The document discusses homeostasis and cell injury. It defines homeostasis as the body's ability to maintain stable internal conditions despite external changes. It provides examples of homeostasis systems like temperature regulation and blood sugar levels. The document also discusses feedback mechanisms that help regulate homeostasis. It then covers causes of cell injury like hypoxia, chemicals, infections, and genetics. It explains the process of cell injury, including damage to mitochondria, membranes, ribosomes and the nucleus. Overall, the document provides an overview of homeostasis and the pathways involved in cell injury.

1. SUBHAM SOURAJIT
ASST PROFESSOR
DEPT OF
PHARMACOLOGY

2.  Homeostasis word is made up of two Greek words i.e. homeo means
same and stasis refers to stand.
 Homeostasis is defined as the ability of the body to maintain the
internal environment stable despite the changes in its external
environment which is necessary for normal functioning and survival
of organism. The liver, kidney and brain help to maintain
homeostasis.
Some examples of homeostasis system-
 Temperature regulation- The human body uses a number of
processes to control its temperature, keeping to an average value 37
degree Celsius. One of the physical responses to maintain body temp
is sweating. If temp is high sweating increases and if low sweating
decreases and reduces blood circulation to the skin.
 Maintenance of iron level: When the body iron level are too low,
then hepcidin (regulator of iron metabolism) in the duodenal
epithelium (part of small intestine) is decreased. This causes an
increase in ferroportin (iron exporter, exports iron from blood to cell)
activity, stimulating iron uptake in the digestive system. An iron
surplus will follow the reverse of this process.

3.  Maintenance of sugar level: Blood glucose is regulated with two
hormones, insulin and glucagon, both released from the pancreas.
When blood sugar level is too high insulin is released from
pancreas and when blood sugar level is too low glucagon is
released.
 Maintenance of blood and fluid volume: The maintenance of
blood and fluid volume takes place through secretion of two
hormones Anti-diuretic Hormone and Aldosterone.
It the body is becoming fluid-deficient, there will be an
increase in the secretion of these hormones (ADH), causing fluid
to be retained by the kidneys and urine output to be reduced.
Conversely, if fluid levels are excessive, secretion of these
hormones (aldosterone) is suppressed, resulting in less retention
of fluid by the kidneys and a subsequent increase in the volume
of urine produced.
 Osmoregulation- Osmosis is the essential process that is carried
out in the body for the proper functioning of cells. Water
movement in the body is carried out through Osmosis. Osmosis is
carried out by balancing both sides of the cell membrane, for the
proper functioning of biochemical process of the cells which is
most required.

4. Control centers in the brain and other parts of the body monitor and react to deviation
from homeostasis using feedback mechanism. Feedback system has two types:
 Negative feedback system
 Positive feedback system
Effect of activation of feedback mechanisms on body
 Negative feedback System: A negative feedback system has three basic components. A
Sensor, also referred to a receptor, is a component of a feedback system that monitors a
physiological value. This value is reported to the control center. The control center is the
component in a feedback system that compares the value to the normal range. If the value
changes too much then the control center activates an effector. An effector is the component
in a feedback system that causes a change to reverse the situation and return the value to the
normal range.
 Positive feedback system: Positive feedback system increases the abnormal response instead
of reversing it to normal level. Positive feedback in the body is normal only when there is a
definite end point. Childbirth and the body's response to blood loss are examples of positive
feedback systems that are normal but are activated only when needed.
Childbirth an example of a situation in which the normal state of body is not required.
Numbers of changes in the mother's body are required to expel the baby at the end of
pregnancy and the events of childbirth, once begun, must progress rapidly to a conclusion or
the life of the mother and the baby are at risk. The extreme muscular work of labor and
delivery are the result of a positive feedback system.

5. The first contractions of labor (the stimulus) push
the baby toward the cervix. The cervix contains stretch-sensitive
nerve cells that monitor the degree of stretching (the sensors).
These nerve cells send messages to the brain, which in turn
causes the pituitary gland at the base of the brain to release the
hormone oxytocin into the bloodstream. Oxytocin causes
stronger contractions of the smooth muscles in of the uterus (the
effectors), pushing the baby further down the birth canal. This
causes even greater stretching of the cervix. The cycle of
stretching, oxytocin release, and increasingly more forceful
contractions stops only, when the baby is born. At this point, the
stretching of the cervix halts, stopping the release of oxytocin. A
second example of positive feedback system is stoppage of
blood flow from wound. To counteract the blood flow body can
reduce the blood pressure and blood circulation. But this may
cause the reduction in blood supply to the essential organs like
brain which may leads to death of person. The body responds to
this condition by releasing substances in the injured blood vessel
wall that begin the process of blood clotting. As each step of
clotting occurs, it stimulates the release of more clotting
substances. This accelerates the processes of clotting and sealing
off the damaged area.

6. Cell injury can be defined as an alteration in cell structure or biochemical functioning resulting from some
stress that exceeds the ability of the cell to compensate through normal physiologic adaptive mechanisms. Or it can be
define as a variety of stresses a cell bears as a result of changes in its internal and external environment.
Response of cell to the injury according to severity of injury:
1. When there is increased functional demand cell get adapted to such stimulus and reverts back to original condition when
stress is removed.
2. When stress is mild to moderate the injured cell may recover while injury is persistent cell may die.
3. The residual effects of reversible cell injury may persist in the cell or metabolites may accumulate within the cell.
Causes of Cell Injury
There are numerous causes for cellular injury. To simplify the study we can divide them in to two classes acquired and
genetic causes.
A) Acquired causes the acquired causes include:
I. Hypoxia and ischemia
II. Physical agents
III. Chemical agents and drugs
IV. Microbial agents
V. Immunologic agents
VI. Nutritional derangements
VII. Psychological factors
The cell injury may be occurring by more than one causes of above.
Hypoxia and ischemia: Hypoxia is a deficiency of oxygen, Cells require oxygen for different metabolic functions. If there
is deficiency of oxygen cell cannot perform such functions normally. There are different reasons for hypoxia-
a. Reduced supply of blood i.e. ischemia.
b. Anemia.
c. Carbon monoxide poisoning
d. Increased demand of tissue.

7. Physical agents: These agents cause the physical injuries to the cells or body which may be mild or
severe. The examples include-
i. Mechanical trauma (e.g. Road accidents).
ii. Thermal trauma (heat, cold).
iii. Electricity.
iv. Radiation (UV radiations, Ionizing radiations).
v. Rapid changes in atmospheric pressure.
Chemicals and drugs: Simple chemicals such as glucose or salt in hypertonic concentrations may
cause cell injury directly or by deranging electrolyte balance in cells. Even oxygen at high
concentrations is toxic. These injurious agents include-
a) Insecticides and pesticides
b) O2 at high concentration
c) Hypertonic glucose, salts.
d) Drugs
Infectious agents: These agents range from the submicroscopic viruses to the large tapeworms. In
between are the bacteria, fungi, and higher forms of parasites. The ways by which these biologic
agents cause injury are diverse.
Immunological agents: The immune system serves as essential function in defense against infectious
pathogens, but immune reaction may also cause cell injury.
Nutritional Derangement: Nutritional imbalance continues to be major cause of cell injury. Protein
calorie deficiencies cause a large number of deaths, chiefly among underprivileged population.
Nutritional excess also harmful to cells. e.g. Atherosclerosis due to high cholesterol.
Psychological factors: Some psychological problems also induce cellular injury. E.g.- stress, anxiety,
depression.

8. B) Genetic Causes:
1. Developmental Disease: Group of abnormalities developed
during fetal life. Some chemicals or drugs had ability to
induce teratogenic effects. These teratogens can cause
morphology change in the embryonic development. E.g.
Thalidomide malformation. Children are having abnormal
limbs whose mother had used thalidomide as sedative.
2. Cytogenic Defect: It includes change in number of
chromosomes.
3. Single gene defect: It means the mutation in single gene.
That means DNA's get permanently changed.
4. Storage disease: These errors are introduces in cells during
or before birth. In such cases new born is containing
deficiency or lack of enzymes.
E.g. Glucose -6- dehydrogenase deficiency may cause
hemolytic disease (blood problem in new born)
5. Disorders with multifactorial inheritance: This occurs
due to both genetic as well as environmental factors. E.g.
Colors of hair, eyes, height.

9. Persistent ischemia and hypoxia results
in irreversible changes in structure and function of
the cell i.e. cell death. The pathogenesis of cell
injury involves certain events like damage of cell
membrane, mitochondrial damage, ribosomal
damage, nuclear damage.

10. The mitochondria is damaged by:
 Increase in cytosolic Calcium (cytosolic Ca2+ levels in neurons are crucial for their development and
function), coupled by an increase in inorganic phosphate.
 High inorganic phosphate and fatty acids alone cannot damage the mitochondria but coupled with high
Calcium are extremely damaging to a cell.
 Oxygen deprivation, either by hypoxia or ischemia.
 Defective turnover of mitochondrial proteins.
Thus, they are very sensitive to damage as involves number of causes for damage. After damage of
mitochondria 3 major consequences can occur. They are as follows.
Change in mitochondrial permeability: It can be defined as an increase in the permeability of the
mitochondrial membrane to freely allow entry of molecules less than 1500 Dalton (unit of molecular
weight of protein) in molecular weight.
The outer mitochondrial membrane contains proteins that although allow movement of
molecules upto 5000 dalton, very tightly regulate the movements of molecules in the mitochondria.
Because all the molecules below the 1500 Da cannot be regulated, there is a transition brought by a
high conductance channel, the mitochondrial permeability transition pore (MPTP).
Increase in Oxidative Stress: As a result of the opening of the MPTP channels, antioxidant molecules
such as glutathione (made from the amino acids glycine, cysteine, and glutamic acid, naturally
produced by liver), which are typically stored in the mitochondria to take action on reactive oxygen
species(play important roles in the modulation of cell survival, cell death, differentiation, cell
signaling), are now removed from the mitochondria and this allows reactive oxygen species to build up
within the cell.

11.  Induction of Apoptosis: As the mitochondria is being damaged, it begins to isolate between the inner
and outer membrane, a number of pro-apoptotic proteins such as cytochrome c and proteins that
indirectly activate apoptosis (cell death) inducing enzymes known as caspases. Thus, as permeability
increases, these proteins and pro-apoptotic molecules leak into the cytosol (component of cytoplasm of
a cell) and trigger cell death by apoptosis.
 Membrane Damage: Membranes are damaged in different ways, based on different pathologies. E.g.
– During ischemia.
Pathogenesis of Membrane Damage:
 Accelerated degradation of membrane phospholipids- The calcium from mitochondria and
endoplasmic reticulum shifts into the cytosol (aqueous component of cytoplasm). Increased level of
calcium in cytosol activates endogenous phospholipases from ischemic tissue which degrade
membrane phospholipids.
 b) Decreased Phospholipids Synthesis The production of phospholipids in cells may be disrupted due
to hypoxia and ischemia, or defective mitochondrial function via damage to the mitochondria.
 c) Cytoskeletal damage Cytoskeleton is a microscopic network of protein filaments and tubules in the
cytoplasm of many living cells giving them shape. Cytoskeletal filaments get damaged due to
degradation by activated intracellular proteases or by physical effect of cell swelling.
 Ribosomal damage: Under the influence of damaging factors destruction of polysomes usually
consisting of several ribosomes (monomers), reducing of ribosomes number and separation of the
organelles from intracellular membranes are observed. These changes are accompanied by a decrease
in the intensity of protein synthesis process in the cell. As a result of continued hypoxia ribosomes are
detached from rough ER and polysomes are degraded to monosomes thus causing decrease the protein
synthesis.
 Nuclear Damage: Nuclear changes appear in the form of one of three patterns, all due to nonspecific
breakdown of DNA. The basophilia (high basophil level) of the chromatin (complex of DNA &
protein) may fade (karyolysis- dissolution of a cell nucleus), a change that presumably reflects DNAase
activity. A second pattern (also seen in apoptotic cell death) is pyknosis (irreversible condensation of
chromatin in the nucleus of cell undergoing apoptosis), characterized by nuclear shrinkage and
increased basophilia. Here the DNA apparently condenses into a solid, shrunken basophilic mass. In
the third pattern, known as karyorrhexis (chromatin distributed irregularly throughout the cytoplasm),
the pyknotic or partially pyknotic nucleus undergoes fragmentation. With the passage of time (a day or
two), the nucleus in the necrotic cell totally disappears.