2.

BODY TEMPERATURE DISORDERS

The aim of thermoregulation is to maintain the body core temperature at the set level of about
37oC, with diurnal variations (a maximum of 37.20C at 6 A.M. and of 37.70C at 4-6 P.M).
Body temperature is closely regulated, because temperature changes can significantly affect
cellular functions.
The thermoregulatory centre is the “hypothalamic thermostat”: the preoptic anterior
hypothalamus area and the posterior hypothalamus area. Neurons from both areas receive two
kinds of afferent signals: from peripheral (skin) and central (core) thermal receptors. Than body
temperature is regulated through two parallel efferent processes: behavioural voluntary
(clothing, shelter, physical activity) and physiologic involuntary (skin blood flow, sweating,
shivering) responses. Any deviation between the controlled variable (body temperature) and a
reference variable (“temperature set point” - Tsp) results in heat loss or conservation and
production responses:
- Heat loss is achieved by physical mechanisms on the skin surface (radiation,
evaporation, conduction and convection) and by respiration.
- Heat conservation is ensured by peripheral vasoconstriction (decreases the blood flow),
piloerection and body insulation (skin, subcutaneous tissue, fat, behavioral responses).
- Heat production in the immediate defence of thermoneutrality occurs via the autonomic
nervous system, whereas the delayed control is ensured by the endocrine system.
Autonomic nervous system responses include the release of norepinephrine, increased
muscle tone and shivering. Prolonged exposure to cold causes thyrotropin releasing
hormone (TRH) secretion, thyroid stimulating hormone (TSH) release and an increase in
the basal metabolism.
In a neutral environment, heat production is higher than needed to maintain the core
temperature at 370C. Therefore, the body temperature is controlled by heat loss.
!!! Body temperature depends on site of measurement.
Arterial blood temperature provides the “best” invasive measurement of core temperature. The most accurate
noninvasive index of core temperature is esophageal temperature, followed in preference by rectal,
gastrointestinal tract (telemetry pill), and oral temperature (rectal usually about 1 oF higher than oral). Ear
(tympanic and auditory meatus) temperature should not be relied on for clinical judgment.

There are some things that affect temperature measurements:

- drinking ice in water: transient drop (less than 10 min, avg 0.5oF)
- chewing gum: sustained elevation (approx.20 min, avg 0.3 oF)
- cigarette smoking: sustained elevation (more than 30 min, avg 0.2 oF)
- physical exercise
- physiological conditions:
o In women who menstruate the A.M. temperature rises before ovulation and
remains at that level until menses occur.
o Pregnancy also influence the body temperature.
o Seasonal variations in body temperature may reflect metabolic changes.
Body temperature can increase from:
 impeded heat loss
 increased heat production
 elevated thermoregulatory set point.

2.1.FEVER

Systemic inflammation is accompanied by changes in body temperature (bT), either fever or

hypothermia. Fever use to be defined as an increase in body temperature occurring due to an
1
increase in the temperature set point (Tsp), whereas anapyrexia (regulated hypothermia,
cryexia) was defined as a decrease in body temperature due to a decrease in the temperature
set point.
Fever-inducing substances are called pyrogens. Exogenous pyrogens are components of
pathogens, among which the lipopolysaccharide complexes (endotoxins) of gram-negative
bacteria are particularly effective. Endogenous pyrogens are proinflammatory cytokines, most
importantly IL-1beta, IL-6, and TNF-alpha, and several mediators other than cytokines
(circulating PGE2, anaphylatoxic component 5a of the complement cascade, and platelet-
activating factor).
Over the last decade, a large family of mammalian receptors termed Toll-like receptors (TLR)
have been discovered and identified as receptors for LPS and other microbial pyrogens, by
which peripheral proinflammatory molecules, most notably cytokines (such as interleukin-1, IL-
1), have been proposed to reach the brain.

Classification of febrile diseases

Febrile diseases are classified according to their duration into three main groups:
1. fever of short duration (< 2 weeks)
2. prolonged fever (> 2 weeks)
3. fever of unknown origin (FUO) (at least 2-3 weeks > 38.3 C o) (e.g. infections,
neoplasm, connective tissue disease, granulomatous disease, psychogenic disorders).

FEVER PATHOPHYSIOLOGY
Four major mechanisms by which peripheral proinflammatory molecules signal the brain have
been proposed:
1) Saturable transendothelial transport: circulating cytokines can cross the blood-brain
barrier (BBB) by carrier transport; in addition it has been proposed that cytokines can reach
brain tissue by diffusion through basal laminae.
2) Entry though the organum vasculosum of the lamina terminalis (OVLT) and possibly
other circumventricular organs: cytokines enter the brain through the circumventricular organs,
primarily the OVLT, in which capillaries are fenestrated resulting in a “leaky” BBB.
3) Signal transduction by sensory nerves, primarily the vagus: febrigenic chemical signals
(possibly including IL-1 and PGE2) originate in the liver and bind to the appropriate receptors
on the hepatic vagus, triggering the febrile response to very low, near threshold doses of a
pyrogen.
4) PG synthesis in cells that form the BBB: LPS, IL-1beta, or TNF-alpha has been shown to
rapidly induce expression of PGE2-synthesizing enzymes in the vascular endothelium and
perivascular cells throughout the brain, and PGE2 produced by these cells can freely reach
neurons of thermoeffector circuits to trigger fever.

!!! It has been known for some time that enzymes synthesizing pyrogenic PGE2 may also be involved in production
of mediators causing hypothermia in systemic inflammation: PGD2 and 15-deoxy-delta12-14 PGJ2 (a metabolite
of PGD2).

Both cold-defence and heat-defence responses are initiated by the corresponding change in the
activity of warm-sensitive neurons. The neuronal circuits connecting the warm-sensitive
hypothalamic neurons and thermoeffectors, most notably the vasculature of specialized heat-
exchange organs and the brown adipose tissue, are controlled relatively independently of each
other.
Inflammatory signalling and thermo-effectors pathways involved in fever and hypothermia are
modulated by peptide hormones and neuropeptides. For example:
o Leptin activates thermogenesis

2
 o Orexin (hyposecretins) A has been found to cause immediate hypothermia and
hyperphagia followed by late hyperthermia and hypophagia, and orexin B produces
hyperthermia only and does not lead to hyperphagia
o Brain corticotropin-releasing factor (CRF) may be involved in both body temperature
increasing (pyretic mechanism may be CRF-mediated activation of paraventricular
hypothalamic neurons) and decreasing (antipyretic mechanism may be CRF-mediated
activation of the anti-inflammatory hypothalamo-pituitary-adrenal axis) mechanisms
during fever.

FEVER STAGES
Fever response progresses though three stages.
1. Fever onset (cold stage)
Pyrogens cause Tsp increase (bT < Tsp). The rise of the hypothalamic set level causes
the activation of the neurons from the vasomotor centres inducing peripheral vasoconstriction.
Shunting away the blood from the peripheral area, will decrease heat loss through the skin,
resulting in cooling of the skin. Prolonged vasoconstriction may be harmful by decreasing
organs perfusion and increasing heart load. Additional heat production will rise by shivering and
by increasing liver metabolism. By these mechanisms metabolic acidosis may associate, and in
severe chronic diseases may cause organs failure. In humans, behavioural responses will also
help raise the body temperature. All these responses last until the actual bT level has approached
the new Tsp level.
2. Fever state (hot stage)
bT reaches Tsp. After the new Tsp is reached, as long as pyrogens act on thermoregulatory
centre the temperature is maintained at that level by the normal mechanisms of heat
balance. The actual level of bT matches the new Tsp and there is new temperature
equilibrium at the raised Tsp, so that shivering stops and vasoconstriction ceases.
Prolonged fever, due to an increased heat production, may cause energy deficiency,
metabolic acidosis, fluid and electrolytes loss.
3. Fever deffervescence (sweating stage)
Pyrogens are removed and the hypothalamic Tsp is reset downwards (bT > Tsp), and the
process of heat loss through vasodilatation and sweating is activated. These responses continue
until the blood temperature at the hypothalamic level matches the normal Tsp. Prolonged fever
may decrease heart preload and cause severe fluid electrolyte misbalances.
When fever is resolved bT = Tsp again.

FEVER BENEFITS
The raised bT inhibits the replication of some pathogens while killing others. Moreover, the
plasma concentration of essential metals (iron, zinc and copper) is reduced, blocking pathogen
multiplication. Furthermore, cells damaged by viruses are destroyed and so viral replication is
stopped. Due to these mechanisms, antipyretics should be used only when the harmful side
effects are significant.

FEVER HARMFUL EFFECTS

Fever increases the heart workload (O2 consumption increases by 13%/10C), energy and fluid
requirements, and protein catabolism (skeletal muscle, bone proteins). The clinical results are
fatigue, joint pain and headaches, increase in slow-wave sleep, as well as disturbances of
consciousness and senses (fever delirium), even seizures in certain circumstances.
A fever of more than 41.50C is called hyperpyrexia. It can develop in patients with very severe
infections or in those with cerebral hemorrhage.
Another particular case is the hypothalamic fever, when Tsp rises as a result of local
pathological processes (hemorrhage, tumor, trauma, intrinsic malfunction). These patients have

3
an abnormal response to cold conditions (their bT falls quickly than normal) and an absence of
temperature circadian and hormonal rhythms.

2.2. HYPERTHERMIA

When the thermoregulatory mechanisms are overwhelmed, hyperthermia develops. It is an

uncontrolled increase in the body temperature that exceeds the heat loss mechanisms,
the hypothalamic set point being unchanged.
Malignant hyperthermia is a genetic abnormality of the skeletal muscles, a defect of the
sarcoplasmic transport. Due to that, some inhalation anesthetics (halothane, enflurane,
isoflurane) and depolarizing muscle relaxants (suxamethonium chloride) cause sudden and
excessive Ca2+ release from the sarcolpasmic reticulum. The consequence is generalized and
uncoordinated muscle twitches with muscle hypermetabolism (increased ATP consumption) and
heat production. The development of generalized skeletal muscle rigidity indicates that the
muscle can no longer produce ATP. These will lead to increased carbon dioxide production and
respiratory acidosis along with lactic acid, with subsequent vasodilatation and drop in blood
pressure. The depletion of ATP stores results in disruption of the skeletal muscle cellular
membranes too, allowing potassium, calcium, creatine kinase and myoglobin to leak into the
extracellular fluid space. The secondary systemic manifestations are the cardiac arrhythmias,
disseminated intravascular coagulation and renal failure. Death can result from cardiac arrest,
brain damage, internal hemorrhages or failure of other body systems.
Febrile persons may develop hyperthermia when exposed to high ambient temperature or
physical exercise, or both because there is a lower adaptation possibility (new Tsp closer
to the higher bT limit).
Other hyperthermias:
 Endocrine hyperthermia is caused by an increased heat production (thyrotoxicosis,
pheochromocytoma)
 Neuroleptic malignant hyperthermia is induced by the inhibition of the central
hypothalamic dopamine receptors by neuroleptic medications (e.g., antipsychotics,
antidepressants, antiemetics). The result is muscle rigidity, autonomic disturbances and
hyperthermia.
 Drug-induced hyperthermia can be the result of the use of certain psychotropic drugs:
amphetamines, monoamine oxidase inhibitors, cocaine, LSD, etc.
 Therapeutic Hyperthermia
•Regional hyperthermia: a traditional unproved therapy for many musculoskeletal
diseases, nasal hyperthermia for viral nasopharyngitis
•Whole-body hyperthermia: the adjunctive therapy of cancers by increasing of bT to
up to 42.4 °C.

2.3. HYPOTHERMIA

Hypothermia describes a state in which the body’s mechanism for temperature regulation is
overwhelmed in the face of a cold stressor. Hypothermia is classified as accidental or
intentional, primary or secondary, and by the degree of hypothermia.
Accidental hypothermia generally results from unanticipated exposure in an inadequately
prepared person; examples include inadequate shelter for a homeless person, someone caught in
a winter storm or motor vehicle accident, or an outdoor sport enthusiast caught off guard by the
elements. Intentional hypothermia is an induced state generally directed as neuroprotection
after an at-risk situation.
Primary hypothermia is due to environmental exposure, with no underlying medical condition
causing disruption of temperature regulation. Secondary hypothermia is low body temperature
resulting from a medical illness lowering the temperature set-point.
4
Systemic hypothermia may also be accompanied by localized cold injury (e.g. Frostbite).

RISK FACTORS FOR HYPOTHERMIA

 extreme age (the elderly have a restricted thermoregulatory range; new-born babies
have a relatively big body surface to mass ratio, low heat production and thin
subcutaneous fat layer)
 homeless individuals
 ethanol use
 malnutrition, poverty
 mental illness, neuroleptic drugs
 hypothyroidism.

CAUSES OF HYPOTHERMIA
 increased heat loss
 extreme environmental conditions (immersion in cold water - 5-10oC, wet clothing
in windy weather)
 iatrogenic (e.g., uncovered patients)
 enhanced blood flow to the skin (burns, psoriasis) and low heat conservation.
 decreased heat production
 malnutrition (low glycogen and fat storage)
 hypothyroidism
 liver failure (low gluconeogenesis and altered hypothalamic function =
encephalopathy)
 diabetic ketoacidosis
 spinal cord lesions (at T1 or above will block shivering response)
 episodic spontaneous hypothermia (hyperhidrosis and the absence of shivering due to
agenesis of corpus callosum).
 Impaired thermoregulation
o failure of the hypothalamus thermoregulatory centers to regulate core body temperature
(e.g. CNS trauma, strokes, toxicologic and metabolic derangements, intracranial
bleeding, Parkinson disease, CNS tumors, Wernicke disease, multiple sclerosis)
 Miscellaneous causes: sepsis, multiple trauma, pancreatitis, prolonged cardiac
arrest, uremia.
 Related to drug administration
 drugs (e.g. beta-blockers, barbiturates, opiates, benzodiazepines = inhibit shivering
through a central effect)
 ethanol (inhibits shivering, impairs hepatic gluconeogenesis, induces peripheral
vasodilatation).

ACUTE HYPOTHERMIA STAGES PATHOPHYSIOLOGY

Acute hypothermia can be divided into three stages:
1. 350C - 320C = mild hypothermia or stage of excitement
In this stage there is maximal muscle tremor resulting in a marked increase in resting
metabolic rate, all sources of glucose are used (hyperglycemia), and oxygen consumption
increases up to six times the normal value (hypoxia). Tachycardia and vasoconstriction cause a
rise in the blood pressure. Acral vasoconstriction causes pain. The person is first fully awake,
later confused and even apathetic and eventually judgement becomes impaired.
2. 320C - 290C = moderate hypothermia or stage of exhaustion
The sources of glucose become exhausted (hypoglycemia). Bradycardia, arrhythmia
with low blood pressure and depressed breathing with hypoxia and respiratory acidosis occur.

5
Due to blood, glucose and oxygen supply deficiency to the CNS the person begins to have
hallucinations and to behave surprisingly, and then loses consciousness and no longer feels pain.
3. Under 290C = severe hypothermia or stage of paralysis
In this stage coma develops, there are no papillary reflexes; ventricular fibrillation, asystole
and apnea follow.
The lower the temperature, the longer the brain can tolerate circulatory arrest (e.g., at
30 C, 10-15 minute; at 180C, 60-90 minute). This is why some persons have survived extreme
0

hypothermia and why low temperature is used in induced therapeutic hypothermia (during open
heart surgery, organ preservation for transplantation).

HYPOTHERMIA EFFECTS
Hypothermia effects are related to the cell injury.
Cardiovascular system:
 Acute exposure causes a sympathetic stimulation resulting in tachycardia, increased
cardiac output, peripheral vasoconstriction;
 Below 32oC, cardiac output and heart rate decrease, atria fibrillation is common, J waves
 Below 28 oC, ventricular fibrillation may occur.
Kidneys:
 Due to peripheral vasoconstriction and lower intravascular volume, cold diuresis occurs
in a compensatory fashion.
 Impaired function of the epithelial transport causes water and sodium loss due to the low
resorption by kidneys.
Water and electrolyte depletion will cause:
 water migration in the interstitial (edema) and intracellular (cell overhydration) areas
 hypotension
 hemoconcentration, which increases the risk of thrombosis.
Hemostasis:
 low temperature makes the clotting factors inefficient, resulting in disseminated
intravascular coagulation (DIC)
 hypothermia causes thrombocytopenia.
Acid-base balance:
 Decreased perfusion will increase lactic acid
 Acidosis will cause hypokalemia (! If cell injury is severe there is hyperkalemia).
Respiratory system:
 Cold exposure induces bronchorrhea and bronchospasm
 Early tachypnea is followed by hypoventilation
 Decrease of the CNS function causes loss of cough reflex and pulmonary edema may
occur
 Shift of oxygen dissociation curve of hemoglobin to the left impairs oxygen delivery to
hypothermic tissues with severe hypoxia.
Nervous system:
 Cerebral blood flow decreases and nerve conduction velocity slows down as the
neuronal metabolism decreases  dysarthria, amnesia, hallucinations, confusion, slow
pupil reflexes, delayed deep tendon reflexes, paradoxical undressing, coma
 enhanced secretion of hypothalamic releasing hormones by acute cold exposure,
followed by inhibition of ACTH and steroid hormones in severe hypothermia
 !!! isoelectric EEG is not indicative of brain death and may be reversible.
Digestive tract:
 intestinal hypomotility
 decreased liver metabolism
6
  acute pancreatitis (50%) and insulin inhibition with hyperglycemia.

Re-warming of hypothermic patients should be attempted even if the core temperature is below
20oC. However, it may be associated with lethal complications (especially if it is done externally
and rapidly - more quickly than a few degrees C per hour) like to multiple organ failure, DIC,
hyperkalemia.
!!! In stage one, re-warming is done passively and externally. In stage two, active
warming must be done (warm infusions, electric blankets, hemodialysis with heat
exchanger) under careful monitoring. In stage three, extracorporeal circulation is the
most effective method of re-warming.

Long-term sequelae of successfully treated hypothermia include heart failure, myocardial

infarction, liver and kidney failure, abnormal erythropoiesis, pancreatitis and neurological
disorders.

INDUCED HYPOTHERMIA
In therapeutic hypothermia the aims are to reduce cell injury by:
o Reducing cerebral metabolism (approximately 6-8% per 1ºC)
o Reducing excitatory amino acids (glutamate release)
o Stabilization of the blood-brain barrier
o Attenuation of oxygen free radical production and lipid peroxidation
o Restoration of normal intracellular signaling mechanisms (including calcium modulation)
and inhibition of deleterious signaling mechanisms, such as apoptotic signaling
o Restoration of protein synthesis and gene expression
o Inhibition of deleterious inflammatory products (e.g. cytokines, interleukins, arachidonic
acid cascade end products)
o Attenuation of CSF platelet-activating factor (PAF)
o Inhibition of cytoskeletal breakdown.
In the heart, hypothermia may decrease the area of injury, promote epicardial reflow, decrease
myocardial metabolic demand, and preserve intracellular high-energy phosphate stores. In
cardiac surgery induced hypothermia (core temperature < 28 oC) protect the myocardium
and CNS from hypoxia during circulatory arrest induced for the repair of different cardiac
lesions or neurosurgery. Drugs administered preoperatively (i.e. anaesthetics, muscle relaxants)
inhibit the thermoregulatory defence mechanisms of heat production (incr. metabolic rate, incr.
muscle activity, sympathetic activation), and the stages of accidental hypothermia are bypassed,
setting the core temperature below 28 oC.

7
3. INFLAMMATION PATHOPHYSIOLOGY
Inflammation is a reaction of vascularised tissue to an injury (injury at biochemical level). It is the
initial field of battle, is part of a physiological process for repairing damage. Inflammation is considered
a dual process since it combines two functionally different characteristics, one that repairs and another
that produces damage. It is a cascade of changes that continues as long as the tissue injury persists. When
this process is not controlled and inflammation spreads, it loses its repairing function and may even
cause damage.
Due to the genetic determination, the changes have the same chronology in all inflammatory
responses, with individual variations. First it is a local response to cellular injury and than a systemic
response to injury.
Clinically inflammation was characterized by redness, heat, pain, swelling, and often loss of
function. It may progress acutely or chronically.
Causes of acute inflammation are the general causes of cell injury: biological, chemical and physical
factors, trauma, surgery, infection, immune responses, ischemic damage etc., of exogenous or
endogenous origin.

!!! The difference between inflammation and infection is that the first is a defence reaction and the
second represents an invasion of living tissues by pathogenic microorganisms.

In inflammation, under normal circumstances, tightly controlled responses protect against further
injury and clear damaged tissue. So, the benefits of inflammation are:
o Restricts tissue damage to smallest possible area
o Alerts body to treat of tissue injury
o Prepares injured area for healing.
The inflammatory response may also be harmful to host tissues if it is deficient or in excess. In
disease states pathologic inflammation can lead to marked tissue destruction and organ dysfunction.

3.1. ACUTE INFLAMMATION STAGES

Acute inflammation progresses through three stages:

1. Neurologic response
2. Acute vascular response
3. Acute cellular response or immune phase
The neurologic response consists of sympathetic nervous system activation by nociceptors
stimulation with subsequent brief arteriolar vasoconstriction. If excessive, vasoconstriction may
produce ischemia and as a result cellular edema.

!!! Nevertheless, it should be considered that ischemia and cellular edema in this phase are in large part
due to tissue injury.

!!! The injured tissue seems to adopt an ischemic phenotype (hypoxic): injured cells turn to glycolisis to
meet their energetic demands in hypoxia. Hyperglycemia induced by catecholamines, among other
factors, would also favor the selective support of glucose and therefore the “glycolytic switch” in order
to obtain ATP in the injured tissue. In addition to altering cellular energy metabolism, hypoxia leads to
an inhibition of differentiation and maintains the undifferentiated cell state.

2. Acute vascular response consists of:

 Vasodilatation
 Increased permeability
 Increased blood viscosity.
Pain is associated to this stage (see inflammatory pain in pain course).
Vasodilation follows the initial vasoconstriction that reverses 10 to 15 minutes after injury. The
transition from vasoconstriction to vasodilation is mediated by diverse factors, for example endothelial
8
products, and mast-cell-derived factors such as leukotrienes, prostaglandins, and, in particular, histamine.
Vasodilation opens new capillaries and increase local blood flow and intravascular pressure, causing
early transudate into interstitium (vascular permeability still not increased yet!!!). Clinically, these
changes will cause local heat (calor) and redness (rubor). The duration of these responses depends on
how long the stimulus lasts.

!!! Transudate = extravascular fluid with low protein content (specific gravity<1.015), that is an
ultrafiltrate of blood plasma resulting from hydrostatic pressure imbalance across the vascular
endothelium.

Vasodilation would also occur with reperfusion injury (after ischemia from the neurologic
response) which, in turn, causes interstitial edema.

For the increased permeability the following mechanisms have been suggested:
 In the venules endothelial gaps occur rapidly, due to the chemical mediators (e.g. histamine,
bradykinin, leukotrienes, substance P, etc.). These changes are usually reversible and short-lived (15-
30 min), known as the immediate transient response. The mechanism is an endothelial cell
contraction plus intracellular transcytoplasmic channel formation (transcytosis). Only venules are
involved because there is a greater density of receptors for the mediators in that region.
 Cytokines, hypoxia and severe injuries induce a delayed and long-lived response (4-6 hours) of the
endothelial cells stimulating cytoskeletal reorganisation and endothelial cell retraction.
 Other mechanisms that may be involved in the increased vascular permeability are those that cause
direct endothelial cell destruction:
 Direct endothelial cell injury with cell necrosis, known as the immediate sustained response
 Leukocyte-mediated cell injury
 Apoptosis.
Increased vascular permeability leads to the escape of a protein-rich fluid called exudate into the
interstitial space or body cavities.

!!! Exudates = extravascular fluid with high protein content (with specific gravity >1.020), a lot of
cellular debris and blood cells due to the alteration of small blood vessel permeability in the area
of injury.

The protein loss decreases the intravascular osmotic pressure and increases the extravascular osmotic
pressure. Together with the increased hydrostatic pressure, owing to vasodilatation, these changes cause
a marked fluid outflow and accumulation in the extravascular space, called edema. Clinically, it causes
local swelling (tumor) and limited function (functio laesa).
Increased vascular permeability and edema formation will increase intravascular blood cells
concentration (especially the red blood cells) and blood viscosity, proning to stasis and thromby
formation.
A fundamental role of vascular permeability change is to facilitate the delivery of cells and
inflammatory mediators to sites of tissue injury. So, initially edema formation can be protective in a
number of ways:
 Dilution of the injurious agent
 Favouring microorganism killing by the escaped antibodies and complement factors
 Fibrin formation and polymerization ensures a localization and isolation of the
inflammatory process, conditions needed for leukocyte action and for reducing the spread of
inflammation.
 While the progression of the interstitial edema produces progressive distancing of the
epithelial cells from the capillaries, it simultaneously enhances lymphatic circulation
(circulatory switch), which assumes an unusually important role for local cleaning process.
Edema, in the broadest sense, is not purely protective. It may also have harmful effects by:
 obstruction (e.g., laryngeal edema obstructs the upper airways)
 compression (e.g., cerebral edema will raise the intracerebral pressure)
 functional changes (e.g., decreased oxygen diffusion in pneumonia).
9
 3. Acute cellular response or immune phase
The inflammatory cellular response is the delivery of leukocytes to the site of injury. The leukocytes
destroy the offending agent, necrotic tissues and foreign antigens, favouring healing. If the leukocyte
action is not adequate (deficient or increased) or prolonged, it may also induce tissue damage.
The first change in the cellular response is leukocyte extravasion, which is the moving of leukocytes
from the vessel lumen to the interstitial tissue. The process can be divided into the following steps:
 Margination, rolling and adhesion in the vascular lumen.
 Transmigration across the vascular endothelium, called diapedesis.
 Migration in interstitial tissues toward the chemotactic stimulus.

Under normal flow conditions, erythrocytes in the venule are confined to a central axial column and
leukocytes towards the wall of vessels. In early inflammation, the blood flow slows down and more
leukocytes accumulate along the endothelial surface, a process which is called margination. Then, the
white blood cells tumble slowly along the endothelium and adhere transiently, a process which is called
rolling. Finally, the leukocytes rest and adhere firmly, a process called pavementing. After firm
adhesion, transmigration takes place: leukocytes insert pseudopods into the junctions between the
endothelial cells, squeeze through the interendothelial junctions, and eventually cross the basement
membrane and escape into the extravascular space.
The complementary binding of adhesion molecules to the leukocytes and the endothelial cell surface
controls leukocyte adhesion and transmigration. Some chemical mediators (chemoattractants, cytokines,
lactoferrin, etc.) modulate this process by three main mechanisms:
 redistribution of adhesion molecules on the cell surface (e.g., P-selectin is normally
present in the Weibel-Palade bodies of the endothelial cells, and after stimulation with histamine,
thrombin and PDF are redistributed to the cell surface), helping leukocytes to roll.
 induction, synthesis and surface expression of adhesion molecules on endothelial cells
(e.g., E-selectins).
 increased avidity of leukocyte adhesion molecules binding (e.g. integrins), necessary for
the firm adhesion and transmigration.
The central role of certain specific adhesion molecule–ligand pairs has been confirmed in human
diseases. For instance, α4β1 plays a key role in the recruitment of lymphocytes to the central nervous
system in multiple sclerosis, and blocking this interaction suppresses disease activity. Eosinophils also
use the same adhesion receptors to migrate into the lung in allergen-induced asthma.
Beyond an eminent role in hemostasis and thrombosis, platelets are characterized by expert
functions in assisting and modulating inflammatory reactions and immune responses. This is achieved by
the regulated expression of adhesive and immune receptors on the platelet surface and by the release of a
multitude of secretory products including inflammatory mediators and cytokines, which can mediate the
interaction with leukocytes and enhance their recruitment. In addition, platelets are characterized by an
enormous surface area and open canalicular system, which in concert with specialized recognition
receptors may contribute to the engulfment of serum components, antigens, and pathogens. Platelet-
dependent increases in leukocyte adhesion may account for an exacerbation of atherosclerosis, for
disorders of arterial repair processes.
The type of migrating leukocytes depends on the age of the inflammatory process and on the type of
stimulus. In most forms of acute inflammations, neutrophils predominate over the first 6-24 hours, and
are then replaced by monocytes over the following 24-48 hours. Moreover, neutrophils undergo
apoptosis after 24-48 hours whereas monocytes survive longer. According to the type of stimulus,
neutrophils predominate in bacterial infections, lymphocytes may be the first in viral infections, and
eosinophils may be the main cell type in some hypersensitivity reactions.
Leukocytes move in the interstitial tissue toward the injury site is called chemotaxis. It is a
locomotion oriented along a chemical gradient of the chemoattractants. There are two groups of
chemoattractants:
o Exogenous: bacterial products (peptides, lipids)
o Endogenous: components of the complement system (C5a), lipooxygenase pathway
products (LTB4) and cytokines (chemokines).
The chemotactic agents bind to leukocyte specific receptors and activate the leukocyte contractile
mechanism responsible for cell movement. In addition, they activate other leukocyte responses:

10
 o production of arachidonic acid metabolites
o degranulation and secretion of lysosomal enzymes
o activation of the oxidative burst
o modulation of leukocyte adhesion molecules.
Excessive chemotactic factors release increase acute cellular response tissue damage.
The leukocytes accumulated at the inflammatory site try to destroy the inflammatory agent and the
destroyed tissue by phagocytosis. This process progresses in three steps:
1. Recognition and attachment
2. Engulfment
3. Killing/degradation by:
a. oxygen-dependent mechanisms (reactive oxygen metabolites- myeloperoxidase
system, nitric oxide)
b. oxygen-independent mechanisms, through the action of the substances released from
leukocytes granules (cationic proteins – e.g., bactericidal permeability increasing
protein, major basic protein, defensin; lysozyme; lactoferrin; etc.)

Phagocytosis disorders (deficiencies, excesses) cause tissue injury.

3.2. INFLAMMATORY MEDIATORS

The inflammatory mediators control inflammatory responses. They may be exogenous or

endogenous. They are released in waves. In some cases, as with cytokines, these products serve as a
primary communication system between cells, orchestrating subsequent infiltration and activation.
Other molecules, such as reactive oxygen intermediates, act as effectors that directly kill pathogens.
However, damage to normal tissues can be a byproduct of these events.

INITIATION OF THE INFLAMMATORY RESPONSE (FIRST WAVE OF THE INFLAMMATORY

RESPONSE)
When normal tissue encounters an injury, resident cells are stimulated by engagement of pattern
recognition receptors expressed on their cell membranes. This primitive pattern recognition system is
known as innate immunity. The ability to recognize specific foreign molecular structures is encoded in
the host genome and provides intergenerational immunologic memory. Innate immunity leads to rapid
deployment (minutes to hours) of host defences. This rapid response is normally transient, although it
can persist in pathogenic states, can create a hazardous milieu that is toxic to normal cells through
the production of oxygen radicals, nitric oxide, and other reactive intermediaries. These molecules can
damage DNA and harm bystander cells, or even lead to neoplasia.

SECOND WAVE OF THE INFLAMMATORY RESPONSE

Activation of innate immunity quickly leads to the robust influx of inflammatory cells. Resident
cells, such as vascular endothelial cells (ECs), mast cells, dendritic cells, and interstitial fibroblasts,
respond by releasing soluble mediators, including the eicosanoids and pro-inflammatory cytokines.
These mediators amplify the inflammatory response and recruit additional leukocytes. Locally stimulated
cells, along with the newly arrived inflammatory cells, release toxic reactive intermediates of nitrogen
and oxygen as well as a myriad of proteases, principally matrix metalloproteinases (MMPs), serine
proteases, and cysteine proteases. These molecules are designed to help destroy infectious agents and
remove damaged cells, thus clearing the injured site for tissue repair. Although these processes are
carefully balanced and controlled under ordinary circumstances, prolonged stimulation of acute
inflammatory mechanisms can cause severe tissue destruction.

ENDOGENOUS INFLAMMATORY MEDIATORS

The endogenous inflammatory mediators sources are the plasma and the tissues and they may be
grouped into three categories:
 Mediators stored within cells and released on demand
 Activated plasma protein cascades
 Newly synthesized in and released from cells on demand.
Table 1: Chemical mediators of inflammation.
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 GROUP MEDIATOR SOURCE EFECTS
Mediators Histamine Mast cells,
stored basophiles, o Both histamine and serotonine cause vasodilatation and
within platelets increase vascular permeability in the early period of
cells and inflammation. In addition, histamine enhances leukocyte
released on Serotonin Platelets
rolling and firm adhesion, and induces gaps in the
demand endothelial cell lining, enhancing leukocyte
extravasation.
Lysosomal Neutrophils, o Cationic proteins (some attract mononuclear
enzymes macrophages phagocytes, other induce the release of histamine)
o Acid proteases (activated when increase production of
lactic acid due to glycolysis decrease the local pH at 3.0)
o Neutral proteases, like collagenases, elastases, enzymes
that degrade cartilage and basement membranes (are
active at neutral pH and may cause tissue damage; some
may generate chemotactic factors from C5 and produce
kinins).
Activated Kinin system o vasodilatation and increase vascular permeability
plasma o some of the kinins are able to cause pain (bradikinine).
protein Coagulation o Factor Xa increases vascular permeability and
cascades system leukocyte extravasion.
o Thrombin causes increased leukocyte adhesion and
stimulates fibroblast proliferation.
Fibrinolytic o Feeds back to activate more Hageman factor
system o Digests the Hageman factor into particles that tend to
activate prekallikrein (amplification loop in the kinin-
generating system)
o Some Fibrin degradation products are chemotactic for
neutrophils and increase vascular permeability
o Activates C1 to trigger the classical pathway of
complement activation
o Can cleave C3 directly and initiate alternate pathway of
complement activation
Complement o amplify the inflammatory response and mediate tissue
system injury
Newly Prostaglandins All leukocytes, o act both at peripheral sensory neurons and at central sites
synthesised platelets, within the spinal cord and brain to evoke pain and
in and endothelial cells hyperalgesia
released o synergize with bradykinin (BK) and histamine to
from cells enhance vascular permeability and edema
on o PGE2 derived from COX2 mediates a central febrile
demand. response
Leukotrienes All leukocytes
o slow and sustained smooth muscle–contracting abilities.
promote plasma leakage from postcapillary venules,
upregulation of expression of cell surface adhesion
molecules, and bronchoconstriction.
Platelet- All leukocytes, o vasoconstriction (!!!In very low concentrations it
activating endothelial cells induces vasodilatation and increased permeability in
factors venules)
o bronchoconstriction
o increased leukocyte adhesion, aggregation, chemotaxis,
degranulation and oxidative burst
o platelet activation.
Oxygen- All leukocytes o kill pathogens
derived free
radicals

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 Nitric oxide Macrophages o vasodilator
o reduces platelet aggregation and adhesion
o regulates leukocyte recruitment
o antimicrobial activity
Cytokines Lymphocytes, o Pleiotropic effects
macrophages,
endothelial cells

Once activated and released from the cells, many of these mediators are short-lived (decayed,
inactivated, inhibited or scavenged). Most mediators have the potential to cause harmful effects.
Production of lysosomal proteases that degrade the ECM represents a key mechanism of tissue
turnover in inflammation. This process is generally considered detrimental in diseases marked by
overproduction of proteases (e.g., for cartilage in osteoarthritis, for synovium in rheumatoid arthritis,
for alveoli in chronic obstructive lung disease, and for colonic epithelium in inflammatory bowel
disease). Lysosomal enzymes are controlled by antiproteases (e.g., α1-antitrypsin, α2-macroglobulin). A
deficiency of these inhibitors (e.g., α1-antitrypsin deficiency) may lead to sustained action of leukocyte
proteases. High levels of active proteases can directly digest the ECM or activate the pro-enzyme forms
of MMPs.
The plasma-derived mediators are interconnected plasma systems, the interconnections serving the
purpose of positive amplification loops. The disorder of one plasma system affects the others.

Complement plays a critical role in immune regulation. Individuals with genetic or acquired
complement factors deficiencies have increased susceptibility to many diseases, an increased incidence
of infections and autoimmune diseases. For instance:
o C1q deficiency is associated with hypogammaglobulinemia and infections.
o C2 and C4 deficiencies cause disorders similar to SLE due to failure of complement-dependent
mechanism to eliminate immune complexes.
o C3 deficiency causes severe, life-threatening infections (Neisseria meningitis, S. pneumoniae)
because the C5a chemotactic fragment is not generated, and C3b deficiency impairs
opsonization.
o C5 deficiency causes an increased susceptibility to bacterial infections due to impaired
chemotaxis.
o C6, C7 and C8 deficiencies impair complement-mediated lysis and increase the susceptibility to
meningococcal and gonococcal infections.

Deficiencies of the complement inhibitors cause complement mediated disorders. For example:
o Paroxysmal nocturnal hemoglobinuria is a chronic hemolytic anemia caused by recurrent bouts of
complement-induced red blood cell lysis, due to the deficiency of convertase regulators.
o Hereditary angioneurotic edema is caused by the deficiency of C1 inhibitor. This leads to
uncontrolled C1s activity and resulting production of kinin (C1-inhibitor also inhibits proteases of
the fibrinolytic, clotting, and kinin pathways). Kinin increases vascular permeability causing edema.
The skin, gastrointestinal tract, and respiratory tract may be affected by the edema.

Kinins actions are associated with the secondary production of other mediators of inflammation,
including nitric oxide, mast cell–derived products, and the pro-inflammatory cytokines IL-6 and IL-8. In
addition, kinins can increase IL-1α production through initial stimulation of TNF-α, and can increase
prostanoid production through activation of phospholipase A 2 and release of AA. Kinins excess will
cause not just increases vascular permeability than also inflammatory mediators excess.

Prostaglandins production is increased in most inflammatory conditions, including arthritis and

inflammatory bowel disease. COX2 also plays a key role in platelet–endothelial cell interactions by
increasing the production of prostacyclin (PGI 2) in endothelial cells. Increased risk of myocardial
infarction associated with the use of selective COX2 inhibitors might be related to unopposed
production of thromboxane A2 by COX1 in platelets, and increased oxidative stress.
Leukotrienes importance depends on the specific target organ of an inflammatory response. For
instance, leukotriene receptor antagonists have demonstrated efficacy in asthma, whereas similar
approaches have been less impressive in rheumatoid arthritis.
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 Cytokines play a key role in the establishment and perpetuation of inflammatory diseases. In
rheumatoid arthritis, autocrine and paracrine cytokine networks (IL-1, TNF-α, IL-15, IL-17 and IL-
18) play a critical role in the perpetuation of inflammation. In allergic asthma, IL-13 is emerging as a
central inflammatory cytokine. That is why inhibitors of TNF-α are effective therapeutic agents in
inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and IL-1
inhibitors are beneficial in genetic diseases such as Muckle-Wells syndrome and familial cold
autoinflammatory syndrome.

!!! When cells are activated by various stimuli, their membrane lipids are rapidly remodeled to
generate active lipid mediators that serve as intracellular or extracellular signals. Arachidonic acid
(AA) is a fatty acid derived from dietary sources or from the essential fatty linoleic acid, through
activation of phospholipase A2 (PLA2), by mechanical, chemical, physical stimuli or other mediators.
Steroids inhibit PLA2. AA metabolites (eicosanoides) are synthesized by two major classes of
enzymes: cyclooxigenases (COX1 and COX2) and lipooxigenases. Some of these enzymes have
restricted tissue distribution. AA is involved in many biological processes including inflammation.
The cyclooxigenase pathway, blocked by aspirin and indomethacin (NSAID), produces
prostaglandins (PG). The most important ones in inflammation are:
 PGE2 (vasodilator, increases vascular permeability, hyperalgesic)
 TXA2 or thromboxane (potent vasoconstrictor, platelet aggregator)
 PGI2 or prostacyclin (vasodilator, inhibitor of platelet aggregation, potentiates chemotactic and
permeability-increasing effects of other mediators).
Prostaglandins are also involved in the pathogenesis of pain and fever in inflammation.
The lipooxigenase pathway can occur in neutrophils, platelets and mast cells. It produces a variety of
compounds, the most important of which are LT (leukotrienes):
 LTB4 is chemotactic
 LTC4, LTD4, LTE4 produce slow and sustained contraction of the smooth muscle (as opposed to
histamine).
Cell-cell interactions are important in the biosynthesis of LT. AA products can pass from one cell type
to another, and so different cell types can cooperate to generate eicosanoids (transcellular
biosynthesis). For example, lipoxins A4 and B4 (LXA4, LXB4) are generated by the action of a
platelet lipooxygenase on neutrophil LTA4. Lipoxins have proinflammatory and antiinflammatory
effects: e.g., they inhibit neutrophil chemotaxis and adhesion, stimulate monocyte adhesion, attenuate
the vasoconstrictor effect of LTC4, and stimulate vasodilatation.

!!! The «self-inflammatory syndrome» or autoinflammatory syndrome gathers diseases all

characterized by a recurrent inflammatory syndrome with fever, in the absence of infection or
neoplasia. It is based on a genetic support characterized by mutations in genes implied in the
inflammatory response and in the activation of the cytokine network. The diseases associated
with this syndrome are familial Mediterranean fever (FMF), TRAPS (tumor necrosis factor
receptor super family 1 A-associated periodic syndrome), familial cold urticaria, the Muckle-
Wells syndrome, the hyper IgD syndrome and CINCA. The clinical symptoms of all these
diseases included in the auto-inflammatory syndrome are quite similar: recurrent attacks, with
fever, articular, abdominal, cutaneous symptoms, and an inflammatory syndrome.

Macrophages, neutrophils, and other phagocytic cells can generate large amounts of highly toxic
reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) that can directly
kill pathogens. ROIs may combine with NO and form other reactive nitrogen intermediates.
Uncontrolled production of ROIs and RNIs can also lead to tissue damage due to oxidative, nitrosative
or nitrative stress.

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 !!! Nitric oxide synthases (NOS) convert l-arginine and molecular oxygen to l-citrulline and nitric oxide
(NO). There are three known isoforms of NOS: neuronal NOS (ncNOS or NOS1) and endothelial cell
NOS (ecNOS or NOS3) are both constitutively expressed, whereas macrophage NOS (macNOS, iNOS,
or NOS2) is induced by inflammatory cytokines such as TNF-α and IFN-γ. The expression of NOS2 is
suppressed by TGF-β. Products of viruses, bacteria, protozoa, and fungi, as well as low oxygen tension
and low environmental pH, enhance NOS2 gene transcription.

Oxidative stress is caused by an imbalance between the production of reactive oxygen species
(ROS) or reactive nitrogen oxide species (RNOS) and a biological system's ability to readily detoxify it
or easily repair the resulting damage. In humans oxidative stress is involved in many diseases, such as
atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease and chronic
fatigue syndrome
Nitrosative stress occurs when intermediates are produced from nitrosate thiol, hydroxy and amine
groups, resulting in inhibition of enzyme and DNA activity. Nitrosative stress can only occur in the
presence of high localized fluxes of NO (e.g as in inflammation).
Nitrative stress occurs by means of nitration of various biomolecules including proteins, lipids, and
nucleic acids. It has been linked to diseases like bronchial, neurodegenerative disorders, microvascular
degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of
prematurity.
NO excess due to an overproduction of iNOS dangerously reduces leukocyte recruitment, and may
cause inflammatory tissue damage. For example in insulin-dependent diabetes mellitus IL-1 induces
iNOS synthesis and NO mediated pancreatic tissue damage.
NO deficiency enhances microbial replication and may lead to severe infections.
The ability of ROIs or RNIs to serve as critical signal transduction molecules that regulate
expression of inflammatory genes is equally important. The excess production of ROIs or RNIs is one
of the principal factors inducing the expression of the nuclear factor kB (NF-kB). Enhanced NF-kB
activity causes or exacerbates chronic inflammatory diseases as rheumatoid arthritis and others. In
some cases, ROIs can contribute directly to the initiation of chronic disease. Atherosclerosis is an
especially important example.
Together with prostaglandins, the production of NO by NOS2 and ROIs are key mechanisms by
which macrophages paradoxically impair T-cell proliferation in response to mitogens or antigens. This
may serve to control inflammatory processes or to delete autoreactive T cells, but in excess it at least
partially accounts for the immunosuppressed state seen in certain infections, malignancies, and graft-
versus-host reactions.

3.3. PHAGOCYTOSIS DISORDERS

Disorders in phagocytes are quantitative or qualitative, both genetic and acquired. They lead to an
increased susceptibility to infections.

3.3.1. QUANTITATIVE DEFECTS

 Neutropenia or granulocytopenia = the total number of normal circulating cells is suppressed due
to decreased production or increased destruction:
o Causes of decreased neutrophil production
 inherited defective bone marrow development (e.g., reticular dysgenesis)
 administration of bone marrow depressant drugs
 leukemia
 autoantibodies that inhibit granulopoiesis.
o Causes that increase neutrophil destruction
 autoimmune reactions after the administration of certain drugs (e.g. oxacillin,
quinidine) that may induce antibodies capable of opsonizing neutrophils
 hypersplenism = exaggeration of the destructive function of the spleen with resultant
deficiency of peripheral blood cells.
 Asplenia: congenital, surgical, by organ destruction (e.g. malignancy, sickle cell disease)
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3.3.2. QUALITATIVE DEFECTS

 Defects in leukocyte adhesion

Deficiencies of the molecules involved in the adhesion process induce extravasion deficiencies. All
extravasion deficiencies cause recurrent bacterial infections and impaired wound healing.
 Defects in phagocytosis
The defect may involve any of these steps: chemotaxis, margination, migration and engulfment or
killing and digestion.
o Job syndrome = defective chemotaxis of neutrophils leading to lack of inflammatory
response, very high levels of IgE and eosinophilia. The results are recurrent infections,
staphylococcal abscesses, chronic eczema and otitis media.
o “Lazy leukocyte” syndrome = neutropenia, defective chemotactic response of neutrophils
and abnormal inflammatory response leading to severe microbial infections.
o Tuftsin deficiency = familial deficiency of the phagocytosis-promoting molecule tuftsin,
cleaved from an immunoglobulin-like molecule (leukokinin) in the spleen and needed for
normal engulfment, leads to severe infections with C. albicans, S. aureus and S. pneumoniae.
o Chronic granulomatous disease (CGD) = inherited defects of the neutrophil cytochrome b,
induces enzymatic inability to generate toxic oxygen metabolites and suppress intracellular
killing of ingested microorganisms, with recurrent infections
o Myeloperoxidase deficiency (MPO) = superoxide and hydrogen peroxide are formed in
normal amounts, but due to lack of MPO, neutrophil killing is impaired, causing an increased
susceptibility to Candida albicans and S. aureus.
o Chédiak-Higashi syndrome = neutrophils contain abnormally giant lysosomes, which can
fuse with the phagosome but their ability to release their content is impaired, resulting in
delayed killing of ingested microorganisms. Clinically, partial albinism is associated to the
recurrent and severe pyogenic infections.
 Phagocyte-mediated tissue damage
The metabolic and membrane perturbations that occur in leukocytes during chemotaxis, activation
and phagocytosis cause the release of leukocyte products (lysosomal enzymes, oxygen reactive species,
arachidonic acid metabolism products) not only within the phagolysosomes, but also out of the cell.
These substances are harmful for the endothelial cells, causing tissue damage and amplifying the initial
inflammatory stimulus.
The main ways by which these leukocyte products are released extracellularly are:
o Regurgitation during feeding = the phagocytic vacuole remains transiently open to the
outside before complete closure of the phagosome.
o Frustrated phagocytosis = in cells exposed to indigestible materials (immune complexes),
phagocytosis does not occur, but the lysosomal enzymes are released into the medium.
o Surface phagocytosis = phagocytes facilitate ingestion of the target by trapping it against a
resistant surface and lysosomal enzymes are released extracellular.
o Cytotoxic release = occurs after the phagocytosis of potentially membranolytic substances
(e.g., urate crystals).

3.4. SYSTEMIC EFFECTS OF INFLAMMATION

Cytokines released by macrophages at the site of injury do not act only locally, but also induce
responses in the entire organism, activating the so-called systemic acute-phase response (SAPR).
SAPR is an early and highly complex reaction of the organism to tissue injury. The acute-phase changes
are non-specific and their purpose is to restore homeostasis and to remove the cause of disturbance. The
SAPR includes:
 Behavioural changes (anorexia, somnolence, malaise, fatigue, tiredness)
 Fever: the hypothalamic set point of body temperature is shifted towards a higher level
 Leukocytosis with neutrophilia and thrombocytosis: initially, it reflects the increased release of
leukocytes and platelets from the storage pool and later it reflects increased production by bone
marrow
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  Coagulation pathway is stimulated.
 Complement activation and antibody synthesis are stimulated.
 Acute-phase proteins (APP): the positive APP synthesis is stimulated; the negative APP are
decreased during inflammation (e.g., albumin, transferrin), potentially to starve the
microorganisms.
 Hypoferremia: taking iron from bacteria in the plasma reduces their proliferation. The decrease in
red blood cells (anemia) also contributes to decreased iron availability to pathogens.
 Changes in lipid metabolism: lipolysis is enhanced, causing hypertriglyceridemia,
hypercholesterolemia, increased LDL and HDL decrease.
 Muscular protein catabolism increases, and amino acids transfer to the liver, causing weight loss.
 Gluconeogenesis increases.
 Hormonal changes: ACTH and glucocorticoid hormones release is stimulated, acting as a negative
feedback on APP synthesis.

The APP can be divided into two groups:

o Type I APP: C-reactive protein (CRP), serum amyloid A
(SAA), complement C3, etc.; are induced by IL-1 and TNF-
α.
o Type II APP: fibrinogen, haptoglobin, α1-antichemotrypsin,
α1-antirypsin, α2-macroglobulin; are induced by IL-6
cytokines.
!!! The APP have essential roles:
 Inhibition of the extracellular proteases, blood clotting,
fibrinolysis
 Modulation of immune cells function
 Neutralization and clearance of harmful components from
the circulation.
!!! Some APP (e.g. CRP, SAA, haptoglobin) are expressed in
nonhepatic tissues too (kidney, spleen, heart, brain, lungs,
thymus, testis, epididymis).

Several studies have demonstrated that there is a correlation between the elevated serum APP and
severity of certain diseases:
 In rheumatoid arthritis, persistent elevation of C-reactive protein is associated with functional
deterioration.
 In inflammatory bowel diseases (Crohn’s disease, uncreative colitis) acute-phase reactants
change along with disease activity.
 In myocardial infarction, the tissue necrosis induces IL-6 synthesis and APP elevation
(fibrinogen, C-reactive protein, α1-antitrypsin). In addition, it increases von Willebrand factor,
clotting factor VIII, plasma antithrombin III whereas the protein C system is downregulated
 In depressed, manic, schizophrenic patients has been found an increased secretion of positive
APP and a decreased level of negative APP has been found.
 In individuals with high stress perception, mental stress increases C3 and α1-acid glycoprotein.

3.5. OUTCOMES OF ACUTE INFLAMMATION

All the changes related to the response to injury are organized in a multiring circus, having a
relatively uniform pattern in most injuries. The basic process may be influenced by many variables, some
depending on the injurious agent and the others depending on the host. The most frequent factors related
to the injurious agent that may change the inflammatory responses are:
 amount/dose of the agent
 its strength, virulence
 duration of exposure
 the intrinsic nature of the agent.
Systemic and local host factors interfere with inflammatory responses. The most important systemic
factors are:
 Nutrition
17
  Proteins: protein undernourishment depresses the immune system and inflammatory
response, delays wound healing.
 Vitamin C: lack of vitamin C inhibits collagen fiber secretion, due to the failure of
proline hydroxylation fibroblasts.
 Vitamin A: vitamin A favors epithelial proliferation and differentiation, and counteracts
the inhibitory effect of the steroid hormones.
 Zinc: is necessary for the function of many enzymes (e.g., nucleic acid polymerases).
 Steroid hormones: inhibit wound healing and fibrous tissue production.
 Age: age-related immune system function and vascular system changes influence the
evolution of inflammation
 Diabetes: in diabetes mellitus there is an immune defense and arterial perfusion deficiency,
and neuropathy, which negatively influence the inflammatory responses.

Some local factors that may delay the inflammatory responses are:
 the presence of foreign bodies or infection
 excess of mobility in the wound

Generally, acute inflammations may have one of the four outcomes:

1. Complete resolution
2. Abscess formation
3. Fibrosis
4. Chronic inflammation.
Acute inflammation is a normal physiologic response, but it may cause serious host injury if it is
allowed to persist. Hence, additional mechanisms are required to re-establish homeostasis once this
response is initiated. Suppression of acute inflammation by removal or deactivation of mediators and
effector cells permits the host to repair damaged tissues through elaboration of appropriate growth
factors and cytokines. The precise mechanisms controlling the switch from predominantly pro-
inflammatory to anti-inflammatory pathways are not fully understood. However, as in the initial
generation of an inflammatory response, components of resolution include:
o a cellular response (apoptosis)
o formation of soluble mediators (such as anti-inflammatory cytokines and antioxidants)
o production of direct effectors (such as protease inhibitors).
Apoptosis is a normal process by which inflammatory cells are removed from healing sites, with the
clearance of neutrophils representing a prominent example. Apoptosis abnormalities were found in some
pathologic conditions. In leukocytoclastic vasculitis, abundant neutrophil apoptosis is one of the
pathologic criteria for this diagnosis. Defective apoptosis or even persistence of apoptotic cells that
escape clearance may contribute to chronic inflammatory and autoimmune diseases like SLE. In
rheumatoid arthritis (RA) a combination of impaired clearance of dying cells and genetic factors, may
blend into a susceptible environment which leads to an immune response and antibodies are produced
(the antibodies can be detected in serum many years before onset of the first symptoms of arthritis).
While some inflammatory and immune cells are being deleted, other cell lineages expand during the
resolution phase. Mesenchymal cells, especially fibroblasts, proliferate and produce new matrix that can
contract to form a fibrotic scar. Resolution of inflammation is abnormal in diseases in which tissue
fibrosis represents a major pathologic manifestation (e.g. scleroderma is marked by diffuse fibrosis). In
addition, mesenchymal stem cells that either reside in the tissue or migrate from the peripheral blood can
differentiate into the appropriate organ-specific lineage. The pluripotential cells, in the presence of the
appropriate milieu, can become other cells: adipocytes, chondrocytes, bone cells, or other terminally
differentiated stromal cells.
Just as there are cytokines that initiate and induce the inflammatory response, an additional array of
cytokines displays primarily anti-inflammatory activities (e.g. TGF-β, IL-4, IL-10, and IL-13).

18
 !!! Lack of balance between pro-inflammatory and anti-inflammatory cytokines is of vital importance in
pathogenesis of inflammatory diseases (e.g. rheumatoid arthritis, IBD). Biological therapy is a type of
treatment that involves neutralization of pro-inflammatory cytokines, use of anti-inflammatory
cytokines and inhibition of neutrophils adhesion.

Cytokine decoy receptors can also downregulate the inflammatory response. These cytokine inhibitors
can be released as a coordinated attempt to prevent unregulated inflammation, as in septic shock.

!!! Cytokine decoy receptors recognize certain inflammatory cytokines with high affinity and
specificity, but are structurally incapable of signaling or presenting the agonist to signaling
receptor complexes. They act as a molecular trap for the agonist and for signaling receptor
components. Moreover, silent nonsignaling receptors could act as decoys for chemokines.
Therefore, the use of decoy receptors is a general strategy to regulate the action of primary
pro-inflammatory cytokines and chemokines.

COX2 induced by pro-inflammatory mediators appears early and can contribute to inflammatory
responses. However, COX2 expression late in the process can prevent NF-KB activation.
An extensive array of antioxidant defenses exists to protect cells from the effects of ROIs and RNIs.
Antioxidants can be divided into the antioxidant enzymes (catalase, superoxide dismutase), chain-
breaking antioxidants (vitamin C, albumin, reduced glutathione, vitamin E, ubiquinol-10, carotenoids,
and flavonoids), and transition metal–binding proteins (ceruloplasmin, ferritin, transferrin, and
lactoferrin). Insufficient production of intracellular antioxidants can suppress lymphocyte responses and
could account for defective T-cell receptor signaling and blunted immunity in T cells derived from
rheumatoid arthritis synovium.
ROIs can damage DNA, which is a common sequela of the genotoxic environment created by
inflammation. If DNA damage is excessive programmed cell death begins. The burden of mutations
induced by ROIs or RNIs in chronic inflammation can potentially accumulate over time and eventually
lead to amino acid substitutions in key regulatory proteins (e.g. ulcerative colitis, neoplastic disease).
A specialized mechanism for inhibiting MMP function, tissue inhibitors of metaloproteinases –
TIMPs, has also evolved and can be induced during the reparative phase of inflammation. Examples of
disease states with an unfavorable balance between TIMPs and MMPs include loss of cartilage in
arthritis and regulation of tumor metastasis.
Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated
production of both pro- and anti-inflammatory mediators that are mainly produced within tissues.
Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to
peripheral blood, leading to the concept of compartmentalization.. All mediators contribute in synergy
to tissue injury, organ dysfunction, and possibly to lethality. While anti-inflammatory mediators
predominate within the blood stream to avoid igniting new inflammatory foci, their presence within
tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in
the different compartments.

!!! Sepsis presents in two distinct, but related, clinical syndromes, acute septic shock and severe sepsis.
Acute septic shock syndrome occurs suddenly, and the patient dies within 24–48 hours and is due to
sudden overproduction of tumor necrosis factor-a (TNF-a). In contrast, severe sepsis runs a protracted
course over several weeks; shows only minimal signs of inflammation or necrosis till the patients
succumb to the disease. Some patients with severe sepsis will eventually develop septic shock. Thus,
both severe sepsis and acute septic shock are a continuum syndrome pattern and may occur in the
same patient but at different periods of time indicating that the causative mediators of these two phases
of the same disease are likely to be different.

Patients with sepsis-after surviving the initial hyperinflammatory phase, display features consistent
with immunosuppression: loss of delayed hypersensitivity, inability to clear infection, and predisposition
to nosocomial infections. Immunosuppression is thought to be facilitated by negative regulators of toll-
like receptors. The immune dysregulation observed in sepsis corresponds to a reprogramming of
circulating leukocytes.
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 Proinflammation involves complex pathways that include stress response, heat shock protein, NF-
kB, iNOS, and free radical activation/induction. It may represent a common precondition in different
disease states. Proinflammation usually shortens biological 'battles' and therefore ameliorates disease-
related detrimental or subjectively unpleasing phenomena. These pathways that have originally been set
in place to overcome stress/infections, but may further have the capacity of exerting detrimental effects.
This may occur when a challenge becomes overwhelming, when the fine balance between the different
anti- and proinflammatory mechanisms can not be kept, when patterns of chronic pathophysiological
processes are presented. Some studies suggest that proinflammation plays a role in the pathogenesis of
infectious and parasitic diseases, cardiovascular diseases, inflammatory bowel diseases, autoimmune
diseases (rheumatoid arthritis, systemic sclerosis, myasthenia gravis, systemic or cutaneous lupus
erythematosus), diabetes mellitus type 1, asthma, multiple sclerosis, Alzheimer's and Parkinson's disease.
The paradigm that persistent infections and chronic inflammation contributes via cytokine- and
chemokine-mediated misbalanced immune response to carcinogenesis becomes more and more
attractive in cancer research. Besides genetic factors, the epigenetics of impaired cell signaling and signal
transduction by proinflammatory cytokines and chemokines are important potentiators of carcinogenesis.
The activation of the NF-KB, for example, a hallmark of inflammatory responses that is frequently
detected in tumors, might constitute a missing link between inflammation and cancer.
In conclusion within the inflammatory process a fine balance exists between the beneficial effects of
inflammation (adaptive response) and the potential for the process itself to cause and aggravate tissue
injury (maladaptive response).

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