Cell Injury Mechanisms

What is cell injury?

When basic cell functions or viability are threatened

When does cell injury usually occur?

Due to situations where the ability of the cell to respond or adapt is exceeded

Is cell injury reversible or irreversible?

Can be either or

What are general causes of cell injury?

-Physical agents

-Chemicals

-Nutrients

-Infectious agents

What cells are highly susceptible to hypoxia?

Neurons and cardiac myocytes

What cells can survive in the absence of adequate oxygen?

Fibroblasts or squamous epithelium

What influences cell susceptibility?

Metabolic status

What are the mechanisms of cell injury?

-Loss of membrane integrity

-Loss of ability to produce energy

-Genetic damage

Describe loss of membrane integrity

-Damage to the plasma membrane removes the barrier to the extracellular environment and the gradients that it forms

-Damage to organelle membranes disrupts the segregation of reactions within a cell

What are the mechanisms of loss of membrane integrity?

-Free radical-induced damage

-Phospholipase-induced damage

-Direct membrane damage

Describe free radical injury

-Free radicals are chemicals with unpaired electrons that readily react with surrounding molecules

-A chain reaction occurs as the electron passes from molecule to molecule

-Free radicals can damage membranes as well as other cell components

When are free radicals formed?

During metabolism and by normal cell reactions:

-Oxidation reduction reactions during aerobic respiration (oxygen-derived products are the most important types of free radicals in tissues and cells)

-Biotransformation of chemical substances (transient, highly reactive intermediate compounds are formed)

-Nitric oxide metabolism

What are the effects of reactive oxygen metabolites?

-Protein and membrane degradation

-DNA damage

-Inflammation

What are reactive oxygen metabolites implicated in?

-Aging

-Neurodegeneration

-Neoplasia

-Cell injury and death

-Chronic inflammation

What are protective mechanisms for free radical injury?

-Vitamins A, C, and R (antioxidants): phytochemicals

-Iron and copper binding proteins (ferritin and ceruloplasmin among others)

-Specific enzymes (superoxide dismutase, catalase and glutathione peroxidase among others)

What cleaves phospholipids out of the membrane?

Activated membrane phospholipases

What activates membrane phospholipases?

-Increased cytoplasmic Ca2+ among other activators

-Decreased energy (decreased energy results in interference with membrane pump function and increased cytoplasmic Ca2+)

What can cause direct injury to membranes?

-Bacterial toxins

-Xenobiotics

-Complement

What is ATP?

Cellular energy

What pathways produce ATP?

-Oxidative phosphorylation (mitochondria: highly efficient)

-Anaerobic glycolysis (cytoplasm: poorly efficient)

What are the mechanisms of injury causing loss of ability to produce energy?

-Failure of energy-dependent membrane pumps (Na+/K+ and Ca2+/Mg2+)

-Decreased intracellular pH

-Decreased protein synthesis

-Cytoskeletal degradation (Ca2+: induced coagulation)

-Membrane degradation

-Leakage of organelle contents

-Organelle dysfunction

What is the role of calcium in cell injury?

-Mitochondrial injury

-Phospholipase activation

-Protease activation

-Endonuclease activation

What is a mutation?

Permanent damage to DNA

What are the outcomes of genetic injury?

-No effect on the cell or tissue

-Cell dysfunction leading to disease (developmental anomalies, storage diseases)

-Cell transformation leading to neoplasia

-Cell death (apoptosis)

Cell injury can either be ______ or _______

Sublethal or lethal

What are the outcomes of sublethal cell injury?

Can be reversible (the cell returns to normal) or progress to cell death

What are examples of sublethal cell injury?

-Cell swelling

-Intracellular accumulations

-Neoplastic transformation

What are examples of lethal cell injury?

-Apoptosis

-Necrosis (oncotic death)

What causes cell swelling?

Membrane ion pumps fail to maintain osmotic gradients across the membrane

-Water enters the cell or an intracellular organelle along an osmotic gradient

What is the morphology of cell swelling?

-Affected cells or organelles are swollen and finely vacuolated

-"Hydropic change"

What causes intracellular accumulations?

-Abnormal metabolism, functional demands that exceed the capability of the cell, or exposure to injurious agents can lead to accumulation of various intracellular substances

-Can be endogenous or exogenous

What are endogenous intracellular accumulations?

Excess normal or abnormal metabolic products that accumulate in a cell

What causes endogenous intracellular accumulations?

-Abnormal metabolism

-Demand that exceeds capability of the cell

-Cell injury that inhibits cell functions

What are some examples of endogenous intracellular accumulations?

-Metabolic storage diseases

-Lipidosis

-Glycogenosis

-Intracellular pigments (lipofuscin, iron/hemosiderin)

Describe lipidosis

-Metabolic pathways in cells are inhibited by injury or overwhelmed by excess demand (triglyceride accumulation is one common manifestation of metabolic change)

-It can be physiological as well as pathological

What are physiologic causes of lipidosis?

-High fat ration

-Increased periparturient energy needs

-Anorexia

What are pathologic causes of lipidosis?

-Hepatotoxins

-Hypoxia

-Starvation

In what cells is lipidosis most apparent?

In cells which metabolize large amounts of fat

When lipidosis is due to cell injury, it often occurs concurrently with what other cell change?

Cell swelling

What is the morphology of lipidosis?

Cytoplasmic vacuoles of variable size

When does glycogen accumulate?

Due to abnormal metabolism

How do cells look in glycogenosis?

Swollen

What causes endogenous accumulations of hemosiderin?

Intracellular aggregates of ferritin (an iron-protein conjugate)

What are hemosiderin accumulations commonly associated with?

-Increased rbc senescence

-Hemolysis

What are lipofuscin-ceroid accumulations?

Undegradable remnants of oxidized membrane lipids

When can lipofuscin-ceroid accumulate?

As part of aging or due to excessive membrane oxidation

What are exogenous intracellular accumulations?

Substances that accumulate that are not native to the cell environement

What are some general examples of exogenous intracellular accumulations?

-Viral proteins and nucleic acids ("inclusions")

-Carbon

-Non-nutritive minerals (eg: lead)

Describe transformation

-As a result of genetic injury, some cells undergo neoplastic transformation

-Transformed cells may have abnormal growth, often abnormal function, and abnormal morphology

-They are not "injured" in the traditional sense, they are detrimentally changed

What is the morphology of transformed cells?

-Cells may appear normal (some degree of hyperplasia may be present)

-Some cells appear poorly differentiated (anaplasia)

-Some cells have variable sizes/shapes/appearance (pleomorphism)

What is lethal cell injury?

When the insult to the cell exceeds the cell's ability to adapt or respond

How quickly does lethal cell injury occur?

It is immediate

What may determine the outcome for an injured cell?

The severity of the insult

What are the patterns of cell death?

-Apoptosis

-Necrosis

What is apoptosis?

Programmed cell death: the mechanism to remove damaged or unneeded cells in the least disruptive way possible

Is apoptosis an active or passive process?

Active

What are the physiologic causes of apoptosis?

-Patterned death during embryogenesis

-Hormone/cytokine-induced death (tissue involution)

-Maintain balance in proliferating populations

-Removal of cells following completion of their purpose (inflammatory cells following the end of the stimulus)

-Removal of self-reactive lymphocytes

What are the pathologic causes of apoptosis?

-Unrepaired DNA damage (damaged or transformed cells)

-Heat

-Hypoxia (mitochondrial injury)

-Viral infection

-Physical pressure (ureteral or secretory duct obstruction)

What is necrosis?

Death due to injury that disrupts the ability of the cell to continue to function

Is necrosis an active or passive process?

Passive

What is autolysis?

Self-digestion of a cell or tissue (this occurs in any cell or tissue that has died)

What is postmortem autolysis?

Self-digestion of cells/tissues/organs after an animal dies

What are the causes of necrosis?

Direct injury to the cell:

-Hypoxia

-Direct membrane injury

What are the mechanisms of necrosis?

Degradative activity of lytic enzymes:

-Lysosomal enzymes degrade cell

-Enzymes may come from the same cell (autolysis)

-Enzymes may come from other cells (heterolysis)

What is the morphology of necrosis?

-Eosinophilia (protein denaturation)

-Smooth, homogenous ("ground glass") cytoplasm (deterioration of organelles)

-Cytoplasmic vacuolation

-Nuclear degeneration (karyolysis, karyorrhexis, pyknosis)

-Inflammation in response to necrosis