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Cell Homeostasis

The normal cell is a restless pulsating structure, constantly modifying its organization and function in response to changing demands and stress. If the cell suffer from excessive stress it can undergo adaptation preserving health of the cell despite continued stress.


Cell Injury

If no adaptive response is possible or the cell's adaptive capability is exceeded, cell injury develops. Cell injury is reversible up to the certain point, but in the case of persistent and severe stress the cell suffers irreversible injury and die.


Causes of Cell Injury

1. Hypoxia
2. Physical Agents
3. Chemical Agents & Drugs
4. Infectious Agents
5. Immunologic Reactions
6. Genetic Defects
7. Nutritional Imbalances


1. Hypoxia

Decreased availability of O2 needed in cells. Blood unable to deliver O2 where needed.


Causes of Hypoxia

A) Ischemia
B) Cardiopulmonary Failure
C) Loss of oxygen carrying capacity of the blood


A) Ischemia

Most common cause: Obstructed blood flow. Arterial flow or venous drainage obstructed by vascular diseases -> loss of blood supply to tissues. Distal areas suffer most because blood doesn't get to peripheral parts.


B) Cardiopulmonary Failure

lack of oxygenation of blood. Lungs not doing their job. Blood can reach periphery but lacks O2


C) Loss of O2 carrying capacity of blood

EXAMPLES: Anemia or CO poisoning.
If not enough hemoglobin/RBCs = anemia. 
OR Sickle cell - weird shape doesn't allow for easy binding of O2 to hemoglobin.
-Hemoglobin = iron + protein. Lacking iron means can't synthesize hemoglobin. OR if bone marrow not producing enough RBCs. 

Lack of production of B12 = lacking intrinsic factor in gut. Leads to pernicious anemia and that causes hypoxia. Have to bypass gut with B12 - need to go directly into bloodstream. If too much blood is too thick and leads to ischemia.


2. Physical Agents (examples)

A) Mechanical trauma - any physical trauma
B) Extremes of heat or cold - 
C) Sudden changes in atmospheric pressure - Nitrogen in blood can turn from gas into liquid form that can lead to obstructed blood flow (ischemia). Scuba diving - coming back up and not slow adjustment = the bends?
D) ionizing radiation - formation of OH radicals - 
E) electric energy


3. Chemical Agents and Drugs

Virtually any chemical agent or drug, even a substance such as glucose may generate cell adaptation, injury or death. (water)
Act on vital cell functions - membrane permeability, osmotic homeostasis, or integrity of different enzymes or cofactors.
EXAMPLES: mercury, salts, trace amounts of agents (poisons), air pollutants, insecticides, herbicides, recreational and therapeutic drugs.


4. Infectious Agents (examples)

A) Viruses
B) Rickettsiae - bacteria often carried by small insects (ticks, fleas and lice) WHY ITS OWN CATEGORY?
C) Bacteria
D) Fungi - nearly untreatable.
E) Parasites.


5. Immunologic reactions (3 types)

Immune system overdoes it and attacks
A) Anaphylactic reaction to the foreign proteins - Shock = quick drop in blood pressure.
B) Deposition of immune complexes - to neutralize invader (antigen) by forming complex. Tissue recognizes complex as foreign body - attacks and causes inflammation. Tissue becomes less functional.
C) Autoimmune reactions - Body recognizes its own as enemy. Similar to B but doesn't form complex (myasthinia gravis). Antibodies acting on own tissue and preventing it from acting normally. Examples: Psoriasis. Multiple Sclerosis.


6. Genetic Defects (2 types)

May result in gross defects or subtle alterations in protein structure 
A) Congenital malformations
Monosomy / Trisomy
B) Chromosomal (DIPT)
-Deletions - Losing piece of lineup.
-Insertions - A piece of another chromosome inserted into another one. 
-Point mutations - changing a single base nucleotide
-Translocations - arrangement of parts between nonhomologous chromosomes


7. Nutritional Imbalances (4 types)

  • 1. Protein-calorie deficiencies - marasmus (lack of calories) and kwashiorkor (lack of protein but enough energy intake)
    • hypoproteinemia → less protein in blood, more water → bulging stomach with skinny limbs
  • 2. Dietary excesses - strongly implicated in atherosclerosis and obesity.
  • 3. Vitamin deficiencies (avitaminoses)
    • Pernicious anemia: A decrease in red blood cells when the body can't absorb enough vitamin B12; doesn’t have enough intrinsic factors that stomach makes 
  • 4. Vitamin excesses (hypervitaminoses)


If the stress is removed in time full cell integrity can be restored. Characteristics of acute cell injury are:

1. cell swelling - first manifestation of cell injury.
2. mitochondrial swelling
3. plasma membrane alterations
4. dilation of ER
5. nuclear alterations
If stress removed in time - it will be restored (reversible)


Steps to Cell Injury

Less oxygen -> Less ATP -> 
A) More anaerobic glycolysis -> lactic acidosis -> lowering pH -> clumping of chromatin in nucleus
B) Na-K pump dysfunctions -> cell, ER swelling due to Na/water accumulation, loss of microvilli
C) Detachment of ribosome -> reduced amount of protein synthesis


Cell Swelling

Mitochondrial oxidative phosphorylation stopped/slowed due to hypoxia = less ATP
-Decrease in Na-K pump leading to accumulation of Na and Cl which leads to accumulation of water and acute cellular swelling.


Characteristics of IRREVERSIBLE Acute Cell Injury

1. Excessive damage of plasma membrane
2. Vacuolization (formation of vacuoles) of mitochondria 
3. Swelling of lysosomes
4. massive calcium influx into cell - extremely damaging. 
5. Release of oxygen free radicals - Missing one electron. Becomes unstable and wants to borrow electron. Destroys surrounding tissue.


Calcium Influx into Cell and Its Effects

Damage to ER, mitochondria (first) and cell membrane (later) leads to increase in Ca++. 
1. Increased Mitochondria permeability (can lead to apoptosis due to release of cytochrome C)
2. Activating enzymes (4)- ATPase (ATP depletion), phopholipase (break down phospholipid membrane), protease (break down protein - cell membrane detaches from cell - succeptible to stretching and rupturing), endonuclease (DNA damage)


3 Causes of Cell Membrane Damage

1. progressive loss of membrane phospholipids (Ca++)
2. cytoskeletal abnormalities (Ca++)
3. toxic oxygen radicals


3. Toxic oxygen radicals

Radicals increased in ischemic tissues especially upon restoration of blood flow, and may be cause of reperfusion injury (tissue damage caused when blood returns after period of ischemia). 

This cause of cell injury is emerging as a final common pathway of tissue damage in such processes as:

  • chemical and radiation injury
  • oxygen and other gaseous toxicity
  • cellular aging
  • microbial killing by phagocyte cells
  • inflammatory damage



How Oxygen Free Radicals damage cells initiate a number of autocatalytic reactions, but three are particularly relevant to cell injury:

1. Lipid peroxidation - Results in loss of membrane integrity.
2. Lesions in deoxyribonucleic acid (DNA) - Can cause cell death or malignant transformation.
3. cross-linking of amino acids - Leads to eventual degradation of protein


2 Types of Cell Death

1. Necrosis
2. Apoptosis


2. Apoptosis

Genetically pre-programmed cell death.

Apoptosis is probably responsible for a number of physiologic events like programmed destruction of cells during embryogenesis, hormone dependent involution of endometrium during menstrual cycle. 

Can be triggered by pathologic stimuli such as irradiation and virus infections, like in viral hepatitis where apoptotic cell fragments, called Councilman bodies can be found in the liver.


Steps of Cell Death

-Degradation of enzymes followed by digestion of cell and denaturation of proteins.
-Changes to nucleus
1. Pyknosis - nuclear shrinkage
2. Karyorrhezis - nucleus fragmentation
3. Karyolysis - nuclear degradation


Types of Cell Necrosis (4)

1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseous necrosis
4. Gangrenous necrosis


1. Coagulative necrosis

Hypoxic death in all tissues except brain. 

Increased acidity breaks down proteins and proteins responsible for proteolysis of the cell.

Leads to: Outline of cell for a few days then removed by fragmentation/phagocytosis by WBCs. Creates dead tissue visible for a few days before disappearing.


2. Liquefactive necrosis

Mainly caused by focal (localized) BACTERIAL infections and hypoxic death of BRAIN CELLS. 

Bacterial infection leads to inflammatory cells which produce rapid death and complete dissolution of tissues (no outline)

Result is often an abscess, or in the brain result can be formation of cavity or cyst.

Resulting from action of hydrolytic enzyme including autolysis and heterolysis.


3. Caseous necrosis

combination of coagulative and liquefactive necrosis

Refers to lesions in tuberculosis.

Appears as white and "cheesy" (caseous) amorphous debris composed of fragmented, coagulated cells within inflammatory border (AKA granulomatous reaction)


4. Gangrenous necrosis

Combo of Coagulative and Liquefactive necrosis.

Usually applies to lower limb.

Dry gangrene - Coagulative necrosis (hypoxia)
Wet gangrene - Liquefactive necrosis (bacterial infection)


Reasons for Intracellular Accumulation

1. Escalated production of endogenous substances
2. Deposition of exogenous substances
3. Inadequate metabolic rate or inability to eliminate accumulating waste.


1. Escalated production of endogenous substances

A. Lipofuscin
B. Melanin
C. Hemosideran


Escalated production of endogenous substances: Lipofuscin

"aging pigment" aka "liver spots"- is seen in cells undergoing regressive changes. 

It is fine granular, yellow-brown pigment. It is located in liver and/or heart in aging persons or patients with severe malnutrition or cancer.


Escalated production of endogenous substances: Melanin

"black pigment" - is non-hemoglobin-derived pigment endogenously formed by oxidation of tyrosine by enzyme called tyrosinase in melanocyte cells or neurones of substantia nigra.
Mainly found in skin and eye.


Escalated production of endogenous substances: Hemosideran

is pigment which accumulates in the body when excesses of iron is present either locally or systemically (when excess iron is present - breakdown of RBCs and release of iron from heme). 

Extreme cases of iron accumulation, hemochromatosis usually is associated with damage of liver and pancreas.

more details in outline


Causes of:
2. Deposition of exogenous substances

A) Anthracosis - (inhalation of coal dust)
B) Siderosis - (inhalation of iron dust)
C) Silicosis - (inhalation of silica from quartz)
D) Asbestosis - (inhalation of asbestosis dust)
E) Tattooing


Deposition of exogenous substances: Anthracosis

- (inhalation of coal dust) most common form. 
Inhaled and picked by alveolar macrophages and through lymphatic channels transported to tracheobronchial lymphatic nodes. 
-Can lead to serious lung disease known as coal worker's pneumoconiosis.


Deposition of exogenous substances: Siderosis

- (inhalation of iron dust)
-Occurs among welders, miners and represents benign form of pneumoconiosis.


Deposition of exogenous substances: Silicosis

(inhalation of silica from quartz/flint) is pneumoconiosis caused by exposure to silica (SiO2) 
The lungs bear characteristic nodules with concentric composition of collagen fibers called "onion-skin". It occurs in workers tunneling siliceous rock, stonecutting, and ceramics manufacture.


Deposition of exogenous substances: Asbestosis

(inhalation of asbestosis dust) is bilateral, diffuse interstitial fibrosis of the lungs. 
-Delayed onset after years of exposure to asbestos fibers. Can lead to mesothelioma.


Deposition of exogenous substances: Tattooing

is defined intentional or accidental injection of inks or dyes into dermis.

is defined intentional or accidental injection of inks or dyes into dermis.


Causes of:
3. Inadequate metabolic rate or inability to eliminate accumulating waste.

A) Lipid accumulation
B) Protein accumulation
C) Glyocogen accumulation
D) Complex lipids and carbs (sugars) accumulation
E) Pigments accumulation


A) Lipid accumulation

Fatty change - Fat vacuoles in cells. Most often seen in the liver (single major organ involved in fat metabolism) but can occur elsewhere.

Mainly alcohol abuse but also protein malnutrition, diabetes mellitus and obesity.

In heart - prolonged moderate hypoxia leads to fat accumulation - tiger effect because it's striped.


Fatty Liver Due to Alcohol Abuse

Liver taxed with too much detoxification and cells begin to die and scar tissue formed. The more scar tissue, the less the liver can adapt. Alcohol converted to fat.

Can block blood flow causig pressure to build up at portal vein and liquid leaks out into stomach - Ascites


B) Protein accumulation

is usually related to disorders producing heavy proteinuria (often kidney damage - diabetes)


C) Glyocogen accumulation

Formed and stored in liver and lesser extent muscles. Accumulates in liver or muscle due to:
a) abnormalities in glucose metabolism
b) Genetic deviation in glycogen metabolism


D) Complex lipids and carbs (sugars) accumulation

When lipids/carbs have abnormal structure and CAN'T METABOLIZE in usual fashion.

EXAMPLE: Reticuloendothelial cells collect these complexes resulting in massive hepatomegaly (enlarged liver) and splenomegaly (enlarged spleen).


E) Pigments accumulation

Pigments that accumulating in the body can be of exogenous or endogenous origin.


Cellular Adaptations to Injury (5)

1. Atrophy
2. Hypertrophy
3. Hyperplasia
4. Metaplasia
5. Dysplasia


1. Atrophy

Shrinkage in the size of the cell by loss of cell structural components. 
Atrophic - when entire tissue shrinks because of atrophy of cells.


Reasons for Atrophy (6)

- decreased workload (e.g., hospitalization)
- innervation loss (e.g., alpha-motor neuron disease)
- diminished blood supply (e.g., atherosclerosis)
- inadequate nutrition (e.g., protein deficiencies)
- loss of endocrine stimulation (e.g., menopause)
- aging
EXAMPLE: Alzheimer's - gyri narrowed and sulcy widened toward frontal lobe


2. Hypertrophy

Increase in the size of the tissue/organ.

Caused by increased demand OR hormonal stimulation.

DEMAND: Hypertrophy of heart due to workload increase from interference with aortic outflow or hypertension
HORMONAL: Estrogen stimulated growth of uterus during pregnancy/menstruation.


3. Hyperplasia

An increase in the number of cells in an organ or tissue. 
-Hormonal - puberty
-Compensatory - portion of liver removed and eventually restored to normal weight.
-Excessive hormonal (abnormal menstrual bleeding), chemical or mechanical stimulation (callus)


4. Metaplasia

Switching of cell types (better able to withstand stress)

USUALLY epithelial cells but occurs in mesenchymal cells (lymphatic/circulatory) too.
EXAMPLE: Squamos change that occurs in the respiratory tract in chronic cigarette smoker. In this case the normal columnar ciliated epithelium of the trachea and bronchi are replaced by stratified squamous epithelium.


5. Dysplasia

An alteration in size, shape and organization in epithelial or mesenchymal cellular components. 

It usually happens in the cervix and respiratory tract, and is strongly implicated as a PRECURSOR OF CANCER at these locations.


Normal Death of RBCs

runs out of energy - Na-K pump starts failing. Na starts accumulating in cell. Then Cl follows. Then NaCl followed by water. Then it grows in size and gets stuck in spleen (too big to permeate). Then bursts. Apoptosis?