Cell Injury 3: Irreversible Cell Injury - Necrosis

Irreversible injury can lead to _____ or _____, ultimately resulting in ___ ____.

necrosis, apoptosis, cell death

Irreparable DNA damage to a cell can lead to ______, _______ or _____ which may cause ______ transformations.

apoptosis, senescence, dysplasia, neoplastic

Describe the morphological alterations in a reversible cell injury.

- cell swelling, fatty change, plasma membrane blebbing,

loss of microvilli, mitochondrial swelling, dilation of ER,

eosinophilia

Describe the morphological alterations in an irreversible cell injury.

• Necrosis

• Apoptosis

- necrosis (oncotic necrosis)

• eosinophilia (decreased RNA + protein condensation)

• nuclear shrinkage, fragmentation, dissolution

- apoptosis (apoptotic necrosis)

• Nuclear chromatin condensation, formation of apoptotic bodies (nuclear and cytoplasmic fragments)

Describe the five types of Necrosis.

1. Coagulative necrosis

• ischaemia / toxin induced

• liver, heart, kidney, skeletal muscle

• basic tissue architecture preserved (temporarily)

2. Liquefactive necrosis

• ischaemia / toxin induced in CNS

3. Caseous necrosis

• Mycobacterial infections eg Tuberculosis

• component cells dead, tissue architecture lost

• "cottage cheese-like" macroscopic appearance

4. Gangrenous necrosis

• 3 Types: dry / moist / gaseous

• ischaemia, bacterial toxins, other toxins, frostbite

5. Enzymatic necrosis

• adipose tissue necrosis due to leakage of pancreatic enzymes (lipases)

What does the cytoplasm look like in the early phase of cell death?

Early phase

• Cytoplasm becomes homogeneous pink in HE section

Increased eosinophilia (Red-color)

• Decrease/loss of RNA (responsible for cytoplasmic basophilia)

• Consolidation of cytoplasmic components upon cell collapse, causes cytoplasm to become more consolidated - red color

• Degradation of cytoplasmic proteins → ghost-like appearance of the cell

Necrotic cells become "individualized"

• lose adherence to basement membranes and adjacent cells

• found free in tubules, alveoli, follicles, and other lumens or surfaces

What does the cytoplasm look like in the late phase of cell death?

Cell rupture with loss of integrity and release of cell contents

What nuclear changes occur during cell death?

pyknosis

• shrunken, dark, homogeneous, round

karyorrhexis

• nuclear envelope ruptured

• dark nuclear remnants released into cytoplasm

karyolysis

• nucleus very pale

• dissolution of chromatin by DNAses

absence

• completely dissolved or lysed

What are some common causes of coagulative necrosis?

• Hypoxic cell injury - local loss of blood supply

• Bacterial or chemical toxins

• Local action of irritating substances

What is infarction?

Necrosis due to ischaemia

What do nephrotoxins do?

cause renal tubular degeneration and coagulative necrosis

What types of plants produce nephrotoxins, which are toxic to cattle?

• Oak, acorn (tannins)

• Oxalate (Rhubarb, sorrel, dock)

What types of plants produce nephrotoxins, which are toxic to cats?

• Easter Lily

What types of plants produce nephrotoxins, which are toxic to pigs?

• Redroot Pigweed (Phenolic Compounds)

What types of plants produce nephrotoxins, which are toxic to dogs?

• Raisins / Grapes (Toxic agent unknown)

What are some examples of heavy metal nephrotoxins?

How about chemicals?

Therapeutic drugs?

→ heavy metals

- mercury

- lead

→ chemicals

- ethylene glycol

→ therapeutic drugs

- antibiotics

- chemotherapeutics

Describe how ethylene glycol (What is the common name for this fluid) causes acute renal tubular necrosis.

Anti-freeze fluid poisoning

1.) First it is activated in the liver, alcohol dehydrogenase mediated activation to toxic metabolites

2.) Takes ethylene glycol to glycolic acid and glycoaldehyde glyoxylate (Toxic metabolites)

3.) Glycoaldehyde glyoxylate causes renal tubule epithelial degeneration

• Also formation of oxalate crystals which deposit in the renal tubules of the kidney

• Subsequent renal tubule obstruction, mechanical damage and further degeneration & necrosis

What are some examples of viral infections which cause necrosis?

Viral infections

Infectious Bovine Rhinotracheitis (IBR)

• Bovine Herpesvirus 1 (BHV-1)

Canine parvoviral enteritis

• Canine Parvovirus 2 (CPV-2)

Canine infectious hepatitis

• Canine Adenovirus 1 (CAV-1)

What are some examples of bacterial infections which cause necrosis?

Bacterial infections

Tuberculosis (Mycobacteria)

Mycobacterium tuberculosis, M. bovis, other

Salmonellosis (S. enterica, serotypes S. typhimurium, S. choleraesuis, S. dublin etc.)

Clostridial infections (Cl. perfringens, Cl. difficile, CI. chauvoei, Cl. septicum, other...)

Describe the pathological features of infectious Bovine Rhinotracheitis (Bovine Herpesvirus 1).

• transient, acute, febrile illness

• severe hyperaemia and focal necrosis of

• nasal, pharyngeal, laryngeal, tracheal (+/- bronchial) mucosae

• thick plaques of fibrinonecrotic exudate ("diphtheritic membranes")

• cover the laryngeal and tracheal mucosae

• contribution of secondary bacterial infection

Describe the pathological features of canine parvovirus enteritis.

• Segmental necrosis and hemorrhage of intestines (Digestive organs)

• Variable dilation of intestinal loops

• Granular texture of serosal surface

What is the pathogenesis of the parvovirus enteritis CPV-2 virus?

1.) Initial multiplication in lymphoid tissues (viraemia)

2.) Necrosis of crypt epithelial cells leads to crypt dilation

3.) Villous atrophy results from inability to replace enterocytes from crypts

Describe the pathological features of canine infectious hepatitis (CAV 1).

• Liver enlarged and friable, often see fibrin on capsular surface of liver lobes

• Granular appearance of serosal surfaces

• Gallbladder wall thickened by oedema

• Hepatocyte necrosis and loss

• Large basophilic intranuclear inclusions in hepatocytes

How does liquefactive necrosis occur?

(individual neurones initially show coagulation necrosis followed by a liquefactive process affecting the neuroparenchyma)

• hypoxia or toxin induced neuronal necrosis

• Leads to enzymatic dissolution of the neuropil (liquefaction)

What is the pathological process of liquefactive necrosis in the CNS?

• Little (or absent) fibrous connective tissue in the CNS

• Lack of support for the necrotic tissue

• Results in a cavity filled with

  • fluid and debris of neuronal membrane lipids

• Debris will be cleared up by macrophages (gitter cells)

What is a common example of liquefactive necrosis in cattle?

• Bovine Thiamine (Vit B1) deficiency (Polioencephalomalacia)

What is a common example of liquefactive necrosis in equines?

• Red discoloration of gray matter

• Fumonisin B1 - moldy corn poisoning

Liquefactive necrosis in other tissues is typically associated with _____ _____ _____. How does this occur?

pyogenic bacterial infections

How?

• recruitment of inflammatory cells (mainly neutrophils)

• release of lytic enzymes

• destruction of bacteria + degeneration & necrosis of neutrophils

leads to: ABSCESS (pus-filled cavity)

• can be considered a type of liquefactive necrosis

• with dehydration → pus inspissation = caseous necrosis

What is caseous necrosis?

• dead tissue converted into a granular, friable mass

(resembles cottage cheese)

What is the microscopic appearance of caseous necrosis?

• Microscopic appearance

- collection of fragmented / lysed cells with an amorphous granular appearance

- tissue architecture obliterated, no cell outlines visible (Distinction from coagulative necrosis)

- dystrophic calcification often seen centrally

What are some classic examples of caseous necrosis?

- TUBERCULOSIS

- Corynebacterium pseudotuberculosis in sheep

Chronic lesions seen in tissues attributed to caseous necrosis are often associated with….

poorly degradable bacterial lipids

Describe the pathological process of mycobacterium bovis (Bovine tuberculosis) infection.

1.) Inhalation of bacteria

2.) Bacilli spread within alveolar spaces in the lung

3.) Phagocytosed by alveolar macrophages

• Bacteria could be killed an infection stopped OR

• Inhibition of macrophage bactericidal activity, macrophages killed, bacterial spread, propagation of infection

Describe the pathological process of CLA (Caseous lymphadenitis) in sheep/goats.

Caused by cornebacterium pseudotuberculosis

• Associated with shearing wounds - arthropod bites or contaminated dips

• Spread by ruptured abscesses, oral and nasal secretions

• Incubation period 3 months (Chronic progressive disease)

• Ill-thrift (Failure to thrive)

• Carcase condemnation (Economic impact)

Describe the features of “moist” gangrene.

• Initial lesion is coagulative necrosis, followed by invasion by saprophytic/putrefactive bacteria that produce liquefactive necrosis

• Tissues are red-black, soft, and wet.

Describe the features of “gas” gangrene.

• Invasion by gas-producing bacteria

• Tissues are dark red to black with gas bubble formation.

Describe the features of “dry” gangrene.

• Decreased vascular perfusion/loss of blood supply

• Lack of putrefactive bacteria

• Shrivelled, dry, black/brown

What histological findings will you see considering “moist” gangrene?

• Histological findings

• Coagulative necrosis + proliferating bacteria

• Liquefaction +/- gas bubbles

What are some examples of “moist” gangrene?

• Ischaemic necrosis of extremities (tight bandage)

• Lung necrosis due to inhalation of digesta

• Staphylococcal mastitis in cows

How does “dry” gangrene typically occur?

• coagulation necrosis secondary to infarction with mummification (dehydration)

• A result of:

  • peripheral arteriolar vasoconstriction and capillary damage

  • Affects extremities

    • distal limbs, tail, ears, udder

• ingested toxins

- ergot and fescue poisoning

• cold

- frostbite

What might fescue toxicity cause?

• Bovine digital dry gangrene

How is gas gangrene or malignant oedema caused?

anaerobic bacteria proliferating & producing toxins in tissues

• Clostridium perfringens type A

• Clostridium septicum

• other clostridia (Cl. sordelli, Cl. novyi type A)

bacteria introduced by penetrating wounds into muscle/subcutis

What is the gross and microscopic appearance of “gas” gangrene?

- tissues are dark red to black

- sero-haemorrhagic exudate

- gas bubble formation

- coagulation necrosis of muscle

What is blackleg and how is it caused?

Clostridium chauvoei

• Dry Gangrene

bacteria not introduced with a penetrating wound

• spores spread haematogenously from the intestine & lodge into muscles (and remain latent)

• until good conditions: local tissue trauma with hypoxia occur

• anaerobic conditions

• spores germinate

• bacterial proliferation & toxins production/release

  • Causes muscle hemorrhage and necrosis with bubbles produced by bacteria

What are some examples of enzymatic fat necrosis?

• Acute pancreatic necrosis / pancreatitis

  • Saponification caused by enzyme leakage

• Release of activated pancreatic lipases → destruction of peripancreatic adipose tissue

What are some examples of traumatic fat necrosis?

• Crushed fat

  • Pelvic fat in dystocia

  • Sternal fat of recumbent animals

What are some examples of nutritional fat necrosis?

• Steatitis / yellow fat disease

• Consumption of diet high in polyunsaturated fats and low in antioxidants (Vitamin E) → reactive oxygen species → cause lipid peroxidation

What are some examples of iodpathic fat necrosis?

• Abnormal fat necrosis of cattle

• Necrotic fat in mesentery, omentum and retroperitoneum

List examples of fat necrosis.

• Enzymatic

• Traumatic

• Nutritional

• Idiopathic

What are some possible sequelae to Necrosis?

• inflammatory reaction within viable tissue

• band of white blood cells

• hyperaemia (Increased blood flow)

• digestion and liquefaction of necrotic tissue

• phagocytosis by macrophages

• drainage through blood/lymphatic vessels

• regeneration of normal tissue or fibrous scarring

What does sequelae mean?

a condition which is the consequence of a previous disease or injury