A common cause of injury to cells and tissues is the inflammatory reaction that is elicited by pathogens, necrotic cells, and dysregulated immune responses, as in autoimmune diseases and allergies. In all these situations, inflammatory cells, including neutrophils, macrophages, lymphocytes, and other leukocytes, secrete products that evolved to destroy microbes but also may damage host tissues. These injurious immune reactions are classified under hypersensitivity. Their mechanisms and significance are discussed in Chapter 5.
In the previous discussion, we addressed the mechanisms of cell injury according to the initiating cause, and highlighted the principal pathways of injury that are triggered in different pathophysiologic situations. Some abnormalities characterize cell injury regardless of the cause, and are thus seen in a variety of pathologic situations. Two of these changes are described next.
Mitochondria may be viewed as “mini-factories” that produce life-sustaining energy in the form of ATP. Not surprisingly, therefore, they also are critical players in cell injury and death. Mitochondria are sensitive to many types of injurious stimuli, including hypoxia, chemical toxins, and radiation (
Fig. 2.19 ). Mitochondrial changes occur in necrosis and apoptosis. They may result in several biochemical abnormalities:
Failure of oxidative phosphorylation leads to progressive depletion of ATP, culminating in necrosis of the cell, as described earlier.
Abnormal oxidative phosphorylation also leads to the formation of ROS, which have many deleterious effects, as already described.
Damage to mitochondria is often associated with the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial
ATP Production Leakage ofgeneration of ROS
Fig. 2.19 Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis. This pathway of apoptosis is described in more detail later. ATP, Adenosine triphosphate; ROS, reactive oxygen species.
permeability transition pore. The opening of this channel leads to the loss of mitochondrial membrane potential and pH changes, further compromising oxidative phosphorylation.
• Mitochondria also contain proteins such as cytochrome c that, when released into the cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis, as discussed earlier.
Increased membrane permeability leading ultimately to overt membrane damage is a feature of most forms of cell injury that culminate in necrosis. The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma membrane, and membranes of lysosomes. As noted earlier, increased permeability of the plasma membrane and lysosomal membranes is not a feature of apoptosis.
Mitochondrial membrane damage. As discussed earlier, damage to mitochondrial membranes results in decreased production of ATP, with many deleterious effects culminating in necrosis.
Plasma membrane damage. Plasma membrane damage leads to loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores.
Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell. Activation of these enzymes leads to enzymatic digestion of cell components, and the cells die by necrosis.
Differentinitiatingeventscausecellinjuryanddeathbydiversemechanisms.