The consequences of an injurious stimulus also depend on the type, status, adaptability, and genetic makeup of the injured cell. The same injury has vastly different outcomes depending on the cell type. For instance, striated skeletal muscle in the leg tolerates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes of ischemia. The nutritional (or hormonal) status also can be important; understandably, a glycogen-replete hepatocyte will survive ischemia better than one that has just burned its last glucose molecule. Genetically determined diversity in metabolic pathways can contribute to differences in responses to injurious stimuli. For instance, when exposed to the same dose of a toxin, individuals who inherit variants in genes encoding cytochrome P-450 may catabolize the toxin at different rates, leading to different outcomes. Much effort is now directed toward understanding the role of genetic polymorphisms in responses to drugs and toxins, a field of study called pharmacogenomics. In fact, genetic variations influence susceptibility to many complex diseases as well as responsiveness to various therapeutic agents. Using the genetic makeup of the individual patient to guide therapy is one example of “precision medicine.”
Cell injury usually results from functional and biochemical abnormalities in one or more of a limited number of essential cellular components (
Fig. 2.15 ). As we discuss in more detail later, different external insults and endogenous perturbations typically affect different cellular organelles and biochemical pathways. For instance, deprivation of oxygen and nutrients (as 42CHAPTER 2 Cell Injury, Cell Death, and Adaptations
Fig. 2.15 The principal biochemical mechanisms and sites of damage in cell injury. Note that causes and mechanisms of cell death by necrosis and apoptosis are shown as being independent but there may be overlap; for instance, both may contribute to cell death caused by ischemia, oxidative stress, or radiation. ATP, Adenosine triphosphate; ROS, reactive oxygen species.
in hypoxia and ischemia) primarily impairs energy-dependent cellular functions, culminating in necrosis, whereas damage to proteins and DNA triggers apoptosis. However, it should be emphasized that the very same injurious agent may trigger multiple and overlapping biochemical pathways. Not surprisingly, therefore, it has proved difficult to prevent cell injury by targeting an individual pathway.
As we discussed in the beginning of this chapter and have alluded to throughout, there are numerous and diverse causes of cell injury and cell death. Similarly, there are many biochemical pathways that can initiate the sequence of events that lead to cell injury and culminate in cell death. Some of these pathways are recognized to play important roles in human diseases. In the following section, we organize our discussion of the mechanisms of cell injury along its major causes and pathways, and discuss the principal biochemical alterations in each. For the sake of clarity and simplicity, we emphasize the unique mechanisms in each pathway, but it is important to point out that any initiating trigger may activate one or more of these mechanisms, and several mechanisms may be active simultaneously.