Applied Physiology on Cell, Cell Junctions, Transport through cell Membrane , Acid-base Balance.
[1]. Cell Applied Physiology .
Genetic disorder .
A genetic disorder is a disorder that occurs because of the abnormalities in an individual’s genetic material (genome). Genetic disorders are either hereditary disorders or due to defect in genes.
Causes of Gene Disorders .
Genetic disorders occur due to two causes:
1. Genetic variation: Presence of a different form of gene
2. Genetic mutation: Generally, mutation means an alteration or a change in nature form or quality. Genetic mutation refers to change of the DNA sequence within a gene or chromosome of an organism, which results in the creation of a new character.
Classification of Genetic Disorders .
Genetic disorders are classified into four types:
1. Single gene disorders
2. Multifactorial genetic disorders
3. Chromosomal disorders
4. Mitochondrial DNA disorders.
1. Single Gene Disorders .
Single gene disorders or Mendelian or monogenic disorders occur because of variation or mutation in one single gene. Examples include sickle cell anemia and Huntington’s disease.
2. Multifactorial Genetic Disorders .
Multifactorial genetic disorders or polygenic disorders are caused by combination of environmental factors and mutations in multiple genes. Examples are coronary heart disease, Alzheimer’s disease, arthritis and diabetes.
3. Chromosomal Disorders .
[1]. Chromosomal disorder is a genetic disorder caused by abnormalities in chromosome. It is also called chromosomal abnormality, anomaly or aberration. It often results in genetic disorders which involve physical or mental abnormalities.
[2]. Chromosomal disorder is caused by numerical abnormality or structural abnormality.
[3]. Chromosomal disorder is classified into two types:
i. Structural abnormality (alteration) of chromosomes which leads to disorders like chromosome instability syndromes (group of inherited diseases which cause malignancies)
ii. Numerical abnormality of chromosomes which is of two types:
a. Monosomy due to absence of one chromosome from normal diploid number. Example is Turner’s syndrome, which is characterized by physical disabilities
b. Trisomy due to the presence of one extra chromosome along with normal pair of chromosomes in the cells. Example is Down syndrome, which is characterized by physical disabilities and mental retardation.
4. Mitochondrial DNA Disorders .
[1]. Mitochondrial DNA disorders are the genetic disorders caused by the mutations in the DNA of mitochondria (non chromosomal DNA).
[2]. Examples are Kearns-Sayre syndrome (neuromuscular disorder characterized by myopathy, cardiomyopathy and paralysis of ocular muscles) and Leber’s hereditary optic neuropathy (disease characterized by degeneration of retina and loss of vision).
Cell death .
Cell death occurs by two distinct processes:
1. Apoptosis
2. Necrosis.
Apoptosis .
[1]. Apoptosis is defined as the natural or programed death of the cell under genetic control. Originally, apoptosis refers to the process by which the leaves fall from trees in autumn (In Greek, apoptosis means ‘falling leaves’). It is also called ‘cell suicide’ since the genes of the cell play a major role in the death
[2]. This type of programmed cell death is a normal phenomenon and it is essential for normal development of the body. In contrast to necrosis, apoptosis usually does not produce inflammatory reactions in the neighboring tissues.
Functional Significance of Apoptosis .
The purpose of apoptosis is to remove unwanted cells without causing any stress or damage to the neighboring cells. The functional significance of apoptosis:
1. Plays a vital role in cellular homeostasis. About 10 million cells are produced everyday in human body by mitosis. An equal number of cells die by apoptosis. This helps in cellular homeostasis .
2. Useful for removal of a cell that is damaged beyond repair by a virus or a toxin .
3. An essential event during the development and in adult stage.
Examples:
1. A large number of neurons are produced during the development of central nervous system. But up to 50% of the neurons are removed by apoptosis during the formation of synapses between neurons .
2. Apoptosis is responsible for the removal of tissues of webs between fingers and toes during developmental stage in fetus .
3. It is necessary for regression and disappearance of duct systems during sex differentiation in fetus .
4. The cell that looses the contact with neighboring cells or basal lamina in the epithelial tissue dies by apoptosis. This is essential for the death of old enterocytes that shed into the lumen of intestinal glands. 5. It plays an important role in the cyclic sloughing of the inner layer of endometrium, resulting in menstruation .
6. Apoptosis removes the auto aggressive T cells and prevents autoimmune diseases.
Activation of Apoptosis .
Apoptosis is activated by either withdrawal of positive signals (survival factors) or arrival of negative signals.
Withdrawal of positive signals .
[1]. Positive signals are the signals which are necessary for the long-time survival of most of the cells. The positive signals are continuously produced by other cells or some chemical stimulants.
[2]. Best examples of chemical stimulants are:
i. Nerve growth factors (for neurons)
ii. Interleukin-2 (for cells like lymphocytes).
The absence or withdrawal of the positive signals activates apoptosis.
Arrival of negative signals .
[1]. Negative signals are the external or internal stimuli which initiate apoptosis.
[2]. The negative signals are produced during various events like:
1. Normal developmental procedures .
2. Cellular stress .
3. Increase in the concentration of intracellular oxidants .
4. Viral infection .
5. Damage of DNA .
6. Exposure to agents like chemotherapeutic drugs, X-rays, ultraviolet rays and the death-receptor ligands.
Death-receptor ligands and death receptors .
[1]. Death-receptor ligands are the substances which bind with specific cell membrane receptors and initiate the process of apoptosis. The common death-receptor ligands are tumor necrosis factors (TNF α, TNF β) and Fas ligand (which binds to the receptor called Fas) .
[2]. Deathreceptors are the cell membrane receptors which receive the death-receptor ligands. Well-characterized death receptors are TNF receptor-1 (TNFR1) and TNF-related apoptosis inducing ligand (TRAIL) receptors called DR4 and DR5.
Role of mitochondria in apoptosis .
[1]. External or internal stimuli initiate apoptosis by activating the proteases called caspases (cysteinyl-dependent aspartate specific proteases). Normally, caspases are suppressed by the inhibitor protein called apoptosis inhibiting factor (AIF).
[2]. When the cells receive the apoptotic stimulus, mitochondria releases two protein materials. First one is Cytochrome C and the second protein is called second mitochondria-derived activator of caspases (SMAC) or its homologudiablo.
[3]. SMAC/diablo inactivates AIF so that the inhibitor is inhibited. During this process, SMAC/diablo and AIF aggregate to form apoptosome which activates caspases. Cytochrome C also facilitates caspase activation.
Apoptotic Process .
Cell shows sequence of characteristic morphological changes during apoptosis, viz.:
1. Activated caspases digest the proteins of cytoskeleton and the cell shrinks and becomes round.
2. Because of shrinkage, the cell losses the contact with neighboring cells or surrounding matrix .
3. Chromatin in the nucleus undergoes degradation and condensation .
4. Nuclear membrane becomes discontinuous and the DNA inside nucleus is cleaved into small fragments
5. Following the degradation of DNA, the nucleus breaks into many discrete nucleosomal units, which are also called chromatin bodies .
6. Cell membrane breaks and shows bubbled appearance .
7. Finally, the cell breaks into several fragments containing intracellular materials including chromatin bodies and organelles of the cell. Such cellular fragments are called vesicles or apoptotic bodies .
8. Apoptotic bodies are engulfed by phagocytes and dendritic cells.
Abnormal Apoptosis .
[1]. Apoptosis within normal limits is beneficial for the body. However, too much or too little apoptosis leads to abnormal conditions.
[2]. Common abnormalities due to too much apoptosis:
1. Ischemic related injuries .
2. Autoimmune diseases like:
i. Hemolytic anemia .
ii. Thrombocytopenia .
iii. Acquired immunodeficiency syndrome (AIDS) .
3. Neurodegenerative diseases like Alzheimer’s disease.
[3]. Common abnormalities due to too little apoptosis:
1. Cancer .
2. Autoimmune lymphoproliferative syndrome (ALPS).
Necrosis .
[1]. Necrosis (means ‘dead’ in Greek) is the uncontrolled and unprogrammed death of cells due to unexpected and accidental damage. It is also called ‘cell murder’ because the cell is killed by extracellular or external events.
[2]. After necrosis, the harmful chemical substances released from the dead cells cause damage and inflammation of neighboring tissues.
Causes for Necrosis .
Common causes of necrosis are injury, infection, inflammation, infarction and cancer. Necrosis is induced by both physical and chemical events such as heat, radiation, trauma, hypoxia due to lack of blood flow and exposure to toxins.
Necrotic Process .
Necrosis results in lethal disruption of cell structure and activity. The cell undergoes a series of characteristic changes during necrotic process, viz.
[1] . Cell swells causing damage of the cell membrane and appearance of many holes in the membrane.
[2] . Intracellular contents leak out into the surrounding environment.
[3] . Intracellular environment is altered .
[4] . Simultaneously, large amount of calcium ions are released by the damaged mitochondria and other organelles.
[5] . Presence of calcium ions drastically affects the organization and activities of proteins in the intracellular components.
[6] . Calcium ions also induce release of toxic materials that activate the lysosomal enzymes.
[7] . Lysosomal enzymes cause degradation of cellular components and the cell is totally disassembled resulting in death .
[8] . Products broken down from the disassembled cell are ingested by neighboring cells.
Reaction of Neighboring Tissues after Necrosis .
Tissues surrounding the necrotic cells react to the breakdown products of the dead cells, particularly the derivatives of membrane phospholipids like the arachidonic acid. Along with other materials, arachidonic acid causes the following inflammatory reactions in the surrounding tissues:
[1] . Dilatation of capillaries in the region and thereby increasing local blood flow.
[2] . Increase in the temperature leading to reddening of the tissues .
[3] . Release of histamine from these tissues which induces pain in the affected area .
[4] . Migration of leukocytes and macrophages from blood to the affected area because of increased capillary permeability .
[5] . Movement of water from blood into the tissues causing local edema .
[6] . Engulfing and digestion of cellular debris and foreign materials like bacteria by the leukocytes and macrophages .
[7] . Activation of immune system resulting in the removal of foreign materials .
[8] . Formation of pus by the dead leukocytes during this process .
[9] . Finally, tissue growth in the area and wound healing.
Cell adaptation .
[1]. Cell adaptation refers to the changes taking place in a cell in response to environmental changes. Normal functioning of the cell is always threatened by various factors such as stress, chemical agents, diseases and environmental hazards.
[2]. Yet, the cell survives and continues the function by means of adaptation. Only during extreme conditions, the cell fails to withstand the hazardous factors which results in destruction and death of the cell.
[3]. Cellular adaptation occurs by any of the following mechanisms.
1. Atrophy .
2. Hypertrophy .
3. Hyperplasia .
4. Dysplasia .
5. Metaplasia.
Atrophy.
Atrophy means decrease in size of a cell. Atrophy of more number of cells results in decreased size or wasting of the concerned tissue, organ or part of the body.
Causes of Atrophy .
Atrophy is due to one or more number of causes such as:
1. Poor nourishment .
2. Decreased blood supply .
3. Lack of workload or exercise .
4. Loss of control by nerves or hormones .
5. Intrinsic disease of the tissue or organ.
Types of Atrophy .
Atrophy is of two types, physiological atrophy and pathological atrophy. Examples of physiological atrophy are the atrophy of thymus in childhood and tonsils in adolescence. The pathological atrophy is common in skeletal muscle, cardiac muscle, sex organs and brain.
Hypertrophy .
Hypertrophy is the increase in the size of a cell. Hypertrophy of many cells results in enlargement or overgrowth of an organ or a part of the body. Hypertrophy is of three types.
[1] . Physiological Hypertrophy .
[1]. Physiological hypertrophy is the increase in size due to increased workload or exercise.
[2]. The common physiological hypertrophy includes:
i. Muscular hypertrophy: Increase in bulk of skeletal muscles that occurs in response to strength training exercise
ii. Ventricular hypertrophy: Increase in size of ventricular muscles of the heart which is advantageous only if it occurs in response to exercise.
2. Pathological Hypertrophy .
[1]. Increase in cell size in response to pathological changes is called pathological hypertrophy.
[2]. Example is the ventricular hypertrophy that occurs due to pathological conditions such as high blood pressure, where the workload of ventricles increases.
3. Compensatory Hypertrophy .
[1]. Compensatory hypertrophy is the increase in size of the cells of an organ that occurs in order to compensate the loss or dysfunction of another organ of same type.
[2]. Examples are the hypertrophy of one kidney when the other kidney stops functioning; and the increase in muscular strength of an arm when the other arm is dysfunctional or lost.
Hyperplasia .
[1]. Hyperplasia is the increase in number of cells due to increased cell division (mitosis). It is also defined as abnormal or unusual proliferation (multiplication) of cells due to constant cell division.
[2]. Hyperplasia results in gross enlargement of the organ. Hyperplasia involves constant cell division of the normal cells only. Hyperplasia is of three types.
1. Physiological Hyperplasia .
Physiological hyperplasia is the momentary adaptive response to routine physiological changes in the body. For example, during the proliferative phase of each menstrual cycle, the endometrial cells in uterus increase in number.
2. Compensatory Hyperplasia .
[1]. Compensatory hyperplasia is the increase in number of cells in order to replace the damaged cells of an organ or the cells removed from the organ.
[2]. Compensatory hyperplasia helps the tissues and organs in regeneration. It is common in liver. After the surgical removal of the damaged part of liver, there is increase in the number of liver cells resulting in regeneration.
[3]. Compensatory hyperplasia is also common in epithelial cells of intestine and epidermis.
3. Pathological Hyperplasia .
[1]. Pathological hyperplasia is the increase in number of cells due to abnormal increase in hormone secretion. It is also called hormonal hyperplasia.
[2]. For example, in gigantism, hypersecretion of growth hormone induces hyperplasia that results in overgrowth of the body.
Dysplasia .
[1]. Dysplasia is the condition characterized by the abnormal change in size, shape and organization of the cell.
[2]. Dysplasia is not considered as true adaptation and it is suggested as related to hyperplasia. It is common in epithelial cells of cervix and respiratory tract.
Metaplasia .
Metaplasia is the condition that involves replacement of one type of cell with another type of cell. It is of two types.
1. Physiological Metaplasia .
Replacement of cells in normal conditions is called physiological metaplasia. Examples are transformation of cartilage into bone and transformation of monocytes into macrophages.
2. Pathological Metaplasia .
[1]. Pathological metaplasia is the irreversible replacement of cells due to constant exposure to harmful stimuli.
[2]. For example, chronic smoking results in transformation of normal mucus secreting ciliated columnar epithelial cells into non-ciliated squamous epithelial cells, which are incapable of secreting mucus.
[3]. These transformed cells may become cancerous cells if the stimulus (smoking) is prolonged.
Cell degeneration .
[1]. Cell degeneration is a process characterized by damage of the cells at cytoplasmic level, without affecting the nucleus.
[2]. Degeneration may result in functional impairment or deterioration of a tissue or an organ.
[3]. It is common in metabolically active organ like liver, heart and kidney.
[4]. Degenerative changes are reversible in most of the cells.
Causes for Cell Degeneration .
Common causes for cell degeneration:
1. Atrophy, hypertrophy, hyperplasia and/or dysplasia of cell .
2. Fluid accumulation in the cell .
3. Fat infiltration into the cell .
4. Calcification of cellular organelles.
Cell aging .
[1]. Cell aging is the gradual structural and functional changes in the cells that occur over the passage of time. It is now suggested that cell aging is due to damage of cellular substances like DNA, RNA, proteins and lipids, etc.
[2]. when the cell becomes old. When more cellular substances are damaged, the cellular function decreases. This causes deterioration of tissues, organs or parts of the body.
[3]. Finally, the health of the body starts declining and this leads to death. So, the cell aging determines the health and life span of the body.
[2]. Cell Junctions Applied Physiology .
Tight Junctions Applied Physiology.
Diseases caused by mutation of genes encoding proteins of tight junction:
1. Hereditary deafness .
2. Ichthyosis (scaly skin) .
3. Sclerosing cholangitis (inflammation of bile duct causing obstruction) .
4. Hereditary hypomagnesemia (low level of magnesium in the blood) .
5. Synovial sarcoma (soft tissue cancer) .
Functions of tight junction are affected by some bacteria and viruses also.
Gap Junctions Applied Physiology .
Mutation in the genes encoding the connexins causes diseases such as:
1. Deafness .
2. Keratoderma (thickening of skin on palms and soles) .
3. Cataract (opacity of lens in eye) .
4. Peripheral neuropathy (damage to the nerves of peripheral nervous system) .
5. Charcot Marie Tooth disease (a form of neuropathy) .
6. Heterotaxia (abnormal arrangement of organs or parts of the body in relation to left right symmetry).
Anchoring Junctions Applied Physiology .
1. Dysfunction of adherens junction and focal junction .
Dysfunction of adherens junction and focal junction in colon due to mutation of proteins results in colon cancer. It also leads to tumor metastasis (spread of cancer cells from a primary tumor to other parts of the body)
2.Dysfunction of desmosome .
Dysfunction of desmosome causes bullous pemphigoid (autoimmune disease with tense blistering . eruptions of the skin). The patients with this disease develop antibodies against cadherins
3. Dysfunction of hemidesmosome .
Dysfunction of hemidesmosome also causes bullous pemphigoid. The patients develop antibodies against integrins.
[3]. Transport through Cell Membrane Applied Physiology .
Abnormalities of Sodium-Potassium Pump .
Abnormalities in the number or function of Na+-K+ pump are associated with several pathological conditions. Important examples are:
[1] . Reduction in either the number or concentration of Na+-K+ pump in myocardium is associated with cardiac failure .
[2] . Excess reabsorption of sodium in renal tubules is associated with hypertension.
Channelopathies or ion channel diseases .
Channelopathies or ion channel diseases are caused by mutations in genes that encode the ion channels.
1. Sodium Channel Diseases .
Dysfunction of sodium channels leads to muscle spasm and Liddle’s syndrome (dysfunction of sodium channels in kidney resulting in increased osmotic pressure in the blood and hypertension). : Kinesin and dynein motor molecules
2. Potassium Channel Diseases .
Potassium channel dysfunction causes disorders of heart, inherited deafness and epileptic seizures in newborn.
3. Chloride Channel Diseases .
Dysfunction of chloride channels results in formation of renal stones and cystic fibrosis. Cystic fibrosis is a generalized disorder affecting the functions of many organs such as lungs (due to excessive mucus), exocrine glands like pancreas, biliary system and immune system.
Acid-Base Balance Applied Physiology .
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| Biochemical changes in arterial blood during acid-base disturbance |
Acidosis .
Acidosis is the reduction in pH (increase in H+ concentration) below normal range.
Acidosis is produced by:
1. Increase in partial pressure of CO2 in the body fluids particularly in arterial blood .
2. Decrease in HCO3 – concentration.
Alkalosis .
Alkalosis is the increase in pH (decrease in H+ concentration) above the normal range .
Alkalosis is produced by:
1. Decrease in partial pressure of CO2 in the arterial blood .
2. Increase in HCO3 – concentration. Since the partial pressure of CO2 (pCO2 ) in arterial blood is controlled by lungs, the acid-base disturbances produced by the change in arterial pCO2 are called the respiratory disturbances.
On the other hand, the disturbances in acid-base status produced by the change in HCO3 – concentration are generally called the metabolic disturbances.
The acid-base disturbances are:
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| Causes of acidosis |
1. Respiratory acidosis .
2. Respiratory alkalosis .
3. Metabolic acidosis .
4. Metabolic alkalosis.
Respiratory acidosis .
[1]. Respiratory acidosis is the acidosis that is caused by alveolar hypoventilation. During hypoventilation the lungs fail to expel CO2 , which is produced in the tissues.
[2]. CO2 is the major end product of oxidation of carbohydrates, proteins and fats. CO2 accumulates in blood where it reacts with water to form carbonic acid, which is called respiratory acid.
[3]. Carbonic acid dissociates into H+ and HCO3 – . The increased H+ concentration in blood leads to decrease in pH and acidosis.
[4]. Normal partial pressure of CO2 in arterial blood is about 40 mm Hg. When it increases above 60 mm Hg acidosis occurs.
Causes of Excess CO2 in the Body .
Hypoventilation (decreased ventilation) is the primary cause for excess CO2 in the body. Some of the conditions when increase in pCO2 and respiratory acidosis occur due to hypoventilation .
Respiratory alkalosis .
Respiratory alkalosis is the alkalosis that is caused by alveolar hyperventilation. Hyperventilation causes excess loss of CO2 from the body. Loss of CO2 leads to decreased formation of carbonic acid and decreased release of H+. Decreased H+ concentration increases the pH leading to respiratory alkalosis. When the partial pressure of CO2 in arterial blood decreases below 20 mm Hg, alkalosis occurs.
Causes of Decrease in CO2 in the Body .
[1]. Hyperventilation is primary cause for loss of excess CO2 from the body because during hyperventilation, lot of CO2 is expired through respiratory tract leading to decreased pCO2 .
[2]. Some of the conditions when decreased pCO2 and respiratory alkalosis occur due to hyperventilation .
Metabolic acidosis .
Metabolic acidosis is the acid-base imbalance characterized by excess accumulation of organic acids in the body, which is caused by abnormal metabolic processes. Organic acids such as lactic acid, ketoacids and uric acid are formed by normal metabolism. The quantity of these acids increases due to abnormality in the metabolism.
Causes of Metabolic Acidosis .
Lactic acid .
The amount of lactic acid increases during anaerobic glycolysis in some abnormal conditions such as circulatory shock.
Ketoacids .
[1]. The amount of ketoacids increases because of insulin deficiency as in the case of diabetes mellitus. In diabetes mellitus, glucose is not utilized due to lack of insulin.
[2]. So, lipids are utilized for liberation of energy resulting in production of excess acetoacetic acid and beta hydroxybutyric acid.
Uric acid .
[1]. The amount of uric acid increases in the body due to the failure of excretion. Normally uric acid is excreted by kidneys. But in renal diseases, the kidneys fail to excrete the uric acid.
[2]. Some of the conditions when the metabolic acids increase in the body resulting in metabolic acidosis .
Metabolic alkalosis .
[1]. Metabolic alkalosis is the acid-base imbalance caused by loss of excess H+ resulting in increased HCO3 – concentration.
[2]. Some of the endocrine disorders, renal tubular disorders etc. cause metabolic disorders leading to loss of H+.
[3]. It increases HCO3 – and pH in the body leading to metabolic alkalosis.
[4]. Some of the conditions when excess H+ is lost and HCO3 – content increases leading to metabolic alkalosis .
