Healing and Repair - Pathology

Introduction

• There are several factors on which the ability to heal and repair depends:
  1. Species
     • The ability of the species to cope with that particular inflammation .
     • For example, peritonitis.
       • In cattle, it is often successfully walled off at the initial injury site, preventing spread throughout the whole cavity.
       • In the horse peritonitis is not walled off, and is generally rapidly fatal.
  2. Age
     • Repair is generally more successful in younger animals than older animals.
     • However, in young animals the immune system may still be immature.
       • For example, Pseudorabies virus is more often fatal in pigs under three weeks old, even in the presence of maternal antibody.
  3. Tissue and extent of damage
     • Highly specialised tissue rarely repairs successfully apart from in mild injury.
       • If the functional reserve of the damaged tissue is exceeded, clinical signs of disease related to this insufficiency will occur.
     • When there is substantial fibrosis in the tissue, the tissue may continue to be progressively destroyed.
       • This is due the maturation and contraction of fibrous tissue causing further injury to the adjacent normal tissue.
       • E.g. the liver in cirrhosis, and the kidney in chronic renal disease.

Repair

• Repair occurs through one of two mechanisms:
  • Regeneration
  • Replacement

Regeneration

• In mammals, only epithelial and connective tissues regenerate extensively.
• The ability of tissue to regenerate depends upon whether the tissue is
  • Labile
  • Stable
  • Permanent.

Labile Tissues

• Labile tissues constantly replenish their cells throughout life.
  • For example skin and mucous epithelia normally desquamate their outer layer of cells during life, maintaining their overall composition by division of their basal layers.
• Other examples include bone marrow and fat.
• These tissues regenerate well.
  • Provided the basement membrane is not breached during the inflammatory process, the epithelium migrates to cover the surface defect.

Stable Tissues

• Stable tissues have a limited ability to replace themselves.
• They retain the ability to
  • Replace cells that have undergone programmed cell death when the cells age and cannot continue their function.
    • For example, the liver, some endocrine glands and the renal tubular epithelium.
  • Respond to greater need for their function in the body.
• Blood vessels and fibroblasts are also stable tissues.
  • Have great potential to divide and proliferate.
  • Are the important tissue cells in repair by replacement.

Permanent

• Permanent tissues have poor or no regenerative capacity.
• This group includes tissues in which the cells are highly specialised and generally have only one function, for example:
  • Neuronal cell bodies in the CNS
  • The retina of the eye
  • The cells responsible for hearing in the ear.
• Axons in the peripheral nervous system can regenerate to a limited extent when severed.
• Cardiac muscle myofibres have very poor regenerative capacity, and undergo repair by

fibrosis or fat replacement.

Replacement

• Replacement is essentially endothelial and fibrous tissue proliferation to replace severely damaged tissue.
  • This classical dual replacement gives rise to granulation tissue.

Repair in the Skin

Back to Integumentary System Pathology

• Healing of a wound or surgical incision may be by:
  • First intention
  • Second intention.

Healing by First Intention

• Healing by first intention occurs when the incised ends remain in close apposition to each other anf bacterial contamination is minimal.
  • This may be induced by suturing.
  • For example, a surgical incision.
• Results in minimal scarring.

Process

• Initially, the incision ruptures the dermal blood vessels.
  • The exuded blood forms a fibrinous clot between and above the incision.
    • The clot functions to:
      1. Stem the flow of blood from the injured site.
      2. Adhere the two ends together.
      3. Prevent infection from entering the injured area.
• The basal layer of epithelium wthin 1mm of the wound edge begins to lose its connections with adjacent basal and overlying epithelium.
  • Undergoes mitosis.
  • Begins to migrate down both sides of the wound under the clot using pseudopodia.
    • As they are migrating, cells differentiate to some degree to form more superficial layers of the epithelium.
      • Gives a rather thick, if not very strong, barrier of epidermis.
    • In the area of migration, the skin is usually hypopigmented and lacks hair follicles.
• Within 2-4 days, the migrating basal layer of epithelium from either side meet together under the clot.
  • It is thought that there is passage of substances, from one side to another that prevents further migration and mitosis.
  • This gives reconstituion of an intact barrier to micro-organisms.
• While the epithelial changes are occuring, there is a sudden proliferation of local fibroblasts and accompanying endothelial cells in the dermis surrounding the incision.
  • These grow across the narrow divide from each side and link up in the middle.
    • Takes about 12 hours to accomplish.
  • In the early stages (days 4-7), their alignment may be vertical, but in later stages (7-21 days) both fibroblasts and capillaries line up horizontally across the incision.
  • This dermal repair forms the major portion of strength between the two sides at this time.
    • Gains in strength over a long period of time as the collagen contracts and remodels according to the stresses imposed upon it.

Factors Inhibiting Healing

• Factors inhibiting proper wound healing include:
  1. Protein deficiency
     • May be absolute, as in starvation, or resolute, as in some of the endocrine deficiencies.
       • E.g. hypothyroidism
  2. Vitamin C deficiency
     • Vitamin C is essential for fibroplasia and to maintain the integrity of endothelial and epithelial cells.
  3. Cold
  4. Ageing
  5. Contamination
     • Infection tends not to be a complication as bacteria are generally excluded.
       • Retained foreign material such as hair portions or suture material inadvertently left in the wound will cause infection and/or a foreign body reaction.
  6. Movement
     • Gives persistent trauma.

Healing by Second Intention

• Healing by second intention occurs when the gap between the ends of the incision is too wide to allow close approximation of the ends.
• This process of granulation tissue repair in a large wound is also the underlying process in the repair of:
  • Infarcts and thrombi in vessels.
  • Surface ulcers and diphtheresis.
  • Pyogenic membrane in abscesses.
  • Diffuse fibrosis ( cirrhosis ) in the liver.

Process

• In comparison to healing by first intention, there is a more massive fibroblastic and endothelial proliferation in the wound which fills and repairs the defect.
• There is also considerable surface exudation.
  • The exudate is composed of fibrinous fluid and numerous inflammatory cells, mainly neutrophils and macrophages.
    • The cells are scavengers, and engulf necrotic debris and any bacteria present
    • Macrophages and their secretions are also important for the promotion of fibroplasia.
• The fibroblasts tend to align themselves roughly horizontal to the surface, but the endothelium is perpendicular to the surface.
  • The upper vessels form loops near to the surface.
    • Gives the gross appearance of red granules - this is granulation tissue.
• Well-formed granulation tissue tends to be fairly resistant to surface infection; however, it is rather delicated and so susceptible to trauma and subsequent introduction of infection.
  • Infection is therefore a common complication in the early stages of healing.
• Once the gap has been filled with granulation tissue and is free of infection, the epithelium migrates across.
  • As it migrates, the epithelium secretes collagenolytic substances.
• The epidermis is usually hypopigmented and lacks hair follicles unless they have survived in the granulation tissue.

Factors Inhibiting Healing

• Several factors inhibit healing by second intention.
  1. Movement
     • Movement before sufficient strength has been attained in the bond between the edges can inhibit healing.
  2. Infections
  3. Corticosteroids
     • Prevent proper collagen matrix formation.
     • Inhibit leukocyte emigration and phagocytosis.
       

       Scar tissue (Courtesy of BioMed Archive)
     • Diminish any acute inflammatory response by generally stabilising cellular membranes.

Scarring

• As the fibroblasts mature into fibrocytes, the collagen also matures and contracts and there may be extensive scar formation.
  • There may be considerable depression of the surface in such a scar.
  • The scar may interfere with movement in the area.
• The scar tends to diminish in size over a long period of time, as the underlying collagen remodels according to the stresses imposed upon the area.

Repair in the Bones

Causes of Fracture

• The causes of fracture fit into two distinct categories:
  1. Fracture of trauma
     • Breakage of normal healthy bone due to excessive stress pressure of short duration.
  2. Pathological fracture
     • Breakage of bone weakened by some underlying metabolic, inflammatory or neoplastic condition.

Description of a Fracture

• There are various terms to describe a fracture's appearance.
• Separation of the ends of the fracture may be complete or incomplete.
• When there is no penetration of the overlying skin, a the fracture is described as closed.
• When the sharp ends penetrate the overlying skin, the fracture is compound.
  • In this scenario there is the danger of introducing infection.
• Comminuted describes a fracture where there are multiple small fragments of bone at the site of breakage.
• Where the edges of the fracture are impacted into each other, the fracture is said to be compressed.
• When one side of the fracture is depressed below the plane of the other, the term depressed is used.
  • This occurs in the flat bones of the skull.
• Microfractures are fractures that are only visible on histological section as cracks in the bone.
  • Grossly, there might be evidence of some haemorrhage in the area.

Fracture Repair

Fracture repair (Courtesy of BioMed Archive)

• On breakage, there is rupture of the periosteal, cortical and medullary vessels, causing:
  • A blood clot in the breakage area.
    • Fibrin is the important component.
  • Local necrosis of tissue supplied by these vessels.
    • This lowers the local pH.
• The fate of the blood clot depends upon its location.
  • The periosteal portion is lysed and disappears;
  • The medullary portion is removed by macrophages.
• The necrotic material is removed by phagocytosis.
  • Necrotic bone marrow is removed by macrophages.
    • This is a fairly rapid process.
  • Osteoclasts remove necrotic bone.
    • This is a slow process.
• On the periosteal side, the periosteum proliferates into the clot.
  • Forms a fibrous collar around the bone called the soft callus.
• The cells in the inner aspect of the soft callus, particularly those near the fracture fragments, differentiate into osteoblasts.
  

  Fracture callus (Courtesy of BioMed Archive)
  • Grow across the divide between the two fragments, laying down coarse woven bone.
• The woven bone laid is known as the hard callus.
  • This periosteal coarse bone is of utmost importance in repair.
    • It is responsible for much of the strength of the fracture repair.
  • This is replaced over a period of time by mature compact bone.
    • Aligns itself according to the stresses applied to it.
• Periosteal cells that are further away from the fracture fragments differentiate into cartilage-producing cells.
  • Produce a cone of cartilage between the two fragments.
    • As the local pH changes to more alkaline conditions, this cartilage undergoes calcification, with invasion by blood vessels and osteoblasts.
      • The cartilage is replaced by bone - endochondral ossification.
• On the medullary side, the endosteum proliferates and invades the clot, laying down bone.
  • This bone may totally occlude the medulla and is later remodelled to reconstitute a patent lumen.

Complications

• There are several possible complications that may arise in the repair of bone.

1. Inadequate immobilisation of the fractured ends will lead to incomplete repair by callus formation.
   • An intervening mass of fibrocartilage remains, forming a false joint.
     • In some cases the false joint can even appear to form a synovial lining.
   • If the fractured ends are sufficiently far apart, no substantial callus forms.
     • The intervening space is taken up by connective tissue organisation.
2. Failure to align the fractured ends in proper apposition to one another will produce excessive callus.
   • This takes a longer time to be remodelled by the adult compact bone.
3. Comminution delays healing due to persistent irritation.
4. Infection delays healing due to the effects of the toxins on theproliferating cells.
   • May give rise to a systemic infection affecting the rest of the body.

Repair in the Respiratory Tract

• Severe damage to the alveolar wall results in fibrous tissue organisation of the entire alveolus.
• The appearance of inflammation in the respiratory tract varies with the route of entry of the agent.

Airborne Agents

• Infectious droplets tend to deposit in the anterior ventral portions of the lobes.
  • I.e. in the apical, cardiac and anterior portions of the diaphragmatic lobes.
• Airborne agents produce bronchopneumonia.
  • So-called because the inflammation is initiated and centred upon the airways.
• The usual appearance of bronchopneumonia in ruminants and the pig is as the name suggests.
  • These species have a well developed interstitial septum between groups of lobules, and little or no connection between alveoli from different terminal bronchioles.
    • Therefore, one lobule may show extensive pneumonic changes while the adjacent lobule is free from inflammation.
  • The inflammatory exudate commonly gets stuck in the lower airways.
    • Invokes an inflammatory response in the smooth muscle of the wall of the airway.
      • The wall is weakened, causing it to dilate somewhat.
    • Air trapped distal to the blockage is gradually absorbed into the bloodstream.
      • This causes increased pressure on the injured wall, dilating it further.
    • This is a progressive process and results in irreversible dilatation of the airway lumen and is called bronchiectasis.
• Bronchopneumonia in the dog and cat often tends to be more diffusely spread.
  • These species have a poorly-developed interlobular septum and collateral ventilation between alveoli from different respiratory units.
  • Resolution of bronchopneumonia in the dog and cat is often more or less complete.

Blood-borne Agents

• Blood-bourne agents tend to have a patchy distribution throughout the lung.
• Cause interstitial pneumonia.

Circulating Toxins

• For example, "Fog Fever" in adult cattle.
  • Interstitial emphysema.
  • 3-methyl indole is selectively toxic to Type 1 alveolar epithelium.
    • Derived from excess tryptophan in autumn grass.

Micro-organisms

• A predominantly mononuclear reaction in the alveolar wall can be caused by:
  • Viruses
    • E.g. Canine Distemper
  • Bacteria
    • E.g. Salmonella
  • Protozoa
    • E.g. Toxoplasma gondii

Parasites

• Lungworms (Dictyocaulus vivipara) tend to affect the dorsocaudal areas of the diaphragmatic lobes in their invasion stage as larvae in the blood.
• Later adult stages irritate the airways and also release larvae which are inhaled deeper into the lung.
• In natural outbreaks, both types of lesions are seen.
  • May be complicated by bacterial infection.

Traumatic Implantation

• Traumatic implantation is fairly rare.
• Initially causes a pleural inflammation, with some extension to the adjacent lung tissue.
• For example:
  • Stake wounds in horses.
    • Usually fatal and cause extensive purulent, smelly inflammation.
  • Purulent pleuritis in dogs and cats due to Nocardia from a distant wound.
    • Not uncommon in cats.
    • May take some time to develop fully after the initial wound or cause has healed.
    • Generally fatal.
    • Clinical signs only developing when the lesions have become very extensive.

Repair in the Alimentary Tract

The Gut

• The gut is quite prone to infections.
  • These are generally kept at bay by the profuse gut associated lymphoid tissue and the continuous movement of ingesta.
• In mild infections, the inflammation is usually catarrhal.
  • Particularly in the large intestine where there are numerous goblet cells.
  • There is rapid repair by mucosal epithelium.
• More severe infections may damage the structure of the mucosa.
  • The villi may be stunted following repair.
    • There is a reduced water absorption compounded by loss of electrolytes - malabsorption.
      • Results in diarrhoea and progressive loss of weight.
      • E.g. in Johne's Disease.

The Liver

• The liver retains limited powers to regenerate and has considerable functional reserve.
• Acute inflammation is often due to viruses and bacteria.
  • E.g. Infectious Canine Hepatitis and Salmonellosis in young livestock.
  • The liver is swollen and may display hyperaemia.
  • Small pinpoint foci of necrosis may be seen through the surface.
• Chronic liver damage results in fibrosis - cirrhosis.
  • Generally the sequel to ingestion of a toxic substance over a long period of time.
  • E.g Aspergillosis.
    • Grossly, the liver shows varying fibrosis imparting a pale or greyish colour.
    • In some cases, there may be attempts at nodular regeneration of the hepatic parenchyma.
  • Ragwort poisoning has a fairly similar appearance.
    • The insidious deposition of fibrous tissue eventually becomes self-perpetuating, causing further damage to remaining hepatocytes as it matures and contracts.
    • Eventually neural signs referable to loss of hepatic detoxifying function occur.

The Pancreas

• The pancreas suffers both acute and chronic disease.
• The acute form called acute pancreatic necrosis is the important type in dogs.
  • The aetiology is obscure.
  • The mechanism involves the release of pancreatic enzymes into the surrounding fatty connective tissue.
  • Commonly affects obese females.
  • Animals may either die soon after the initial painful episode, or the inflammation smoulders on, often without clinical signs, until there is little pancreatic tissue left.
  • Diabetes mellitus or pancreatic insufficiency are common sequelae.
• Chronic pancreatitis is seen in the cat.
  • A slow disease often associated with inflammation of both the pancreatic and biliary ducts. *** Fuse before entering the duodenum in cats.
  • Grossly, there is reduction in size and sometimes quite extensive periductal fibrosis and inflammation.

Repair in the Urinary Tract

• The kidney has a great functional reserve.
  • Only 30% of the tissue is required to function properly.

Glomerulonephritis

• Glomerulonephritis and glomerular deposition of amyloid may cause loss of substantial quantities of protein into the urine.
• Oedema develops in the body, generally first in the back legs, then the ventral subcutis, and perhaps in the abdominal cavity.
  • This is called the Nephrotic Syndrome
• Inflammation can arise in the glomeruli, interstitial tissue and in the renal pelvis.
  • In the later stages of chronic inflammation, it may be difficult to determine the initial site of the inflammation.
• In severe chronic inflammation, substantial fibrosis of repair can become self-perpetuating.
  • Produces more and more damage until the whole kidney appears shrunken and distorted .
    • Called "end stage".
• Signs of uraemia develop once the functional reserve has been exceeded.
  • There are also characteristic (though inconsistent) lesions present in other tissues, i.e. the remote effects.
    • Inflammation of the tongue and stomach
    • Atrial endocarditis
    • Parathyroid hyperplasia
    • Widespread calcium deposition
      • Grossly noticeable intercostal muscles from the pleural aspect.
    • Anaemia
    • Hypertrophy of the left ventricle of the heart
    • Facial loss of bone

Pyelonephritis

• Important in the cow and sow.
  • It tends to be quite acute in the sow, and chronic in the cow.
• Arises from infection ascending the urinary tract.
• There is progressive loss of tissue.
  • Starts with necrosis in the pelvic area, then the inflammation spreads up into the cortex.
• Poor prognosis even with therapy.

Cystitis

• Bladder inflammation.
• Common in females.
• A feature of inflammation in the bladder is the considerable dilation of the submucosal vessels - vascular ectasia.
  • Bracken fern poisoning initially causes vascular ectasia and inflammation, but can progress

to tumour formation in the bladder.

Repair in the Genital Tract

Female

• Inflammation of the uterus in livestock can take place at two periods:
  1. At service.
     • Mild.
     • An endometritis.
  2. At parturition.
     • Can be very severe and life threatening.
     • Particularly occurs in assisted parturition.
     • Causes a metritis, involving the whole wall.
• Pyometra
  • Pus in the uterus.
  • Occurs commonly in bitches.
  • Is life threatening
• Mastitis
  • Inflammation of the mammary gland.
  • There are several forms of mastitis.
    1. Life threatening mastitis.
       • Occurs shortly after parturition.
       • E.g. gangrenous mastitis due to Staphylococcus aureus, and Coliform mastitis.
    2. Chronic mastitis.
       • Results in progressive destruction of the glandular tissue and replacement by fibrous tissue.
       • E.g. Streptococcus agalactiae.
  • Some organisms such as Staphylococcus aureus can cause gangrenous, acute and chronic mastitis.

Male

• Prostatitis
  • Inflammation of the prostate.
  • Common in dogs.
  • Causes a bag of pus in the tissue.
  • Results from an ascending infection of the tract.
• Orchitis
  • Inflammation of the testis.
  • Rather uncommon.
  • In bulls, a granulomatous inflammation occurs with Brucella abortus.

Repair in the Central Nervous System

• Encephalitis
  • Inflammation of neural tissue of the brain.
  • Repairs by the proliferation of astrocytes.
    • Astrocytes are the brain's form of fibrous tissue.
    • Called gliosis.
• Perivascular lymphocytic cuffing accompanies neural damage in the brain parenchyma.
• Meningitis
  • Inflammation of the meninges.
  • Purulent meningitis follows haematogenous spread of infection from umbilical infections and certain septicaemias.