ADAPTIVE RESPONSES IN DISEASE

Cells respond to damaging stimuli by extending adaptive processes. As well as mounting an immediate cell stress response, cells can adapt to damaging stimuli, becoming modified to achieve a new, steady state of metabolism and structure that better equips them for survival in the abnormal environment. Cells may adapt to a pathological (disease) stimulus by extending the three normal physiological adaptive responses: increased cellular activity, decreased cellular activity, alteration of cell morphology.

Inability to adapt successfully to an environmental change leads to failure of cellular function and may result in sublethal cellular damage or cell death. Change in cellular growth pattern is an adaptive response in disease. Cells can adapt to certain pathological stimuli by altering their pattern of growth. This may be reflected in changes in the size, number or differentiation of cells in affected tissue.

Certain organs or tissues may adapt to a disease process by increasing functional cell mass. There are two mechanisms of increase. Increased functional demand on a tissue can be met by increase in cell number (hyperplasia), as well as by increase in cell size (hypertrophy).

Hyperplasia is an increase in the number of cells in a tissue caused by increased cell division. As this type of change can occur only in tissues that have the capacity for cell division, hyperplasia is not an adaptive response seen in skeletal muscle, cardiac muscle or nerve cells, which are non-dividing cell populations. Hormonal influences are important in this growth response.

Hypertrophy is an increase in the size of existing cells, accompanied by increase in their functional capacity. Cell enlargement is brought about by increased synthesis of structural components, associated with accelerated activity of cellular metabolism and rises in levels of RNA and organelles required for protein synthesis. Hypertrophy is

particularly seen as a response to increased demand in tissues composed of cells which are unable to divide (skeletal and cardiac muscle). Hypertrophy and hyperplasia may occur independently of each other or together to meet a demand for increased function, and are usually associated with an increase in the size and weight of the organ or tissue concerned. Increased functional demand or endocrine stimulation is the stimulus that usually causes hypertrophy and hyperplasia. These new patterns of growth are stable while the causative stimulus persists, but once it is removed the tissue returns to a normal pattern of growth.

An increase in functional cell mass through hypertrophy or hyperplasia may be physiological.

Hypertrophy in the absence of hyperplasia is typically seen in muscle where the stimulus is an increased demand for work. Increased cell mass in a tissue can result from physiological stimuli and as a response in disease states. If the serum calcium is abnormally low, the parathyroid glands increase the number of parathormone-secreting cells (hyperplasia). If the aortic valve outflow is severely narrowed by disease, the muscle of the left ventricle of the heart responds with an increase in the size of cardiac muscle cells (hypertrophy) to overcome the resistance to flow and to ensure an adequate blood pressure. This is also seen in myocardial muscle when systemic hypertension causes an increased on cardiac function. The increased

mass of the left ventricle is due to enlargement of cardiac muscle cells as a result of hypertrophy. This can be seen by comparing the diameter of fibres from the normal heart with those from the diseased heart. Note that the size of nuclei in the hypertrophied cardiac muscle is also increased; it has been found that such nuclei are frequently polyploid.

According to the stage of adaptation two types of myocardial hypertrophy have been described; concentric and eccentric. In concentric hypertrophy (clinically, no insufficient) the musculature is clearly enlarged, measuring till 1.8 cm, but chambers of the heart are not dilated. In eccentric hypertrophy myocardium is enlarged but chambers of the heart are dilated. This leads to a hemodynamic deterioration with cardiac insufficiency develops.

If a kidney is removed or ceases to function, the remaining healthy kidney increases in size and weight to compensate for the loss. The process of hyperplasia leads to enlargement of structures such as glomeruli, and is often termed compensatory hyperplasia.

Hyperplasia may not be uniform and sometimes occurs as nodules.

Hyperplasia may not occur uniformly throughout a tissue; instead, nodules of excessive cell growth hyperplastic nodules develop between areas of normal tissue, giving rise to the term B nodular hyperplasia. Most examples of nodular hyperplasia occur in tissues in which cells are responding to a trophic hormone. It

is likely that the hyperplasia seen in these conditions is a result of a disturbance in the hormone responsiveness of the target tissue. Nodular hyperplasia is seen most commonly in the prostate gland thyroid gland, adrenal gland and the breast.

Following removal of the stimulus causing hyperplasia or hypertrophy, tissue reverts to normal.

Cell atrophy. Reduced functional demand leads to reduction in cell number or cell size. When the mass of functioning cells in a tissue becomes reduced, the tissue is said to have undergone atrophy. There are two mechanisms of reduction.

Reduced functional demand, reduction in trophic stimuli, or reduction in nutrients are the usual stimuli which cause involution or cell atrophy. Atrophic or involuted tissues are stable patterns of growth that persist while the lack of stimulation or demand causing them remains. However, once appropriate stimulation or demand returns, the tissue reverts to a normal pattern of growth.

In cellular atrophy, structural proteins and organelles of a cell are destroyed, with a parallel reduction in the size and functional capacity of the cell. This is an adaptive response as it allows the cell to survive in adverse conditions by reducing its metabolic overheads.

Cell constituents are eliminated by a process of autophagy: unwanted cell organelles become enwrapped by membrane derived from the endoplasmic

reticulum (ER), forming an autophagic body which subsequently fuses with vesicles containing lysosomal acid hydrolases. The action of the hydrolases brings about degradation of the organelles. Cells which are actively undergoing atrophy can be seen ultrastructurally to contain numerous autophagic vacuoles. These bodies become electron dense, but have internal tubular or vesicular profiles (derived from membrane-fusion events) that have earned them the alternative name of tubulovesicular bodies. Late autophagic bodies become more electron dense and may form residual bodies containing lamellar undigested lipid-rich cell material called lipofuscin.

Reduction in cell mass occurs in some pathological states. Many disease processes lead to a reduction in functional demand, hormonal or nervous stimulation, or nutrition of tissues; atrophy or involution occurs as an adaptive response.

Atrophy may be physiological and pathological. The former is observed during the human life, e.g. atrophy of thymus and sex glands in elderly people. The latter may be general and local. General atrophy is observed in cachexia. There are several types of local atrophy: 1. Disuse atrophy. 2. Ischaemic atrophy. 3. Denervation atrophy. 4. Atrophy due to pressure. 5. Atrophy due to chemical and physical influences.

E.g. skeletal muscle fibres in the leg undergo cellular atrophy if the leg is immobilized, when splinting is used in the treatment of a fracture (disuse

atrophy). Gradual reduction in blood supply to a tissue results in loss of functional cells through involution, as well as through cellular atrophy (ischemic atrophy). Damage to axons supplying muscle causes atrophy of affected muscle fibres (denervation atrophy)

Metaplasia. Tissues may adapt to environmental stimuli by a change in cell differentiation termed metaplasia.

Certain long-standing environmental stimuli render the environment unsuitable for some specialized cell types and, as an adaptive response, the proliferating cells change their pattern of differentiation. These cells can adapt to a change in environment by differentiating to a new, mature, stable type of cell, which better equips them to withstand environmental stress. This process is termed metaplasia.

Metaplasia occurs in many tissue types. In the bronchi, under the influence of chronic irritation by cigarette smoke, the normal ciliated columnar mucus-secreting respiratory epithelium is replaced by squamous epithelium (squamous metaplasia). In the cervix, the normal columnar epithelium of the lower endocervix changes to squamous epithelium in response to exposure to the acid vaginal environment (squamous metaplasia). In the urinary bladder, the normal transitional epithelium may be replaced by squamous epithelium in response to chronic irritation by bladder stones or infection (squamous metaplasia). The esophageal squamous epithelium is replaced by

columnar epithelium in response to exposure to gastric acid in cases of gastric reflux.

Metaplasia most commonly occurs in epithelial tissues, but may also be seen elsewhere. For example, areas of fibrous tissue exposed to chronic trauma may form bone (osseous metaplasia). In many settings, metaplasia co-exists with hyperplasia; e.g., the squamous epithelium that arises by metaplasia in response to stone in the bladder may also be hyperplastic.

Adaptive responses in disease occur only with tolerable environmental changes. The adaptive responses of hyperplasia, hypertrophy, atrophy, involution and metaplasia occur only if the damaging stimulus is tolerable to the affected cells. Failure to adapt leads to cell damage and, if the stimulus is severe or prolonged, may result in cell death. Adaptive responses allow cells to survive in the face of a change in the cellular environment. Failure to adapt is associated with cell damage or cell death.

Stages of individual work in classStudy and describe macrospecimens

Concentric and excentric hypertrophy of the heart. Pay attention to the thickness of the wall and volume of the heart cavity in the both specimens. To what conditions of the heart activity does each of them correspond?

Spleen atrophy. Define the size of the organ and condition of the capsule. What is the evidence of its wrinkling? What is the type of atrophy in this case?

Hydronephrosis. Pay attention to the appearance of the kidney, condition of the pelvis and calyces, thickness of renal parenchyma. Variety of pathology according to prevalence and cause. What kind of macrospecimen correspond to similar processes?

Acromegalia. Pay attention to the size of the skeleton. Which process is in the base of these changes and the cause of them?

Elephantiasis of the lower extremity. The size and the condition of the soft tissues and skin. What is the type of pathology? What is it due to?