Cellular Responses to adaptation, and toxic insults:

Normal cells when affected by physiologic stress & injurious stimuli respond by adaptation & cell injury. Both adaptation and cell injury are reversible responses. If cells can’t adapt, it results in cell injury response. When cell injury is mild and temporary, injury becomes reversible. If cell injury becomes severe and steady, cell death happens. Cell death can be necrosis or apoptosis. The followings are different forms of cell adaptation:

Hypertrophy is mainly the increase in size of the cell resulting in organ enlargement. An example is seen in skeletal and cardiac muscle. Factors that can influence muscle enlargement include: Mechanical stress & hemodynamic load; hormonal changes; vasoactive agents; growth factors.

Demonstrating hypertrophy using heart muscle:

Mechanical stress from weight lifting & hemodynamic load activates mechanical sensors. Vasoactive agents (alpha-adrenergic hormone), and growth hormone (IGF-I) trigger G-protein coupled receptors to cause signal transduction pathways in the cell. Hence, we begin to see molecular and biochemical changes in the muscle fiber. Atrial natriuretic peptide, more contractile proteins and growth factors are produced to increase mechanical efficiency and decrease work load.

Hyperplasia is the increase in the number of cells resulting in increased mass of an organ. It can be physiologic or pathologic

Physiologic: Proliferation of glandular epithelium of breast in puberty and pregnancy from hormonal changes; Regain in tissue mass after an organ damage or partial resection as in, partial hepatectomy. After a partial hepatectomy, cells proliferate by help of growth factors, & regenerate by help of tissue stem cells. 

Pathologic: Excessive hormonal production can lead to abnormal mass increase. endometrial hyperplasia (excess FSH & estrogen); and benign prostatic hyperplasia (excess androgen). Hyperplasia when unchecked can lead to cancer e.g. endometrial cancer.

Atrophy: This is the reduction in cell size and number, resulting in a small organ. It can be physiologic or pathologic:

Physiologic: Notochord and thyroglossal duct atrophy during fetal development; uterine atrophy after childbirth; menopause induced atrophy of endometrium, breast, & vaginal epithelium.

Pathologic: Skeletal muscle atrophy from prolonged bed-rest; old-age atrophy from atherosclerosis; cachexia from malnutrition or cancer.

Pathogenesis of atrophy:

Atrophy happens due to decreased protein synthesis and increased protein lysis. During nutrient deficiency, lysis occurs by ubiquitin-proteosome pathway. Most cases of degradation occur by autophagy. In autophagy(self-eating), cell debris in a vacuole are digested by lysosomal enzymes. Undigested debris remain as lipofuscin granules, which when in surplus, cause a brown tissue discoloration.

Metaplasia is a change from one differentiated cell type to another. E.g. squamous metaplasia, columnar metaplasia. This represents a coping mechanism by cells to withstand injurious stimuli.

Squamous metaplasia is seen among constant cigarette smokers and in Vitamin A deficiency. This occurs for the cell to withstand harsh conditions from injurious stimuli. There is a risk of lung cancer as it  progresses. Columnar metaplasia occurs in reflux esophagitis leading to Barett-esophagus. This might as well result in adenocarcinoma of the esophagus.

Pathogenesis of metaplasia:

Metaplasia happens due to reprogramming of epithelial stem cells, or undifferentiated mesenchymal stem cells. External stimuli such as: growth factors & cytokines promote gene expressions that cause precursor cells to differentiate in a particular way.

Understanding cell injury

Cell injury is a reversible response of cells to injurious stimuli. It can lead to cell death when stimuli are severe of progressive. Hallmark of cell injury includes: Cell swelling; Reduced oxidative phosphorylation and ATP.

Light Microscopic changes in cell injury: Swelling of cell organelles; increased eosinophilic pink staining in cytoplasm; plasma membrane blebbing.

Electron microscopic changes in cell injury: Plasma membrane blebbing and lose of microvilli; mitochondria precipitate with calcium and protein deposits; ER swelling; nuclear alteration.

Causes of Cell injury:

Hypoxia; Chemical agents (barbiturates, insecticides, asbestos); Physical agents (trauma, radiation, temp. extremes, electric shock); immunologic reactions; malnutrition; gene def:ects and polymorphism.

Necrosis:

Necrosis is an irreversible cell death that results from protein lysis and enzymatic breakdown of injured cells. Lysosomes destructive enzymes mobilized to necrotic cells. 

Morphologic changes in a necrotic tissue: 

1. Increased eosinophilia
2. Homogenous glassy appearance
3. Vacuolated cytoplasm containing cell debris
4. Intracytoplasmic Myelin figures from damaged plasma membrane
5. Loss of plasma membrane integrity
6. Nuclear changes: Karyolysis (loss of chromatin & fading basophilia); Pyknosis (solid chromatin & increased basophilia); Karyorrhexis (nucleus fragmentation & loss)

Patterns of Necrosis:

1. Coagulative necrosis: An area of the dead cell is still intact for limited time. Absence of wet areas. Occurs when blood supply to a tissue is obstructed. Seen in all organs except the brain.
2. Liquefactive necrosis: Presence of wet areas of necrotic tissue and pus due to action of digestive enzymes, infection, and leukocytes. This occurs in CNS
3. Gangrenous necrosis: Specific to the limbs when blood flow is obstructed. Combines a mix of coagulative and liquefactive necrosis.
4. Fat necrosis: Produces a chalky-white appearance due to calcium deposit on necrotic tissue. Occurs in acute pancreatitis as lipase is mobilized to pancreas and peritoneal cavity.
5. Caseous necrosis: A cheese-like necrotic tissue common in tuberculous infection.
6. Fibrinoid necrosis: A bright pink amorphous appearance in H&E stain. This follows the deposit of immune complexes in arteries.