

Angiogenesis

Macrophages secrete factors (vscular endothelial growth factor) that activate the budding of new capillaries from local blood vessels

Fibrogenesis

• macrophages release factors that attract fibroblasts to the wound area

  • fibroblasts then proliferate

What do fibroblasts do

make extracellular matrix of connective tissue using protein fibers (collagen, elastin) and ground substance (proteoglycans which attract water and provide resilience)

Proteoglycans are specialized molecules made of a core protein with long chains of sugar molecules attached to it

Granulation tissue

Temporary delicate tissue (red and moist)

It contains macrophages, new capillaries, proliferating fibroblasts and loose extracellular matrix that provides framework (bluprint) for more durable scar tissue formation.

it is a TEMPORARY tissue that will change in the healing process

Granulation relevance in sonography

• tissue around sutures (or bits leftover after removal) can look or feel like a tumour/ recurrent tumour, especially if the suture was from tumor removal!

  • Ultrasound is the first modality to investigate

What type of frequency is useful for investigating granulation tissue?

>10MHz, linear probes are useful

• hypoechoic collection

• small hyperechoic structure in the collection (which is the suture)

• may show vild vascularity on colour dpler

Epithelialization

Epithelial cells at the edges of a wound will proliferate and migrate inwards underneath the scab

• the edges meet, cells divide, and new cells are pushed upwards to thicken the epidermis

• epithelium grows thicker

  • scab will fall off when the wound is almost covered

So does epithelialization occur better with or without a bandaid?

Open wounds require a protective layer! this is to protect it from foreign debris and then due to fragile granulation tissue

• epithelial cell migration requires moist surfaces; thus epithelialization occurs faster when there isnt a scab present

• keratinization of skin is better when it is dry

SO: use a bandaid in the beginning to promote granulation and epithelial cell migration

BUT once the scab/granular tissue hardnes, take the bandaid off for epithelialization

Later scar tissue formation

Collagen fibre synthesis

• starts at day 5; laid down more intensely. Imposed on the granular tissue

Gradual remodelling of the scar, some fibres breaking donw and others forming in a more orderly fashion

blood vessels thrombose and degenerate as they are no longer needed

Remodelling phase of the healing phase

• Fibroblast activity gradually decreases as time passes

  • collagen fibres reorient according to the particular stress on the tisue (use it or lose it!! i.e., broken bone!!

• Remodelling phase starts at 2 weeks and occurs over the course of many months, sometimes taking up to 2 years

• Eventually vascularity is reduced and blood vessels will degenerate

• Scar tissue will appear white if on skin, due to lack of melanocytes and because it is avascular

End of the remodelling phase

• scar fills in the wound gap, but it is not functional tissue

  • it is only functional once tissue stem cells undergo mitosis and replace the scar tissue (fading scars)

List the factors that delay wound healing

1. poor blood supply/ hypoxia

2. large wound size

3. infection

4. persistence of foreign material/ necrotic tissue

5. excessive mobility/irritation

6. poor nutrition

7. prolonged use of corticosteroids

8. advanced age

How could blood flow to a wound area be impaired

Blood could be fine, but cardiovascular is not (ex perfusion problem)

• vasculature to tissue issue i.e., regional ischemia, clots

• capillaries at wound issue i.e., inflammatory edema causing vessel constriction

• Vasculature fine, but pumping wrong (i.e., heart contractility issues)

Vasculature is fine, but blood is not (ex blood oxygenation problem)

• not enough oxygen (hypoxia, respiratory problems), oxygen carrying ability (anemia)

• not enough nutrients (malnutrition), metabolically available nuytrients (diabetes)

• not enough blood (hemorrhage)

What is blood flow required for

• delivery of Oxygen, nutrients, cells involved in healing

  • removal of wastes, toxins and debris

Necrotic tissue delays healing because

it needs to be removed for healing to occur

Macrophages alone cannot deal with an abundance of necrotic tissue

Why might nutritional status delay healing

• poor nutrition= inadequate/incomplete wound healing

• not enough building blocks

Who is at risk for having complicated healing due to low nutritional status?

• individuals of low socioeconomic status

• the elderly (low socioeconomic status/poor diet, and/or impaired digestion)

• alcoholics

• self-imposed diet restriction

  • individuals with chronic conitions such as malabsorption (celiac) or hypermetabolic (cancer)

why might movement inhibit healing

reinjure wound and restarting the process

why might large wound size inhibit healing

wound margins unable to close, causing trouble with fibrinization

why might prolonged use of corticosteroids inhibit healing

• anti-inflammatory actions delay the start of healing process

  • catabolic effects of steroids counter the anabolic steps of healing

What are some complications that could occur with wound healing?

• wound dehiscence (ripping apart)

• hypertrophic scar and keloid formation

• contractures is an abnormal complication where this shrinking goes too far

• stricture (similar to contractures, but they happen inside the body's hollow tubes and passages)

  • adhesions (bands of scar tissue that form between internal organs and tissues, causing them to stick together abnormally)

Wound dehiscence

surgical wound breaks

• due to mechanical injury OR due to poor scar formation (ehlers danlos)

Increased risk should the wound be infected, has excessive strain, age, diabetes, nutritional deficiencies, corticosteroid use tre

treatment for wound dehiscence

repair the wound break

Strictures in wound healing

= buildup of scar tissue, shrinking of hollow structure (internal)

• causes lumen obstruction (narrowing)

  • can also cause tube/duct/tract shortening

Examples of strictures

• esophageal stricture due to GERD, impairing swalling, leading to pain swallowing, epigastric pain and finally weight loss

Adhesions in healing

• scar tissue joining adjacent structures

• fibrin normally present during scar formation, acting like glue to seal an injury

• when fibrin isnt completely resolved (broken down/removed) it can cause impairment of movement or cause twisting

• occurs mainly in abdo surgery where peritoneum and internal organs are stressed (incision, drying out, touching)

  • Can occur anywehre within peritoneum including between pleural membranes especially when due to infection