Homeostasis, Stress reaction, General Adaptation Syndrome

Stress, adaptation, and their relationship to health are a frequent topic of discussion. The human
body and mind respond to stress by activating a complex repertoire of physiologic and behavioral
adaptive responses which, if inadequate or excessive, may affect emotional behavior and have
adverse effects on physiologic functioning. Stress may contribute directly to the production or
exacerbation of a disease, or it may contribute to the development of behaviors such as smoking,
overeating, and drug abuse that increase risk of disease.
Theconcept of stress is commonly viewed within the contextof three major components:
homeostasis, the stressresponse, and adaptation to stress. Ineffecting a state of constancy,
homeostasis requires feedbackcontrol systems that regulate cellular function andintegrate
functions of the different body systems. Constancy in an open system, such as our
bodiesrepresent, requires mechanisms that act to maintain this constancy. In steady states glucose
concentrations, body temperature, and acidbase balance are regulated. Steady-state conditions
require that any tendency toward change automatically meets with factors thatresist change. E.g. An
increase in blood sugar results inthirst as the body attempts to dilute the concentrationof sugar in the
extracellular fluid.
The regulating system that determines the homeostaticstate consists of a number of cooperating
mechanismsacting simultaneously or successively. Blood sugar isregulated by insulin, glucagon, and
other hormonesthat control its release from the liver or its uptake bythe tissues.Homeostasis does not
occur by chance, but is the resultof organized self-government.
Stress or General Adaptation Syndrome
Stress is the acute reaction of organism in response to stressors. It is an adaptive mechanism
and acute defense reaction.
Stress is based on neuro-endocrine and metabolic changes.

The term stress was first employed in a biological context by the endocrinologistHans Selye
in the 1930s.He later broadened and popularized the concept to include inadequate
physiological response to any demand. In his usage stress refers to a condition and stressor
to the stimulus causing it. It covers a wide range of phenomena, from mild irritation to
drastic dysfunction that may cause severe health breakdown.

General Adaptation Syndrome

Body reacts to a stressor, real or imagined a stimulus that causes stress. Acute stressors
affect an organism in the short term; chronic stressors over the longer term.

Hans Selye identified three structural changes in rats subjected repeatedly to noxious stimuli
(stressors):
1. Enlargement of the cortex of the adrenal gland.
2. Atrophy of the thymus gland and other lymphoid tissues.
3. Gastric ulceration.

H. Selye believed that the three changes were caused by nonspecific physiologic response to
any long-term stressor.
He called this response the general adaptation syndrome GAS.
The GAS occurs in three stages:
1. The alarm stage.
2. The stage of resistance or adaptation
3. Stage of exhaustion

Alarm stage - Alarm is the first stage. When the threat or stressor is identified or
realized, the body's stress response is a state of alarm - the central nervous system is
aroused and the body's defenses are mobilized. This is the “ Fight or Flight” response
that prepares the body for immediate action During this stage, adrenaline will be
produced There is also activation of the HPA axis, producing cortisol.
Resistance is the second stage. If the source persists, the body prepares for long-term
protection, secreting hormones to increase blood sugar levels for coping with the
stress. Although the body begins to try to adapt to the strains or demands of the
environment, the body cannot keep this up indefinitely, so its resources are gradually
depleted.
 Stage of Exhaustion is characterized by the progressive breakdown of compensatory
mechanisms as a result of continuous stress.the body experiences ‘ adrenal
exhaustion’ leading to decreased stress tolerance, progressive mental and physical
exhaustion, illness and collapse.The initial autonomic nervous system symptoms may
reappear (sweating, raised heart rate, etc.). If stage three is extended, long-term
damage may result, as the body's immune system becomes exhausted, and bodily
functions become impaired, resulting in decompensation.The result can manifest
itself in obvious illnesses such as ulcers, depression, diabetes, trouble with the
digestive system, or even cardiovascular problems, along with other mental illnesses.

So, the stress response involves the nervous system (sympathetic branch of the autonomic
nervous system), the endocrine system (pituitary and adrenal glands), and the immune
system.
The neuro-endocrine response to stress consists of sympathetic stimulation of the adrenal
medulla to secrete catecholamines (Norepinephrine and epinephrine) and stressor-induced
stimulation of the pituitary to secrete ACTH, which in turn, stimulates the adrenal cortex to
secrete steroid hormones, particularly cortisol.
In general, the catecholamines prepare the body to act, and cortisol mobilizes energy
(glucose) and other substances needed to fuel the action.
Epinephrine exerts its chief effects on the cardiovascular system.
Epinephrine increases cardiac output and increases blood flow to the:
- Heart
- Brain
- Skeletal muscles by dilating vessels that supply these organs (by stimulation of B
adrenoreceptors).
It also dilates the airways, thereby increasing delivery of oxygen to the bloodstream.

Norepinephrine's chief effects complement those of epinephrine.

Norepinephrine constricts blood vessels of the viscera and skin; this has the effect of shifting
blood flow to the vessels dilated by epinephrine.
Norepinephrine also increases mental alertness.

 Stress (neurogenic response to stressor)

 Afferental impulsation stimulates Hypothalamus
 Hypothalamus Stimulates sympathetic neural system - sends messenges to adrenal
gland medullar layer for adrenalin and noradrenalin secretion potentiation
 Catecholamines act on visceral organs
 Visceral organs adapt to stressor
 Adrenalin together with noradrenalin serve to blood circulation centralization
 They cause skin, digestive micro vessels constriction in order to direct blood to
central neural system, heart, lungs
 They increase blood pressure

The Sympathetic Nervous System - SNS system confers an adaptive advantage during a stressful
situation. The SNS manifestation of the stress reaction has been called the fight-or-
flightresponse.This reaction is the most rapid of the stress responses and represents the basic
survival response. The increase in SNS activity in the brain increases attention and arousal, and thus
probably intensifies memory. Increased SNS arousal also results in heart and respiratory rate
increases, moist hands and feet, dilated pupils, dry mouth, and reduced activity of the
gastrointestinal tract.

Epinephrine and norepinephrine plasma levels increase:

 cardiac output
 blood pressure
 ventilation
 blood glucose
 mental alertness

 Stress (endocrine response to stressor)

 Afferental impulsation stimulates Hypothalamus center
 Hypothalamus excrets Releasing factors
  Releasing factors stimulation ACTH (adrenocorticotrophic hormone) excretion by
Hypophysis
 ACTH enhances Corticoids excretion by adrenal gland cortex layer
 Corticoids enhance gluconeogenesis for providing energy supply for coping with
stressor

Corticotropin-Releasing Factor. CRF is central to the endocrine component of the neuroendocrine

response
to stress, and it is the principal regulator of the HPA axis. Corticotropin-releasing factor, also
known as corticotropin-releasing hormone, is a small peptide hormone found in both the
hypothalamus and extrahypothalamic structures, such as the limbic system and brain stem. It is both
an important endocrine regulator of pituitary and adrenal activity, as well as a neurotransmitter
involved in ANS activity, metabolism, and behavior. In response to stressors, CRF is released into
the hypophysial portal vessels that enter the anterior pituitary gland. Receptors for CRF are
distributed throughout the brain as well as many peripheral sites. Corticotropin-releasing factor from
the hypothalamus binds to corticotropes, inducing secretion of adrenocorticotropic hormone
(ACTH) from the anterior pituitary gland into the systemic circulation. Adrenocorticotropic
hormone, in turn, stimulates theadrenal gland to synthesize and secrete glucocorticoid hormones
(e.g., cortisol).
Cortisol is the primary glucocorticoid in humans, representing a major subclass of steroid hormones
that regulate metabolic, cardiovascular, immune, and behavioral responses. A glucocorticoid
negative feedback system exists, whereby the HPA axis is subject to feedback inhibition from
circulating glucocorticoids. These glucocorticoids have a number of direct or indirect physiologic
effects that mediate the stress response, enhance the action of other stress hormones, or suppress
other components of the stress system. In this regard, cortisol acts not only as a mediator of the
stress response but also as an inhibitor so that overactivation of the stress response does not
occur.Cortisol maintains blood glucose levels and enhances theeffect of catecholamines on the
cardiovascular system. Blood glucose levels are elevated rapidly, in part by mobilization of glucose
stores and by inhibition of further storage through the antagonizing effects of insulin.Cortisol also
suppresses osteoblast activity, hematopoiesis, protein and collagen synthesis, and immune
responses. All of thesefunctions are meant to protect the organism against the effects of a stressor
and to focus energy on regaining balance in the face of an acute challenge to homeostasis.

Cortisol's chief effects involve metabolic processes. By inhibiting the use of metabolic substances
while promoting their formation, cortisol mobilizes glucose, amino acids, lipids and fatty acids, and
delivers them to the bloodstream.
Cortisol increases:
  liver protein synthesis
 blood sugar
 myocardial performance
 humoral immunity
 circulated leucocytes (PMNs)
Cortisol decreases:
 Muscle and lymphoid tissue synthesis (catabolizes muscle)
 inflammatory response
 cellular immunity
 fibroblasts (delays healing)

Determinants of stress response gravity are following:

1. Stressors power
2. Duration of exposure to stressors (acute time-limiting, Event-sequencing,Chronic
intermittent, Chronic sustained)
3. External and internal factors
4. Personality
5. Behavior pattern
6. Autonomic nervous system reactivity or lability
7. Social support system

 Acute phase reactions

 They are organism’s general, non specific, adaptive reactions
 During this reactions interleukin 1 synthesis is stimulated (macrophagues,
neutrofiles)
 Interleukin 1 causes acute phase globulin synthesis in liver and its transfer in blood
 Such proteins are: C reactive protein, haptoglobin, complement, ceruloplasmin,
fibrinogen, etc.
 Acute Phase Proteins
 IL 1 strengthens Neutrophil synthesis (neutrophilia)
 IL 1 activates T- and B limphocytes
 IL -1 is an endogenic Pyrogen that activates thermoregulation center in
Hypothalamus
 In the muscles protein catabolism is strengthened, created aminoacids are used for
acute phase protein synthesis and gluconeogenesis in Liver
 The liver responds by producing a large number of acute-phase reactants. At the same
time, the production of a number of other proteins is reduced; these are, therefore,
referred to as "negative" acute-phase reactants
 Possitive Acute Phase Proteins
 o C reactive Proteins destroy or inhibit growth of microbes, activate
complement, strengthen phagocytosis, sometimes inflammation.
 Haptoglobin – glycoprotein interacts with hemoglobin (after hemolysis). After its
phagocytosis, FE is released, that is transferred by blood transferrin to bone marrow.
 Ceruloplasmin decreases free radical oxidation
 Negative Acute Phase Proteins
"Negative" acute-phase proteins decrease in inflammation. Examples include
albumin, transferrin. The decrease of such proteins may be used as markers of
inflammation. The physiological role of decreased synthesis of such proteins is
generally to save amino acids for producing "positive" acute-phase proteins more
efficiently

Heat shock proteins

 Stress (thermal shock) globulins HSP globulins
 Under stress HSPs are found in every cell, in virtually all living organisms, from
bacteria to humans.
 They were called “heat shock” because they were first found in drosophila (fly) at
thermal factor influence on it.
 Lately it was found that such proteins are synthesized not only during thermal but
also during alcohol, toxic, ischemia, oxidants and etc. influence
 They are of high importance in cell physiology, cell, tissue, organ and whole
organism protection
 Production of high levels of heat shock proteins can also be triggered by exposure
to different kinds of environmental stress conditions, such as infection,
inflammation, exercise, exposure of the cell to toxins (ethanol, arsenic, trace
metals and ultraviolet light, among many others), starvation, hypoxia (oxygen
deprivation), nitrogen deficiency (in plants), or water deprivation.
 investigators recognized that many HSPs function as molecular chaperones and
thus play a critical role in protein folding, intracellular trafficking of proteins, and
coping with proteins denatured by heat and other stresses
They differ constitutional and inductive stress globulins
 We meet constitutional globulins during physiological conditions in little
concentrations (in high concentrations during pathology)
 Inductive stress globulins appear only during stress
 HSF factor interacts with HSE, as a result HSP globulin is created
 HSF – Heat shock factor is a monomer that exists in the cytoplasm. The stressor
activates HSF deriving it into trimer, that is brought to nucleus
 In the nucleus activated HSF interacts with special gene fragment HSE – heat shock
element, causes HSP gene transcription and initiates HSP synthesis
Heat shock proteins (HSP) are a class of functionally related proteins involved in the folding
and unfolding of other proteins. Their expression is increased when cells are exposed to
elevated temperatures or other stress. This increase in expression is transcriptionally
regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat
shock response and is induced primarily by heat shock factor (HSF). HSPs are found in
virtually all living organisms, from bacteria to humans.

Increased synthesis of selected proteins in Drosophila cells following stresses such as heat
shock was first reported in 1974.Beginning in the mid-1980s, investigators recognized that
many HSPs function as molecular chaperones and thus play a critical role in protein folding,
intracellular trafficking of proteins, and coping with proteins denatured by heat and other
stresses. Accordingly, the study of stress proteins has undergone explosive growth.

Production of high levels of heat shock proteins can also be triggered by exposure to
different kinds of environmental stress conditions, such as infection, inflammation, exercise,
exposure of the cell to toxins (ethanol, arsenic, trace metals and ultraviolet light, among
many others), starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants), or
water deprivation.

Role as chaperone

Heat shock proteins function as intra-cellular chaperones for other proteins. They play an
important role in protein-protein interactions such as folding and assisting in the
establishment of proper protein conformation (shape) and prevention of unwanted protein
aggregation. By helping to stabilize partially unfolded proteins, HSPs aid in transporting
proteins across membranes within the cell.

Acute-phase proteins are a class of proteins whose plasma concentrations increase (positive
acute-phase proteins) or decrease (negative acute-phase proteins) in response to
inflammation. This response is called the acute-phase reaction (also called acute-phase
response).

In response to injury, local inflammatory cells (neutrophil granulocytes and macrophages)

secrete a number of cytokines into the bloodstream, most notable of which are the
interleukinsIL-1, IL-6 and IL-8, and TNF-α.

The liver responds by producing a large number of acute-phase reactants. At the same time,
the production of a number of other proteins is reduced; these are, therefore, referred to as
"negative" acute-phase reactants. As such, increased acute phase proteins from the liver may
also contribute to the promotion of sepsis.
Positive acute-phase proteins serve different physiological functions for the immune
system. Some act to destroy or inhibit growth of microbes, e.g., C-reactive protein,
complement factors, ferritin, ceruloplasmin, Serum amyloid A and haptoglobin. Others
give negative feedback on the inflammatory response, e.g. serpins. Alpha 2-
macroglobulin and coagulation factors affect coagulation, mainly stimulating it. This
pro-coagulant effect may limit infection by trapping pathogens in local blood clots. Also,
some products of the coagulation system can contribute to the innate immune system by
their ability to increase vascular permeability and act as chemotactic agents for
phagocytic cells.

Proteolytic system activation

 Role of kinin-kallikrein system
The kinin-kallikrein system or simply kinin system is a poorly understood system of
bloodproteins that plays a role in
 inflammation,
 blood pressure control,
 coagulation and
 pain.
 The system consists of a number of large proteins, some small polypeptides and a group
of enzymes that activate and deactivate the compounds
 High-molecular weight kininogen (HMWK) (LIVER) and low-molecular weight
kininogen (LMWK) (numerous tissues) are precursors of the polypeptides. They have no
activity of themselves.
 Activation of kinin-kallikreinsystem causes synthesis of neurovasoactive polypeptides –
Kinins. Immensely important of them are mediators polypeptide bradykinin and kallidin.
They are vasodilators and act on many cell types.
 Bradykinin (BK), which acts mainly on the B2 receptor when kallikrein releases it
from HMWK. It is a nonapeptide.
 Kallidin (KD) is released from LMWK by tissue kallikrein. It is a decapeptide.
 Kallikreins (tissue and plasma kallikrein) are serine proteases that liberate kinins (BK
and KD) from the kininogens Prekallikrein is the precursor of plasma kallikrein. It
can only activate kinins after being activated itself by factor XIIa or other stimuli.

The kinin-kallikrein system or simply kinin system is a poorly understood system of

bloodproteins that plays a role in inflammation, blood pressure control, coagulation and
pain. Its important mediatorsbradykinin and kallidin are vasodilators and act on many cell
types.The system consists of a number of large proteins, some small polypeptides and a
group of enzymes that activate and deactivate the compounds.
Proteins
High-molecular weight kininogen (HMWK) and low-molecular weight kininogen (LMWK)
are precursors of the polypeptides. They have no activity of themselves.
 HMWK is produced by the liver together with prekallikrein. It acts mainly as a cofactor
on coagulation and inflammation, and has no intrinsic catalytic activity.
 LMWK is produced locally by numerous tissues, and secreted together with tissue
kallikrein.
Polypeptides
 Bradykinin (BK) is produced when kallikrein releases it from HMWK. It is a
nonapeptide.
 Kallidin (KD) is released from LMWK by tissue kallikrein. It is a decapeptide.
Enzymes
 Kallikreins (tissue and plasma kallikrein) are serine proteases that liberate kinins (BK
and KD) from the kininogens, which are plasma proteins that are converted into
vasoactive peptides.Prekallikrein is the precursor of plasma kallikrein. It can only
activate kinins after being activated itself by factor XIIa or other stimuli.