Cell Injury 3

What are the possible fates of a cell facing a stressor or injurious stimulus?

• cell death

• adaptation

• reversible cell injury

What determines whether an injured cell recovers or progresses to irreversible injury and death?

• duration/severity

• ATP depletion

What is cell injury

any alteration that impairs a cell's ability to function normally (loss of homeostasis)

What determines cell injury??

depends on: severity, duration, type of injury (etiology), and type of cell (adaptability/susceptibility).

Name as many of the 9 categories of cell injury.

• physical agent

• chemical agent

• immunologic agent

• workload agent

• oxygen depreviation

• free radicals

• nutrional imbalance

• genetics

• infection

What are the 4 cellular systems most vulnerable to injury?

• membrane

• genome

• energy

• protein

What is the word for “Decrease in size/amount of

cell, tissue, or organ”

atrophy

What is the word for “Increase in cell size (more organelles); little/no replicative capacity”?

hypertrophy

What is the word for “Increase in cell number via mitosis; occurs in labile, high-turnover cells”?

hyperplasia

What is the word for “Reversible change of one adult cell type to another of the same germ line”

metaplasia

What is another name for cell swelling?

hydropic degeneration

What is Hydropic Degeneration (Cell Swelling)

AKA cellular swelling, cytotoxic edema, ballooning degeneration

What is the most common and fundamental expression of reversible cell injury

• Hydropic Degeneration (Cell Swelling)

What is the mechanism of Hydropic Degeneration (Cell Swelling)

damage to cellular membranes or the pumps/channels that regulate ion balance → water influx

What is the first morphologic change with almost any type of cell injury

Hydropic Degeneration (Cell Swelling)

Histolopathologic features of oncotic necrosis are?

1. Cytoplasmic changes

2. Nuclear changes

What does Cytoplasmic changes mean

hypereosinophilia (more pink)

What does Pyknosis: mean

the nucleus shrinks and is densely blue

What does Karyorrhexis mean

nucleus fragments

What does Karyolysis mean

nucleus fades aways/dissolves

What is cell injury cascade

molecular/biochemical disruption occurs first —well before any structural (morphologic) change is visible.

Direct clinical consequence of the free-radical/antioxidant pathway —

selenium and vitamin E deficiency remove the cell's ability to neutralize ROS.

Why does morphology change matter?

an animal can die from cellular dysfunction before any lesion develops that anatomic pathology can detect.

What is the % of perianesthetic deaths in young animals presented for elective surgery have NO gross or histologic lesions identified

approximately 40%

What is the first sensitive hypoxic injury

neurons

What is the second sensitive hypoxic injury

fibroblast

What is the third sensitive hypoxic injury

hepatocytes

What is the fourth sensitive hypoxic injury

skeletal muscle

Why are neurons sensitive?

Cannot produce ATP anaerobically — high energy demand, low reserve

Why are cardiac muscles intermediate

Moderate anaerobic capacity

Why are skeletal muscles resistant

Fibroblasts are so resistant they can repopulate hypoxic tissue where other cells cannot regenerate

How does the liver get oxygen? Through which vessels?

• the hepatic artery

• hepatic portal vein

Centrioles

zone hepatocytes sit farthest from the portal area and receive an already-mixed, oxygen- poor blood supply — making them the most hypoxia-sensitive zone of the liver lobule.

What is a free radical?

• molecular species with an unpaired electron in an outer orbit — extremely unstable and reactive.

• Also called reactive oxygen species (ROS).

Free radicals are generated how?

▪ Normal redox metabolism

▪ UV radiation

▪ Inflammation

▪ Toxic chemicals/drugs

▪ Ischemia-reperfusion injury

The Free Radicals damage targets are what?

• membrane (lipid peroxidation)

• DNA (strand breaks)

• Proteins (disrupted folding/enzumatic sites)

How do we Increases in free radical generation can occur with:

▪ Normal redox metabolism

▪ UV radiation

▪ Inflammation

▪ Toxic chemicals/drugs

▪ Ischemia-reperfusion injury

Selenium is a required cofactor for

glutathione peroxidase

What does normal skeletal muscle look like

you can see the striation in the myocyte

What does the abnormal skeletal muscle look like?

in the necrotic myocyte it loses the striation (becomes more pink)and nuclie becomes condensed

Where are free radicals generated

are generated by normal metabolic processes when cells generate energy in mitochondria

What are the three most common free radicals generated by a cell

• Superoxide (O2-) → via SOD

• Hydrogen peroxide (H2O2) → Catalase

• Hydroxyl Radical → most reactive via GPx

UV radiation is a source of?

free radical formation and can directly damage DNA.

What are examples of Endogenous enzymes ?

• **Superoxide dismutase

• catalase

• glutathione peroxidase

What is the role of Endogenous enzymes

Catalyze enzymatic reduction of free radicals to water

What are examples of Exogenous — vitamins

• Vitamin C

• Vitamin E

What is the role of Exogenous — vitamins

Block free radical formation and scavenge free radicals

What are examples of Exogenous — other

• Carotenoids

• polyphenols

What are examples of Exogenous — other

Dietary free radical scavengers

Nutritional Myopathy is also known as

white muscle disease

How does nutrionaly myopathy occur

Nutritional deficiency of selenium and/or vitamin E

What does it look like grossly (white muscle disease)

pale streaks/regions within muscle at necropsy

What does it look histology (white muscle disease)

fragmented, hypereosinophilic myofibers — myonecrosis

What are the consquences of not treating white muscle disease

Without adequate antioxidant capacity, growing animals can develop widespread muscle degeneration and necrosis

Chemical Injury Effect depends on:

agent/mechanism of action, dose, route of exposure, tissue metabolism, route of excretion

What is the defintion of Direct Toxicity

• Chemical causes injury in its original form

• ingest the toxin

What is Indirect Toxicity

Chemical is only injurious after metabolization in the body

Much detoxification occurs in the liver via

cytochrome P450 oxidases

P450 is found at highest concentration in

centrilobular hepatocytes.

Indirect toxicity through biotransformation in the

liver

What is occurring in Phase I bioactivation

converts tryptophan to reactive intermediate such as 3-MI via cytochrome P450 enzymes

What is occurring in Phase II

• conjugation pathways (Glucuronidation, Sulfation, Glutathione conjugation)

• These pathways detoxify 3-MI by converting it to water-soluble conjugates

What is occurring in Phase III

• elimination (Kidney and Intestines)

• in urine and in feces

• Primary route of elimination: Urine

• Secondary route of elimination: Feces

What are the reason for Centrilobular Hepatocytes to occur

• Farthest from the portal area, receive already O2-depleted mixed blood

• Highest concentration of cytochrome P450 oxidases → most metabolic activation of indirect toxins.

What is High-yield integrative point:

the same zone of the liver is the most important location for two entirely different injury mechanisms.

Fatty Change: A reversible cell injury: From Cell Injury 2, expanded Accumulation of intracellular lipid, primarily in the liver (AKA hepatic lipidosis, hepatic steatosis)

▪ Excessive fatty acid entry

▪ Defective fatty-acid oxidation

▪ Decreased apoprotein synthesis

▪ Defective lipoprotein (VLDL) secretion

What does a fatty liver look like grossly

• Enlarged

• tan

• friable

• may float

What does a fatty liver look microscopic ?

• Clear,

• round,

• discrete cytoplasmic vacuoles that displace the nucleus

What is a typical pattern of fatty change in a ruminants (cattle)

• Late pregnancy or early lactation in overconditioned animals

• highest metabolic demand, decreased intake

What is a typical pattern of fatty change in small ruminants

• Pregnancy toxemia

• overweight, late pregnancy, multiple fetuses; decreased intake from space-occupying uterus

What is a typical pattern of fatty change in a small ruminants

• Uncommon; breed predisposition — ponies, minis, donkeys, Morgans

• overweight + genetic risk + negative energy balance

What is a typical pattern of fatty change in a Dog

• Very rare

• think toxin (e.g., Slentrol) rather than a primary metabolic cause

What is a typical pattern of fatty change in a Cat

• Feline hepatic lipidosis

• anorexia in an overweight cat

What is Tension Lipidosis

A focal (not generalized) hepatic lesion

Which animal is almost exclusively getting the chance to have tension lipidosis

cattle

Why does tenision lipidosis occurr in cattle

Occurs adjacent to capsular fibrous adhesions

What is the presumed mechanism tension lipidosis

local hypoxia from tension transmitted to the parenchyma by the adhesion