Causes of Cell Injury

Life meets change & variation everyday. We make appropriate adjustments, so does the cell “the unit of life”. “Homeostasis” is the normal steady dynamic cell state. It is the ability of the body to adjust its physiological processes to maintain internal equilibrium. The cells are under continuous exposure to stress including:
•    Physiological stress, body maintains itself by homeostasis
•    Pathological stress, injury takes place

If reversible injury occurs, body adapts itself, while in case of irreversible injury cell death takes place.

Causes of injury /Types of stress

1. Oxygen deprivation “Hypoxia & ischemia”
2. Free radicals
3. Chemical agents –glucose, hypertonic saline, increased oxygen & poisons
4. Physical agents –trauma, extreme heat / cold , increased atmosphere pressure, radiation, electric shock
5. Infections
6. Immune reactions
7. Genetic defects –gene mutations & chromosomal abnormality, enzyme defects, damaged DNA , misfolded proteins, increased cell susceptibility to injury
8. Nutritional defects –decreased proteins, decreased enzymes, increased cholesterol
9. Aging

1. Oxygen Deprivation

Oxygen deprivation consists of hypoxia & ischemia. It may be caused by:
a.    Decreased oxygen in air
b.    Decreased Hb “anemia”
c.    Respiratory disease leading to decreased oxygen exchange
d.    decreased blood supply

Results may include adaptation by atrophy, cellular injury by inflammation or cell death by infarction. Mitochondrial damage leads to decreased ATP production, leading ultimately to cell death.

Ischemia

Ischemia occurs when blood supply is decreased below physiological requirement. Ischemia leads to hypoxia. Reperfusion leads to recovery or reperfusion injury (myocardial & cerebral infarction), caused by increased calcium influx, increase in inflammatory cells, increased free radicals and immune response against dead tissue.

2. Oxygen derived free radicals

Single unpaired electron is present in outer orbit which reacts with adjacent molecules leading to autocatalytic reactions. As a result, oxidative stress is imposed. Increased reactive oxygen radicals are found either due to increased production or decreased scavenging.
By mitochondrial respiration, superoxides, H2O2 and OH are formed. By inflammation NO is converted into ONOO.

Generation of free radicals

Free radicals may be generated by:
1.    Respiration
–    H2+O=H2O   and
–    O2-(1e), H2O2-(2e), OH-(3e),

2.    Radiation = Hydrolysis
–    H2O=H+OH

3.    Inflammation = rapid burst of ROS in leukocytes
4.    Xanthine oxidase = O2-

5.    Enzymatic metabolism of drugs
–    CCl4→CCl3
–    acetaminophen

6.    Transition metals iron & Cu
–    Fenton’s reaction: H2O2+Fe→Fe+OH+OH-

7.    NO by endothelial cell, macrophages & neuron
–    NO→peroxynitrite (ONOO)

Pathologic effects of free radicals

Free radicals may produce:
1.    Lipid peroxidation of double bonds in unsaturated fatty acids by OH-
2.    Oxidative modification of proteins by enzyme inactivation or degradation
3.    Lesions in DNA e.g. strand breaks & cross linking leading to mutations resulting in aging or malignancy.

Removal of free radicals

Free radicals are removed by:
1.    Spontaneous decay

2.   Antioxidants
a.   Vitamin A, E, & C & glutathione
b.   Albumin, transferrin, ferritin, lactoferrin, ceruloplasmin

3.   Enzymes
a.    SOD in mitochondria
•    O2- →H2O +O2
b.    Glutathione peroxidase
•    OH→H2O2→H2O+O2
c.    Catalase in peroxisomes
•    H2O2→H2O+O2

3. Chemical agents

Chemical agents include the following:
•    Cyanide
•    HgCl leading to increased memebrane  ncreased ty
•    CO→ COHb
•    Ethanol forms acetaldehyde producing fee radicals & fatty change in liver
•    Lead competitive inhibition of Calcium, Fe & Zn
•    Lead in CNS blocks glutamate receptor
•    Lead decreases Hb synthesis

4. Physical agents

Physical agents include the following:
•    Mechanical injury
•    Ionizing radiation
•    Extreme temperatures –Hyper or Hypothermia
•    Extreme air pressure –blast, underwater or vaccum

5. Infectious agents

Infectious agents include:
•    Bacterial toxins
•    Viruses

6. Nutritional imbalance

–    Increased protein in diet
–    Hyper or hypoglycemia
–    Vitamin deficiencies
Function lost before morphological change. Results of injury depends on
–    Type, duration & severity of injury
–    Type of cell specialization, regenerative ability or adaptability