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- 1 Cell Injury
- Reduced Functional Demand: For example, after immobilization of a limb in a cast, muscle cells atrophy, and muscular strength is reduced. When normal activity resumes, the muscle's size and function return.
- Inadequate Supply of Oxygen: Interference with blood supply to tissues is called ischemia. Although total cessation of oxygen perfusion results in cell death, partial ischemia is often compatible with cell viability. Under such circumstances, cell atrophy is common.
Figure 1-1. Atrophy of the brain. Marked atrophy of the frontal lobe is noted in this photograph of the brain. The gyri are thinned and the sulci conspicuously widened. - Insufficient Nutrients: Starvation or inadequate nutrition associated with chronic disease leads to cell atrophy, particularly in skeletal muscle.
- Interruption of Trophic Signals: The functions of many cells depend on signals transmitted by chemical mediators, of which the endocrine system and neuromuscular transmission are the best examples. Loss of such signals via ablation of an endocrine gland or denervation results in atrophy of the target organ. Atrophy secondary to endocrine insufficiency is not restricted to pathologic conditions. For example, the endometrium atrophies when estrogen levels decrease after menopause (Fig. 1-2).
- Aging: The size of all parenchymal organs decreases with age. The size of the brain is invariably decreased, and in the very old, the size of the heart may be so diminished that the term senile atrophy has been used.
- Hormonal Stimulation: Changes in hormone concentrations, whether physiologic or pathologic, can elicit proliferation of responsive cells. The normal increase in estrogens at puberty or early in the menstrual cycle leads to increased numbers of endometrial and uterine stromal cells. Exogenous estrogen administration to postmenopausal women has the same effect. Ectopic hormone production may also result in hyperplasia. Erythropoietin production by renal tumors may lead to hyperplasia of erythrocytes in the bone marrow.
- Increased Functional Demand: Hyperplasia, like hypertrophy, may be a response to increased physiologic demand. At high altitudes, low atmospheric oxygen content leads to compensatory hyperplasia of erythrocyte precursors in the bone marrow and increased erythrocytes in the blood (secondary polycythemia). Chronic blood loss, as in excessive menstrual bleeding, also causes hyperplasia of erythrocytic elements.
- Chronic Injury: Long-standing inflammation or chronic physical or chemical injury often results in a hyperplastic response. Pressure from ill-fitting shoes causes hyperplasia of the skin of the foot, so-called corns or calluses, which reflects the skin's protective capacity.
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Cell Injury
David S. Strayer
Emanuel Rubin
Pathology is the study of structural and functional abnormalities that are expressed as diseases of organs and systems. Classic theories attributed diseases to imbalances or noxious effects of humors on specific organs. In the 19th century, Rudolf Virchow, often referred to as the father of modern pathology, proposed that injury to the smallest living unit of the body, the cell, is the basis of all disease. To this day, clinical and experimental pathology remain rooted in this concept, which is now extended by an increased understanding of the molecular nature of many disease processes.
A living cell must maintain the ability to produce energy, much of which is spent in establishing a barrier between the internal milieu of the cell and a hostile environment. The plasma membrane, associated ion pumps, and receptor molecules serve this purpose. A cell must also be able to adapt to adverse environmental conditions, such as changes in temperature, solute concentrations, oxygen supply, or the presence of noxious agents, and so on. If an injury exceeds the adaptive capacity of the cell, the cell dies. From this perspective, pathology is the study of cell injury and the expression of a cell's pre-existing capacity to adapt to such injury.
Reactions to Persistent Stress and Cell Injury
Persistent stress often leads to chronic cell injury. Whereas permanent organ injury is associated with the death of individual cells, the cellular response to persistent sublethal injury (whether chemical or physical) reflects adaptation of the cell to a hostile environment. Again, these changes are, for the most part, reversible on discontinuation of the stress. The major adaptive responses are atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia, and intracellular storage
of certain endogenous or exogenous materials. In addition, certain forms of neoplasia may follow adaptive responses.
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of certain endogenous or exogenous materials. In addition, certain forms of neoplasia may follow adaptive responses.
Proteasomes are Key Participants in Cell Homeostasis, Response to Stress, and Adaptation to Altered Extracellular Environment
Cellular homeostasis requires mechanisms that allow the cell to destroy certain proteins selectively. Although there is evidence that more than one such pathway may exist, the best-understood mechanism by which cells target specific proteins for elimination is the ubiquitin (Ub)-proteasomal apparatus.
Proteasomes
The importance of the proteosome is underscored by the fact that it may comprise up to 1% of the total protein of the cell. Proteasomes are evolutionarily highly conserved and are present in all eukaryotic cells. Mutations leading to interference with normal proteasomal function are lethal.
Proteasomes exist in two forms. The 20S proteasomes are important in degradation of oxidized proteins. In 26S proteasomes, ubiquitinated proteins are degraded.
Ub and Ubiquitination
Proteins to be degraded are flagged by attaching small chains of Ub molecules to them, thereby serving to identify proteins to be destroyed.
How Ubiquitination Matters
The importance of ubiquitination and specific protein elimination is fundamental to cellular adaptation to stress and injury. Defective ubiquitination may play a role in several important neurodegenerative diseases. Mutations in parkin, a Ub ligase, and also a related enzyme, are implicated in two hereditary forms of Parkinson disease. Manipulation of ubiquitination may be important in tumor development. Thus, papilloma virus strains that are associated with human cervical cancer (see Chapters 5 and 18) produce increased p53 ubiquitination and accelerate p53 degradation. Impaired ubiquitination may also be involved in some cellular degenerative changes that occur in aging and in some storage diseases.
Atrophy is an Adaptation to Diminished Need or Resources for a Cell's Activities
Clinically, atrophy is often noted as a decrease in size or function of an organ that occurs under pathologic or physiologic circumstances. Therefore, atrophy may result from disuse of skeletal muscle or from loss of trophic signals as part of normal aging. At the level of an individual cell, atrophy may be thought of as an adaptive response, whereby a cell accommodates to changes in its environment while remaining viable. Reduction in an organ's size may reflect reversible cell atrophy or irreversible loss of cells. For example, atrophy of the brain in Alzheimer disease is secondary to extensive cell death; the size of the organ cannot be restored (Fig. 1-1). Atrophy occurs under a variety of conditions:
Hypertrophy is an Increase in Cell Size and Functional Capacity
Hypertrophy is an adaptive change that results in an increase in cellular size to satisfy increased functional demand or trophic signals. In some cases, increased cellular number (hyperplasia, see below) may also result. In organs made of terminally differentiated cells (e.g., heart, skeletal muscle), such adaptive responses are accomplished solely by increased cell size (Fig. 1-3). In other organs (e.g., kidney, thyroid), cell numbers and cell size may both increase. Hypertrophy is associated with an initial increase in the degradation of certain cellular proteins, followed by an increase in the synthesis of proteins needed to meet increased functional demand. Programmed cell death (apoptosis, see below) may be inhibited, thereby resulting in an increase in cell survival.
Hyperplasia is an Increase in the Number of Cells in an Organ or Tissue
Hypertrophy and hyperplasia often occur concurrently. The specific stimuli that induce hyperplasia and the mechanisms by which they act vary greatly from one tissue and cell type to the next. Whatever the stimulus, hyperplasia involves stimulating resting cells (G0) to enter the cell cycle (G1) and then to multiply. This may be a response to an altered endocrine milieu, increased functional demand, or chronic injury. These topics are discussed in Chapters 3 and 5.
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| Figure 1-2. Proliferative endometrium. A. A section of the uterus from a woman of reproductive age reveals a thick endometrium composed of proliferative glands in an abundant stroma. B. The endometrium of a 75-year-old woman (shown at the same magnification) is thin and contains only a few atrophic and cystic glands. |
Inappropriate hyperplasia can itself be harmfulâ
