Pathologic Cell Injury and Cell Death I – Mechanism of Reversible Cell Injury
We already know that cells are able to adapt to their surroundings when there is an increased amount of stress to overcome them, just as we will in all our medical exams. If you want a reminder about this, we talked about this in “Cellular Adaptation to Stress.”
But what happens when the cell isn’t able to adapt to its stress and overcome its environment? Alas, it is inevitable that some cells simply are not able to adapt in time, or the stress is far too great to overcome. In this scenario, when cells are stressed so severely that they are unable to adapt to persevere in time, or when they are exposed to some intrinsic abnormality (e.g. genetic abnormality) or inherently damaging agent (eg. virus/bacteria).
From this stage, the cell will be damaged, and will reach a stage of reversible cell injury. If the stress persists, the cell eventually dies, resulting in cell death.
If we were to map out what happens when stress is added to a normally functioning cell, here’s a summary I tried to make for you guys:
Let’s discuss the latter two in detail to fully and completely understand what happens when a cell is stressed.
In this post, we will discuss Reversible Cell Injury, then I will discuss Necrosis, then Apoptosis, and finally, Mechanisms and Causes of Cell Injury.
Reversible Cell Injury:
As the name implies, this occurs if extreme stress persists and the cell is unable to adapt to overcome the stress. This type of injury results in cellular and morphological changes, that can still be reversed if the stress is eventually removed.
There are 3 main hallmarks you can always expect to find in reversibly injured cells.
- Depleted resources of ATP in the cell owing to decreased levels of Oxidative Phosphorylation.
- Hydropic Cellular Swelling, a phenomenon caused by changes in ion concentrations and water influx.
- Organelles within the cell show subtle alterations.
But how do you recognize a cell undergoing reversible cell damage under a light microscope?
- Cellular Swelling
- Organelle Changes
- Fatty Changes
Cellular swelling, also known as hydropic cellular swelling is an enlargement of an acutely injured cell, caused by changes in ion concentration and water influx. It is the first change to occur during cell injury, and is the result of a damaged ability of the cell to regulate ionic and fluid homeostasis due to a failure of the energy dependent ion pumps in the plasma membrane. [Recall that a hallmark of reversibly injured cell is ATP depletion – we can see why these energy dependent ion pumps fail.]
Now let us remember that the concentrations of ions in a particular area of the body determines its osmotic pressure. Thus, the higher the concentration of ions, the higher the osmotic pressure, and the more water will move to the area.
The mechanism of cellular swelling can be understood by understanding the components of ionic regulation, particularly that of Na+.
The components of Na+ regulation include:
- Plasma Membrane
- Plasma Membrane Na+ pump.
- ATP concentration.
Usually, the plasma membrane forms a barrier against excessive amounts of Na+ within the extracellular fluid from entering the cell. However, the plasma membrane is slightly “leaky” to Na+, allowing minimal amounts of Na+ to gradually move into the cell. To compensate this, there is a perpetually active Na+/K+-/ATPase pump, that pumps Na+ out of the cell constantly, in exchange for pumping K+ into the cell. This K+ is able to leave the cell freely. This ensures that Na+ does not buildup within the cell. In cellular injury however, 3 things may interrupt this process:
- The plasma membrane may be damaged, increasing its leakiness to Na+, and thus overriding the capacity of the Na+/K+-ATPase pump to keep Na+ at low levels.
- The Na+K+-ATPase pump may be directly damaged, and thus Na+ is able to slowly build up within the cell without being removed.
- Interfering with the synthesis of ATP, the fuel source for the Na+/K+-ATPase pump.
The end result of all 3 processes is that osmotic pressure builds within the cell due to increased ions, and water and fluids move into the cell, resulting in the cell becoming swelled and water-distended. If this occurs in multiple cells in a tissue or organ, then the organ appears enlarged, with increased turgor, some pallor (paleness) and increased weight.
As extra fluid builds up in the cell, the cell becomes distended and cellular organelles appear to become more spaced out within the cell. More importantly, most of the extra fluid actually builds within the endoplasmic reticulum, causing the ER to appear much more distended. As time goes on, regions of the ER burst and become encapsulated in clear vacuoles containing chunks of the ER. This is known as vacuolar degeneration.
Other histological organelle changes that occur with cell swelling include:
- Plasma Membrane Alterations, such as blebbing, blunting and loss of microvilli. Blebs are focal protrusions of the plasma membrane, and may occasionally detach, without a loss of cell viability.
- Mitochondrial Changes, namely swelling and the inclusion of small, amorphous (ill-formed, vague) densities rich in phospholipid, which correlate with the onset of irreversible damage.
- Dilation of the cisternae of ER, with detachment of polysomes, vacuolar degeneration and presence of intracytoplasmic myelin figures (which will be explained later).
- Nuclear Alterations, with disaggregations of granular and fibrillar elements of the nucleolus. Alternatively, the granular core may completely disintegrate, leaving only a fibrillar element.
And here’s how hydropic cellular swelling looks under the microscope:
Fatty Change (Steatosis):
Yep, fatty change is called steatosis. This steatosis is caused in hypoxic, toxic and metabolic injuries and is related to a dysfunction in the cell’s regulation of synthesis and elimination of triglycerides.
Excess lipids accumulate within the cells, usually parenchymal cells, that forms numerous vacuoles that displaces the cytoplasm.
If these vesicles are large enough to displace and distort the nucleus, it is referred to as macrovesicular steatosis, as in the diagram below.
If not, and the nucleus is undistorted, and there are fewer and smaller vesicles, then microvesicular steatosis results, as shown below.
Steatosis is actually a scenario that occurs in several diseases, and thus there is no one clear mechanism, but rather a number of different mechanisms. To simply categorize steatosis, we can divide diseases associated with microsteatosis and macrosteatosis.
I know, that is quite the list. Luckily, we don’t need to know all (phew). Instead, we can just have a general idea of what may cause what type of steatosis. So just skimming through this once should be fine enough. The very important ones to take note of is that Obesity, Type 2 diabetes, Metabolic Syndrome and Dyslipidemia all cause the macro vesicular steatosis variety.
That’s all for this guys! Next Pathology Topic would be Necrosis, then Apoptosis, and finally I’ll close this series with Mechanisms of Cellular Injury.