Chemical Injury
Chemicals can cause cellular injury by direct (binding to molecular components of the cell) and indirect (lipid peroxidation or formation of free radicals).
Examples:
– Alcohol, ethylene glycol, lead, carbon tetrachloride (CCL4), cyanide and carbon monoxide (CO).
a) Alcohol toxicity
– Ethanol (alcohol) turns into acetaldehyde in the liver by alcohol dehydrogenase.
o This leads to the formation of free radicals and acetic acid by the liver
• Creates a state of acidosis
o Acetic acid leads to fatty change
o Acetate can further breakdown to acetyl CoA and enter the Krebs cycle
• Leads to build-up of ketone bodies
– Manifestations:
o CNS depression, metabolic acidosis
o Inhibition of gluconeogenesis
o Fetal alcohol syndrome (FAS)
• Ethanol can cross the placental barrier and affect the developing fetus
• Children are affected both
physically and cognitively
o Acute toxicity manifests mainly by CNS depression, chronic toxicity manifests mainly by liver damage.
b) Ethylene Glycol Toxicity
– Found in antifreeze, toxicity is usually via ingestion.
– Metabolized to glycolic acid leading to severe acidosis and acute renal injury.
– Direct effect on CNS with altered mental status
o The person will feel drowsy for the first hour following intoxication
– Eventually oxalic acid can be made which is a toxic metabolite
o This leads to the formation of calcium oxalate crystal in urine (renal stones).
– Serum levels of ethylene glycol peak within 1-4 hours
o CNS depression occurs during the 1st hour
– Patients develop heart failure or pulmonary edema within 12 hours
o Renal tubular necrosis within 24-72 hours (late stage).
c) Lead Toxicity
– Lead is a heavy metal, absorbed by inhalation or ingestion (paint, dust, occupational)
o When in the body, lead mimics other metal cofactors (calcium, iron, zinc) in enzymatic reactions.
o As a result, it inhibits 2 enzymes involved in heme synthesis: delta-ALAD (-aminiolevulinic acid dehydratase) and ferrochelatase.
o Lead also interferes with neurotransmitter activity.
– Toxicity can be acute or chronic.
o Not super common anymore with lead free toys, pencils, paints and car gas.
– Manifestations include:
o Anemia (Iron Deficiency): Lead can replace iron in hemoglobin and inhibits the synthesis of RBCs
o Lead can also replace calcium in bone (teeth), blood, and impair nerve
conduction, muscle contraction etc.
Calcium is a co-factor for blood coagulation so risk for bleeding is expected.
• In the cell, calcium is in the cisternae of the endoplasmic reticulum
• Intracellular free calcium stimulates contraction of muscles. Lead replaces this and those mechanisms are impaired.
o Blue gums (lead lines), dense metaphyseal lines on x-ray.
o Peripheral neuropathy (nerve conduction inhibited)
• Manifested as wrist/foot drop in adults, poor hand-eye coordination in children.
o Lead crosses the placenta which can lead to miscarriages, stillbirths, low birth weight, and
cognitive impairments.
d) Carbon monoxide
– Produced from incomplete combustion of organic materials
– Binds to Hb and forms carboxyhemoglobin (COHb)
– This is known as the silent killer (so is hypertension). No taste or smell but it is fatal. The carbon is tightly bound to Hb, so does not release oxygen in the tissues. Tissues get hypoxic and die.
e) Cyanide
– Binds/ inactivates cytochrome oxidase in mitochondria.
– Disrupts mitochondrial cellular respiration.
– Causes respiratory failure.
4. Physical injury
Thermal:
– Hyperthermia (>38.5°C): High heat damages protein and stops enzyme activity (eg. Heat stroke)
– Hypothermia (<35°C): Excessive exposure to cold, alcohol intoxication. (cooling of the surgical field to decrease circulation and reduce bleeding, if overdone → hypoxic tissue.
– Burns
Radiation: UV
– Exposure creates thymine dimers leading to faults in DNA replication when the cell divides and subsequent mutations.
– A method for killing bacteria.
Pressure:
– Air pressure
o Explosion e.g. Blast injuries: complex physical trauma.
o Water pressure.
Surgery:
– Deliberate tissue injury.
– Potential damage to the cells as a post-operative complication.
5. Nutritional Injury
Nutritional Deficits
– Malnutrition: not enough intake of any nutrient (CHO, Fat, Protein, Minerals)
– Dehydration: Water loss (may also result in electrolyte imbalance)
– Hypoalbuminemia: Albumin = 60% of plasma proteins; therefore, it is largely responsible for the oncotic pressure, so low albumin leads to edema/ascites since fluid is not retained in blood vessels.
– Hypoglycemia: Low blood glucose level → low glucose inside cells →reduce energy production.
– Vitamin deficiencies (Vitamins ADEK and folic acid).
Nutritional Excess
– Excess nutrients can also cause injury e.g. Hypervitaminosis D, hypercalcemia.
6. Mechanical Injury
a. Blunt force:
– Application of mechanical energy to the body resulting in the tearing, shearing, or crushing of tissues e.g. MVAs
– Manifestations:
o Contusion / hematoma = bruise.
o Stages:
I. Trauma to the site = rupture of BV → blood (RBCs; low oxygen) in subcutaneous tissue (hematoma) → blue/purple skin.
II. Lysis of the escaped RBCs → free Hb which is decomposed further → hemosiderin (brownish skin).
III. Hemosiderin turns into biliverdin → (yellowish skin)
o Abrasion, laceration, fractures.
b. Penetrating injuries
– Stab wounds, gunshot wounds. If gunshot went into body it is damaging mechanically, can rupture BV→ internal hemorrhage.
– Ruptured spleen = almost fatal (storage site for blood)
c. Asphyxial Injuries
– Effects due to hypoxia
o Suffocation (choking).
o Strangulation (hanging, ligature, manual strangulating).
o Chemical asphyxiants (cyanide and hydrogen sulfide).
o Drowning.
d. Gunshot wounds
– Effects
o Tissue disruption.
o Bleeding, hypovolemic shock.
o Pneumothorax.
– KE = ½ MV2
o Wounds produced by missiles of higher mass (M) and/or velocity (V) produce greater tissue disruption
• I.e. faster & heavier = more damage
7. Infectious Injury
Note: Details of infectious agents in Microbiology course
Bacteria
– Produce toxins (endotoxin or exotoxin).
Viruses
– Decrease the ability to synthesize proteins.
– Change the cell’s antigenic properties.
Other microbes
8. Immunologic and Inflammatory Injury (Details in Microbiology course)
Induced by:
– Cells: phagocytic cells (neutrophils, macrophages, monocytes)
o Alterations in cell membrane
o Changes in membrane permeability
• These changes cause unintentional injuries and problems that will need to be repaired
– Mediators: substances release by immune inflammatory cells
o Histamine, cytokines, antibodies, complement, and proteases
o Histamine from basophils circulates in body leading to itching, edema
**Remember Inflammation = tissue response to ANY injury
9. Genetic Injury
Genetics play a substantial role in cellular structure and function including:
– Cell shape
– Protein structure and functions
– Receptors and recognition
– Transport mechanisms
Examples
– Sickle cell disease (missense mutation in globin protein; abnormal Hb S; red cell hemolysis; anemia)
– G6PD (X-linked; enzyme deficiency; red cell hemolysis; anemia)
– CML (chronic myeloid lymphoma); Philadelphia chromosome
o Chromosome 22 to chromosome 9 translocation.
Pathological themes – Cellular injury
a) Mitochondrial damage
– O2 depletion
– Impaired oxidative metabolism → decreased ATP production
– ROS = Reactive oxygen species (free radicals)
b) Membrane damage:
– Plasma membrane damage: failure of Na-K pump; increases cellular water
– Lysosomal membrane damage: enzyme release, activation & digestion of cell components
– Mitochondrial membrane damage → decreased ATP
c) Protein synthesis impairment:
– Ribosomes separate from the swollen endoplasmic reticulum → decreases protein synthesis
d) Lipid peroxidation:
– Causing damage to phospholipid cell membranes
Manifestations of Cellular injury – Accumulations
a) Water:
– Necessary for life, but when there is too much, this can lead to flooding
– Water accumulation = hydropic degeneration
b) Lipids and carbs
c) Glycogen
d) Proteins
e) Pigments
– Melanin, hemosiderin, bilirubin
f) Calcium
– Calcium is stored inside Cisternae of ER (inactive state) and is only released when needed (e.g. muscle contraction, cofactor in the activation of enzymes)
– Free Ca2+ activates enzymes → hormonal action, calcium mediated, kinases etc
– Therefore, it is essential for the
regulation of body processes to have calcium remain stored in the ER because if calcium were to be free it would continuously activate body processes (above)
g) Urate
Cell Death
Happens when you can’t reverse the changes through adaptation to injury/stress
Apoptosis
Programmed cell death.
Normal occurrence in the body:
– Aging/senescence of cells e.g. RBCs killed every 120 days
– Tissue involution following hormonal withdrawal
– Elimination of self-reactive lymphocytes (immune tolerance) in Thymus
– Breaking self-tolerance → autoimmune disease