Cellular adaption | Hypertrophy | Hyperplasia | Atrophy | Metaplasia | Cellular aging | Sirtuin | viva notes | Left ventricular hypertrophy |

  

CELLULAR ADAPTATION 

Cellular adaptation: 

Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. 

The adaptive changes are: 

1) Hypertrophy: An increase in size and metabolic activity of cells. 

2) Hyperplasia: Increase in number of cells. 

3) Atrophy:  A decrease in size and metabolic activity of cells. 

4) Metaplasia: Differentiation to another type of cell. 

Figure: - Cellular adaption

Hypertrophy  

Hypertrophy: Hypertrophy is an increase in the size of cells that results in an increase in the size of the affected organ. 

Cause/mechanisms: The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components. Hypertrophy is a result of increased cellular protein production. Stimulations for hypertrophy- 

• ▶ Increased metabolic / functional demand.
• ▶ Specific hormonal stimulation. 

Types & sites of hypertrophy: 

1) Physiological: Examples are: 

• ▶ Hypertrophy of pregnant uterus. 
• ▶ Hypertrophy of skeletal muscle due to exercise, e.g. body builders. 

2) Pathological: e.g. Hypertrophy of cardiac muscle due to increased workload. 

❖ Mechanism of left ventricular hypertrophy (LVH): 

Chronic haemodynamic overload mostly resulting from hypertension, defective valves etc.

↓

Induction of number of genes that are involed in encoding transcription factors, growth factors (e.g. TGF-B, IGF-1) and vasoactive agents (e.g. angiotensin-II)

↓

There is increased synthesis of protein, DNA and other intracellular substances 

↓

Synthesis of more cellular proteins and filaments to achieve a balance between the demand and the functional capacity of the cells 

↓

Hypertrophy of cardiac myocytes 

Hyperplasia: 

Hyperplasia is an increase in the number of cells in an organ or tissue, in response to a stimulus. 

Common sites of hyperplasia: 

1. Endometrium.
2. Breast.
3. Prostate. 

Types/causes: 

Physiological: 

1) Hormonal hyperplasia: 

• ▶ Glandular tissue of female breast: During puberty, pregnancy & lactation. Uterine endometrium: During pregnancy. 

2) Compensatory hyperplasia: 

Hyperplasia that occurs after partial hepatectomy.

3) Bone marrow hyperplasia following an acute blood loss or haemolysis: May increase red cell production as much as 8-fold. 

Pathological: 

1. Benign prostatic hyperplasia.
2. Hyperplasia of endometrium in granulosa tumour of ovary.
3. Skin warts due to papilloma virus. Noduler goiter  

Mechanism of hyperplasia:  

Hyperplasia is the result of growth factor-driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells. 

Increased local production of growth factors or hormonal stimulation

↓

Production of transcription factors

↓

Transcription of various cellular genes 

↓

Increase in the number of cells

↓

Increase in tissue mass 

Hyperplasia of uterus in pregnancy: Hyperplasia of uterus in pregnancy occurs due to hormonal influence. 

Pregnancy

 ↓

Estrogen and progesterone is secreted in early pregnancy by corpus luteum & later by the placenta 

 ↓ 

Stimulation of uterine smooth muscle by the estrogen by binding with its receptor

 ↓ 

Increased DNA synthesis and increased cell proliferation

 ↓ 

Hyperplasia of uterus  

❖The classic illustration of compensatory hyperplasia comes from the study of liver regeneration. In individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size. 

Atrophy: 

Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number. 

Types/causes: 

❖ Physiological: 

• ▶ Atrophy during early fetal development: e.g. Atrophy of notochord or thyroglossal duct.
• ▶ The uterus decreases in size shortly after delivery. 

❖ Pathologic: 

• ▶ Localized: e.g. denervation atrophy, disuse atrophy, pressure atrophy.
• ▶ Generalized: e.g. due to starvation, senile atrophy etc. 

Common causes of atrophy: 

1. Decreased workload (atrophy of disuse): e.g. skeletal muscle atrophy in a patient restricted to complete bed rest or when a broken limb is immobilized in a plaster cast.
2. Loss of innervations (denervation atrophy): e.g. Atrophy to the muscle fibers due to damage of the supplying nerves.
3. Diminished blood supply: e.g. Brain undergoes progressive atrophy due to atherosclerosis in cerebral vessels.
4. Inadequate nutrition: e.g. marked muscle wasting in profound protein-calorie malnutrition, chronic inflammation, cancer etc.
5. Loss of endocrine stimulation: e.g. loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium, vaginal epithelium & breast.
6. Aging (senile atrophy): Seen in the brain & heart.
7. Pressure atrophy: Atrophy occurs due to tissue compression for a long time, e.g. an enlarging benign tumor can cause atrophy in the surrounding compressed tissues. 

Mechanism of atrophy: 

Atrophy results from decreased protein synthesis & increased protein degradation in cells. Protein synthesis decreases because of reduced metabolic activity. 

❖Decreased protein synthesis: Due to reduced metabolic activity. 

❖ Increased protein degradation: 

• ▶ By the ubiquitin-proteasome pathway: 

Nutrient deficiency and & disuse 

↓

Activation of ubiquitin ligases 

↓

Attachment of 'small peptide ubiquitin' to cellular proteins 

↓

Degradation of proteins into proteasomes 

Example: Responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia. 

✔ Increased number of autophagic vacuoles: 

• ▶ In many situations, atrophy is also accompanied by increased autophagy, marked by the appearance of increased numbers of autophagic vacuoles.
• ▶ Autophagy (self-cating) is the process in which the starved cell eats its own components in an attempt to reduce nutrient demand to match the supply. 
• ▶ Some of the cell debris within the autophagic vacuoles may resist digestion and persist in the cytoplasm as membrane-bound residual bodies; e.g. lipofuscin granules. 

Brown atrophy: 

Atrophy is accompanied by marked increase in number of autophagic vacuoles. The cellular components in it are digested. Some of the cellular debris may resist digestion and persists as residual body. An example of this is lipofuscin granules, when present in sufficient amount, impart a brown discolouration of tissue that is termed as brown atrophy. 

Differences between hypertrophy and atrophy:

Differences between hypertrophy and atrophy

 

Metaplasia: 

Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. 

Types & example: 2 types (epithelial & connective tissue metaplasia), 

❖ Epithelial metaplasia: 

1. Squamous metaplasia: Most common epithelial metaplasia is columnar to squamous. 

• ▶ Squamous metaplasia of the normal ciliated columnar epithelium of the respiratory tract due to long time smoking.
• ▶ Squamous metaplasia of the columnar epithelium of the ducts of the salivary glands, pancreas and bile duct due to stone.
• ▶ Deficiency of vitamin A → cause squamous metaplasia of the respiratory tract. 

2. Columnar metaplasia: From squamous cell to columnar cell. 

• ▶ In reflux esophagitis, squamous esophageal epithelium is replaced by columnar epithelium. This is called Barrett's esophagus. 

❖ Connective tissue metaplasia: 

1. Formation of cartilage, bone, or adipose cells (mesenchymal tissues) in tissues that normally do not contain these elements.
2. Bone formation in muscle. It is called myositis ossificans. 

Clinical importance/consequences of metaplasia: 

1. There may be neoplastic transformation from metaplasia.
2. Alteration of normal physiological function, such as normal secretory function of the bronchus is lost due to squamous metaplasia. 

Remember: 

In metaplasia, the parenchymal cells are replaced, not transformed into the new type of cell. New type of cells are not produced from normal parenchymal cells, they are produced from multipotent stem cells of the organ (e.g. multipotent stem cells are present under the basement membrane). 

❖ Mechanism of metaplasia: 

Metaplasia does not result from a change in the phenotype of an already differentiated cell type; rather, it results from- 

• ▶ Either reprogramming of local tissue stem cells or, 
• ▶ Alternatively, colonization by differentiated cell populations from adjacent sites. 

Metaplastic change is stimulated by signals generated by- 

✅Cytokines, 

✅Growth factors, & 

✅ Extracellular matrix components in the cell's environment. 

In the case of stem cell reprogramming, these external stimuli promote the expression of genes that drive cells toward a specific differentiation pathway. A direct link between transcription factor dysregulation and metaplasia is seen with vitamin A (retinoic acid) deficiency or excess, both of which may cause metaplasia. Retinoic acid regulates gene transcription directly through nuclear retinoid receptors, which can influence the differentiation of progenitors derived from tissue stem cells. 

Metaplasia is a two-edged sword, because it causes 2 harmful effects at the same time. They are: 

1. Alteration of the normal physiological function: e.g. due to squamous metaplasia in the respiratory tract, an important protective mechanism mucus secretion is lost.
2. Malignant transformation: e.g. squamous cell carcinoma can occur in respiratory tract from metaplastic squamous cells. 

❖ Advantage of metaplasia: 

✅Survival of the cells in adverse environment: 

[We can explain by few examples. The most common epithelial metaplasia is columnar to squamous, as occurs in respiratory tract in response to chronic irritation, and excretory ducts of the salivary glands, pancreas and bile duct due to stone. In all these instances, the more rugged stratified squamous epithelium is able to survive under circumstances in which the more fragile specialized columnar epithelium most likely would have succumbed] 

Disadvantage of metaplasia: (Metaplasia is a two edged sword) 

✅Alteration of the normal physiological function. 

✅Malignant transformation. 

Pathogenesis of metaplasia in bronchus: 

Smoking, chronic bronchitis & vitamin-A deficiency cause chronic irritation of bronchial epithelium & activate the key regulatory proteins for replacement of the normal columnar epithelium of the respiratory tract by squamous epithelium. As a result squamous metaplasia occurs. 

Risk of metaplasia in bronchus: 

1. Due to squamous metaplasia in the respiratory tract, an important protective mechanism mucus secretion is lost.
2. Metaplasia may induce cancer transformation in metaplastic epithelium. Thus, the common form of cancer in the respiratory tract is composed of squamous cells. 

Type of metaplasia in Barrett's esophagus: 

There is columnar metaplasia in Barrett's esophagus. In reflux oesophagitis, squamous oesophageal epithelium is replaced by columnar epithelium. This is called Barrett's oesophagus. 

Pathogenesis of metaplasia in cervix: 

Chronic cervicitis

↓ 

Causes addition of DNA of sperm with the nuclear DNA of the cells of transformation zone (Squamo-columnar junction of cervix) 

↓ 

Atypical epithelial changes 

↓ 

Dysplasia

↓ 

Squamous metaplasia at the transformation zone 

Risk of metaplasia in cervix: Metaplasia may induce cervical carcinoma.

Differences between hyperplasia and metaplasia: 

Differences between hyperplasia and metaplasia:

Differences between metaplasia and dysplasia: 

Differences between metaplasia and dysplasia

Cellular aging: 

Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences. 

Causes & pathogenesis of cellular aging: 

1) DNA damage / defective DNA repair mechanism: Due to 

• ▶ Exogenous agents (physical, chemical & biological factors) or 
• ▶ Endogenous factors (reactive oxygen species, ROS). 

2) Cellular senescence: All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally non-dividing state, known as replicative senescence. 

Mechanism of cellular senescence: 

• ▶Telomere attrition.
• ▶ Activation of tumour suppression genes. 

3) Defective protein homeostasis: Normal folding & degradation of misfolded proteins are impaired. 

4) Deregulated nutrient sensing: 

• By increasing insulin & insulin-like growth factor-1 (IGF-1) activity &
• By decreasing sirtuins. 

Figure: Mechanisms of cellular aging. 

❖ Sirtuin:

Sirtuins are thought to promote the expression of several genes whose products increase longevity. These include - 

• ▶ Proteins that inhibit metabolic activity.
• ▶ Reduce apoptosis.
• ▶ Stimulate protein folding, and 
• ▶ Inhibit the harmful effects of oxygen free radicals.
• ▶ Sirtuins also increase insulin sensitivity and glucose metabolism, and may be targets for the treatment of DM. 

Thank you stay connected..............