BMS 151: Cellular and Tissue Response to Injury

• BMS 151 covers the foundations of pathology, specifically the pathology of cellular and tissue response to injury (part 1).

Learning Objectives

• Define cell injury and describe its various causes and pathogenesis.
• Define cellular adaptation, identify its types, and recognize causes of different forms of cellular adaptation including atrophy, hypertrophy, hyperplasia, and metaplasia.
• Describe the morphological changes in different types of reversible cell injury, and recognize their fate.

Case Scenario: Ali

• Ali is a 44-year-old man with a history of poorly controlled Diabetes Mellitus, presenting vague abdominal pain due to an enlarged liver, determined by ultrasound
• The liver has a preserved shape and a smooth outer surface.
• Ali denies alcohol or drug intake, other than insulin.
• The doctor assured Ali that his liver can return to normal size if he controls his blood glucose level
• Key Questions:
• What is the cause of Ali's enlarged liver?
• Is Ali's case reversible?
• What are the microscopic types of this disease?

Cell Injury Definition

• The normal ability of cells to maintain stable physiologic functions leads to homeostasis.
• Cellular dysfunction leads to organ dysfunction leads to clinical expression.
• Cell injury involves a variety of structural and functional changes in a stressed cell.
• Stresses are due to external and internal environmental changes leading to altered homeostasis.

Cell Injury Causes

• Cell injury is caused by "injurious agents"
• Hypoxia is the commonest cause of cell injury.
• Nutritional disturbances can be excesses like in obesity, or deficiencies as in wasting diseases like diabetes mellitus, tuberculosis and cancer.
• Physical agents can cause cell injury, namely trauma, heat, cold, and radiation.
• Chemical agents cause injuries, such as concentrated acids, alkalies, poisons (CCl4, cyanide), and various drugs.
• Infectious agents, such as viruses, bacteria, and fungi can cause cell injury.
• Immunologic reactions, such as autoimmune diseases, lead to cell injury.

Cell Injury Effects

• The effects of cell injury depend on the nature, duration, and severity of the injurious agents.
• The effects also depend on type and state of the injured cell.
  • For example, brain tissue is very sensitive to hypoxia and endures damage within 2-5 minutes.
  • On the other hand, skeletal muscles can adapt to hypoxia for 2-6 hours.
• Cell injury can manifest in several forms:
  • Cellular adaptation
  • Reversible cell injury
  • Irreversible cell injury
  • Intracellular and extracellular accumulations

Cellular Adaptation

• Cellular adaptation is the modification of cell structure and function in response to stress, preserving the cell's vitality.
• Cellular adaptation is reversible
• Too much stress that exceeds the cell's adaptive capacity leads to cell injury.

Types of Adaptation

• Atrophy: Decrease in cell size and/or number leading to a decrease in organ size.
  • Pathogenesis involves decreased protein synthesis and increased protein breakdown.
  • Physiological examples: aging, uterus atrophy after labor, and thymus atrophy after puberty.
  • Pathological examples: disuse atrophy after bone fracture, neurogenic atrophy due to denervation, and ischemic atrophy.
• Hypertrophy: Increase in the size of mature organs due to increase in cell size.
  • Its pathogenesis involves stimulated increased synthesis of structural proteins due to increased functional demand, growth factor stimulation, and hormonal stimulation.
    • Physiological examples : smooth muscle of uterus hypertrophy in pregnancy, skeletal muscle hypertrophy in athletes.
    • Pathological example is cardiac muscle hypertrophy of the left ventricle in systemic hypertension.
• Hyperplasia: Increase in size of mature organ due to an increase in cell number.
  • Its Pathogenesis includes cell proliferation due to increased functional demand, growth factor stimulation, and hormonal stimulation.
  • Physiological example include hyperplasia of the female breast during puberty, pregnancy, and lactation.
  • Pathological examples include bone marrow after hemorrhage, skin around a wound, liver cells after partial destruction, and prostate/endometrium under hormonal stimulation.
• Metaplasia: Change of one type of tissue to another type within the same category (epithelium to epithelium or connective tissue to connective tissue).
  • It is always pathological and reversible.
  • Pathogenesis involves reprogramming of stem cells to differentiate along a new pathway to tolerate stress.
    • Squamous metaplasia of respiratory epithelium appears in smokers.
    • Squamous Metaplasia of urinary bladder appears in bilharziasis.
    • Intestinal metaplasia of the esophagus appears in reflux esophagitis (Barrett's esophagus).

Reversible Cell Injury

• Reversible cell injury is "degeneration".
• It is caused by mild injurious agents of short duration.
• Reversible cell injury affects active parenchymatous cells rich in mitochondria.
• The functional and morphologic changes are reversible if there is removal of the damaging stimulus.
• Reversible cell injury includes cloudy swelling & hydropic degeneration as well as fatty change.

Cloudy Swelling & Hydropic Degeneration

• Cloudy Swelling & Hydropic Degeneration are a form of reversible cell injury, characterized by intracellular water accumulation.
  • If water accumulation is mild, it's cloudy swelling.
  • If water accumulation is excess, it's hydropic degeneration.
• Cloudy swelling is often the earliest type of cell injury.
• The cause of cloudy swelling & hydropic degeneration is mild injury of short duration.
• Pathogenesis occurs when mitochondrial injury occurs first, which decreases ATP, that leads to decreased Na/K pump causing entry of Na inside the cell.
  • Next anaerobic respiration causes lactic acid accumulation & release of mitochondrial protein within the cytoplasm.
  • This chain of events leads to increase in the cytoplasmic osmotic pressure helping intracellular water accumulation & cell swelling.
• The gross picture of an organ that has undergone cloudy swelling is enlarged; its shape is preserved; its surface is smooth; its color is pale due to compressed capillaries from swollen cells; its capsule is stretched; with a soft consistency; and a cut surface that appears cloudy, opaque, and bulges outwards.
• In regards to the Microscopic appearance:
• Cloudy Swelling: cells are swollen with compressed capillaries in between, the nucleus is normal, and cytoplasm is granular.
• Hydropic Degeneration: cells are swollen with compressed capillaries in between, the nucleus is normal, and the cytoplasm is pale and has multiple vacuoles.
  • Proximal convoluted tubules of the kidney are most affected as their cells are rich in mitochondria.

Fatty Change [Steatosis]

• Fatty change is a form of reversible cell injury characterized by intracellular accumulation of neutral fat.
• The liver is the most commonly affected organ since it is the major site of fat metabolism.
• It's caused by mild injury of short duration.
• Gross Picture: involves an enlarged organ in size with a preserved shape, smooth surface, and yellow color .
  • The capsule is stretched, with a soft consistency and a cut surface that appears yellow, bulges outwards and appears greasy to touch.
• The cells are swollen with compressed capillaries in between, the nucleus is normal, and cytoplasm show:
  • Initially multiple cytoplasmic clear vacuoles.
  • Later the fat globules fuse together forming a big globule that pushes & flattens the nucleus against the cell membrane giving the cell a signet ring appearance.
  • Fat special stains are done on frozen sections.
    • These include Osmic acid → black, Sudan III → orange, and Oil red O → red.

Key Terms

• Decrease in size of mature organ due to decrease in cell size is termed Atrophy.
• Increase in size of mature organ due to increase in cell number is termed Hyperplasia.
• Reversible cell injury characterized by mild intracellular water accumulation is termed Cloudy Swelling.

Key Points

• Enlargement of the female breast at puberty is an example of Physiologic hyperplasia.
• Metaplasia is a Pathologic process.
• The earliest type of cell injury due to lack of oxygen is Cloudy swelling.