Cellular ischemia is a condition characterized by cellular damage from an insufficient blood supply. This reduction in blood flow deprives cells of the oxygen and nutrients required for their survival and function. The consequences of this deprivation can be severe, leading to tissue damage and organ dysfunction. This process is a contributor to many medical events, including heart attacks and strokes.
Causes of Insufficient Blood Flow
The interruption of blood flow that initiates ischemia stems from physical causes that obstruct or narrow blood vessels. A primary cause is atherosclerosis, where plaques of cholesterol, fats, and other substances accumulate on artery walls, narrowing them. If a plaque ruptures, it can trigger the formation of a blood clot, a condition known as thrombosis.
A blood clot can also form elsewhere, travel through the bloodstream, and lodge in a smaller vessel, blocking it completely; this is an embolism. Another cause is vasospasm, a sudden constriction of the muscles in the artery wall that temporarily chokes off blood flow. External compression from a tumor or traumatic injury can also squeeze a blood vessel, impeding circulation.
The Cellular Energy Crisis
Once blood flow ceases, the cell is starved of oxygen, triggering an energy crisis. Oxygen’s primary role is to act as the final electron acceptor in aerobic respiration, the highly efficient process that generates most of a cell’s energy, adenosine triphosphate (ATP). Without oxygen, this process shuts down, causing a rapid drop in ATP levels. The cell then switches to a backup system called anaerobic glycolysis.
This pathway generates a small amount of ATP without oxygen but is far less efficient. A drawback of this mode is the production of lactic acid as a byproduct. As lactic acid accumulates, it lowers the internal pH, creating an acidic environment. This acidity compromises the function of cellular enzymes and other proteins, initiating cellular damage.
Structural Breakdown and Cell Death
The energy deficit leads to the failure of cellular machinery. Ion pumps in the cell membrane, which are heavy consumers of ATP, cease to function. Without these pumps maintaining ionic balance, sodium ions accumulate inside the cell, causing water to follow via osmosis and leading to cellular swelling, or cytotoxic edema.
This membrane damage also allows an uncontrolled flood of calcium to enter the cell. This calcium influx is destructive, as it activates enzymes, including proteases that dismantle structural proteins and lipases that digest membranes. This internal destruction leads to cell death. In severe ischemia, this death occurs through necrosis, where the cell ruptures, spilling its contents and triggering an inflammatory response that can damage neighboring cells.
The Paradox of Reperfusion Injury
Counterintuitively, the restoration of blood flow to ischemic tissue, an event called reperfusion, can cause a second wave of damage. This phenomenon is termed the “oxygen paradox.” When oxygen rushes back into the altered cells, it can lead to the massive production of reactive oxygen species (ROS), or free radicals. These unstable molecules cause widespread oxidative stress, damaging lipids, proteins, and DNA.
The initial ischemic injury combined with this oxidative stress triggers a powerful inflammatory response. Immune cells are recruited to the site of injury, but in their attempt to clear away damaged cells, they can release substances that cause collateral damage to the surrounding tissue.