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Systemic effects of
inflammation

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1. Introduction:
• Inflammation is local response of live and vascularized animal tissue
to injury from any agent which could be microbial, immunological,
physical or chemical…
• The effects of inflammation can be both local or systemic.
• Although inflammation helps clear infections and other noxious
stimuli and initiates repair, the inflammatory reaction and the
repair process can themselves cause considerable harm.

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• Systemic effects of inflammation are mediated by both:
Cell derived mediators: TNF, IL1, IL-6.
Plasma cell derived mediators: fibrinogen.
• Those effects can be due to acute or chronic inflammation.

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2-Systemics effects of inflammation
1. Fever,
2. Elevated levels acute phase proteins,
3. Leukocytosis,
4. Anemia,
5. Systemic Response Inflammatory Syndrome (SIRS).
6. Compensatory anti-inflammatory Response Syndrome( CARS).
7. Others ( sepsis, ARDS, wasting syndrome).

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 Fever
• Defined as an elevation of body temperature above normal circadian
variation.
• For every 1C over 37C, 13% increase of oxygenation consumption.
• Body temperature is controlled by hypothalamus ( peri-optic/post).
• Occurs with an increase in the hypothalamus set point.
• Produced in response to substances called: Pyrogens either
endogenous or exogenous.

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• Bacterial products, such as Lipopolysacchrides (LPS) in gram negative
bacteria (exogenous pyrogens),
• Stimulate leukocytes to release cytokines such as IL-1 and TNF
(endogenous pyrogens),
• Increase the enzymes cyclooxygenases that convert Arachidonic
acid into prostaglandins.
• In the hypothalamus, the prostaglandins, especially PGE 2 ,
stimulate the production of neurotransmitters such as cyclic AMP.
• Which function to reset the temperature set-point at a higher level.

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Reminder

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 Elevated acute phase proteins:
• Are defined as those proteins whose serum concentrations increase
or decrease by at least 25 percent during inflammatory states. Such
proteins are termed either positive or negative APP.
• Mostly are plasma proteins synthesized in the liver.
• Their plasma concentrations may increase to 1000-fold as part of the
response to inflammatory stimuli; Examples:
1. C-reactive protein (CRP),
2. Fibrinogen,
3. Serum Amyloid A protein (SAA).

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FUNCTIONS
• Trapping of micro-organisms and their products
• Activation of the complement system eg crp
• Neutralizing enzymes
• Scavenging free hemoglobin and radicals eg haptoglobin
• Binding cellular remnants like nuclear fractions

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1- C- reactive protein
• It’s an annular pentameric polypeptide synthesized by liver
(hepatocytes) in response to inflammation.
• Stimulate secretion of pro-inflammatory cytokines (IL-6,TNF,adhesion
molecule, endothelin 1 by endothelial cells).
• CRP bind to microbial cell walls (phosphorylcholine) they may act as
opsonins and activate the complement system and bind to phagocytic
cells via Fc receptors, suggesting that it can initiate elimination of
pathogens.

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2- fibrinogen
• As it called factor I, glycoprotein circulates in the blood of vertebrates.
• During injury it is converted enzymatically by thrombin into fibrin
during blood clot formation.
• Fibrinogen binds to erythrocytes and causes them to form stacks
(rouleaux) that sediment more rapidly at unit gravity than do
individual erythrocytes.
• This is the basis for measuring the erythrocyte sedimentation rate
(ESR) as simple test for systematic inflammation response by number
of stimuli e.g.Lipopolysacchrides

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3- Serum Amyloid A (SAA)
• A major human acute phase protein family, are apolipoproteins that are
rapidly associated with high-density lipoprotein following their synthesis and
secretion and can influence cholesterol metabolism during inflammatory
states.
• SAA may increase the adhesion and chemotaxis of phagocytic cells and
lymphocytes.
• Also it’s an acute phase marker that respond rapidly, associated more with
joint disease eg: rheumatoid arthritis.
• it has been associated as marker for: Cardio-vascular diseases, Obstructive
sleep apnea, Coronary heart
diseases.

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 Leukocytosis:
• Leukocytosis is a common feature of inflammatory reactions,
especially those induced by bacterial infection.
• The leukocyte count usually climbs to 15,000 or 20,000 cells/µl, but
sometimes it may reach extraordinarily high levels of 40,000 to
100,000 cells/µl. [normal 4,000-11000 cells/µl].
• The leukocytosis occurs initially because of accelerated release of
cells from the bone marrow (caused by cytokines, including IL-1 and
TNF)
• therefore associated with a rise in the number of more immature
neutrophils in the blood.

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• Prolonged infection also induces proliferation of precursors in the
bone marrow, caused by increased production of colony stimulating
factors (CSFs).
• Bone marrow output of leukocytes is increased to compensate for the
loss of these cells in the inflammatory reaction.

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• Neutrophilia refers to an increase in the blood neutrophil count due
to bacterial cause mostly.
• Lymphocytosis due to viral infections: infectious mononucleosis,
mumps…
• Eosinophilia seen in bronchial asthma, hay fever, and parasitic
infestations, malaria….

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 Anemia:
• Anemia of chronic inflammation is defined as normochromic,
normocytic hypo-proliferative.
• could be due to decreased red cell survival (RBC mass) which may
occur in cases of acute inflammation characterized by increased
marcro-phage activity.
• The release of cytokines IL-1/ IL-6 and TNF alpha may decrease bone
marrow responsiveness to erythropoietin, which may induce
apoptosis or red cell precursors.
• 33-60% patients with rheumatoid arthritis developpe anemia.

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 Systemic inflammatory response syndrome:
• SIRS is nonspecific reaction and can be caused by infectious or non
infectious agents.
• Although inflammation is an essential component of host defense
against different insults, SIRS develops only when localized aggressive
injury process gains access through blood stream and lymphatic to the
whole body.

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1- Epidemiology
• The true incidence of systemic inflammatory response syndrome (SIRS) is
unknown but probably very high, owing to the nonspecific nature of its
definition.
• Not all patients with SIRS required hospitalization or have disease that
progress to serious illness.
• Rangel-Fausto et al published a prospective survey of patients admitted to a
tertiary care center that revealed 68% of hospital admissions to surveyed
units met SIRS criteria.The incidence of SIRS increased as the level of unit
acuity increased. The following progression of patients with SIRS was noted:
26% developed sepsis, 18% developed severe sepsis, and 4% developed
septic shock within 28 days of admission.

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• Another study demonstrated that 62% of patients who presented to
the emergency department with SIRS had a confirmed infection,
while 38% did not. Within the same cohort of patients, 38% of
infected patients did not present with SIRS.

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2- Diagnostic criteria
• Criteria for SIRS are considered to be met if at least 2 of the following
four clinical findings are present:
1. Temperature >38°C or <36°C
2. Heart rate HR > 90 beats/min
3. Respiratory rate > 20 breaths/min OR PaCO2 < 32 mmhg
4. WBC > 12,000/ul OR <4000/ul OR with 10% immature band forms.

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3- Etiology of SIRS
• Can be grouped into two :
Pathogenic such as bacterial, fungal or viral.
Non-pathogenic such as trauma, radiation , chemical.

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4- Pathophysiology of SIRS:
• The transition from local inflammation response to SIRS can be staged
into three:
Stage 1:
Insult cytokines release cellular inflammatory response repair
and recruitment of Reticular endothelial system 
(local inflammation- rubor, tumor, dalor, calor and functio laesa).

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• Stage 2:
Cytokines circulation  stimulation of growth factors
+macrophages and platelets recruitment.
Acute phase response-controlled by ↓proinflammatory
mediators + release of endogenous antagonists.
Manifestation; minimal malaise and low grade fever.

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• Stage 3:
 No Homeostasis restoration + Inflammatory stimuli continue to
exert its effect in systemic circulation significant systemic
reaction.
 Cytokines released destruction rather than protection 
activation of numerous humoral cascades and reticular endothelial
system + loss of circulatory integrity –End organ Failure.

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• Infectious insult(or others) Tissue macrophages, monocytes, mast
cells, platelets, and endothelial cells to produce a multitude of
cytokines.
• The cytokines -TNF-α & IL-1 are released first (responsible for
majority of systemic effects e.g fever).
• NOTE; Infection has been shown to induce a greater release of TNF-α
—thus inducing a greater release of IL-6 and IL-8—than trauma does.
This is suggested to be the reason higher fever is associated with
infection rather than trauma.

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• IL-1 & TNF-α  cleavage of the nuclear factor-kB (NF-kB) inhibitor.
• NF-kB production of mRNA  induces the production other
proinflammatory cytokines , IL-6, IL-8, and interferon gamma being
the primary ones.
• IL-6, stimulate the release of acute-phase reactants such as C-reactive
protein (CRP), Fibrinogen and procalcitonin.

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• ↑CRP and (SAA-from IL1 & TNF-α )bind to microbial cell walls
 opsonization ,fix to the complement promoting the elimination of
the microbes by phagocytosis.
• Elevated serum levels of CRP are now used as a marker for increased
risk of myocardial infarction or stroke in patients with atherosclerotic
vascular disease.

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• Fibrinogen binds to erythrocytes  forms stacks (rouleaux) that
sediment more rapidly at unit gravity than individual erythrocytes.
• This is the basis for measuring the erythrocyte sedimentation rate
(ESR) as a simple test for the systemic inflammatory response, caused
by any stimuli.

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• In response to infection or injury, as is seen with SIRS, HMGB1(High
mobility group box, a protein present in the cytoplasm and nuclei in a
majority of cell types) is secreted by innate immune cells and/or
released passively by damaged cells.
• acts as a potent proinflammatory cytokine and is involved in delayed
endotoxin lethality and sepsis

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5- Role of complement
• Protein complements, C3a and C5a have been the most directly
responsible in release of additional cytokines and to cause
vasodilatation and increasing vascular permeability.

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6- Coagulation and DIC:
• IL-1 and TNF-α  endothelial surfaces  expression of tissue
factor production of thrombin  promoting coagulation
(Thrombosis).
• On the other end Fibrinolysis is impaired by IL-1 and TNF-α via
production of plasminogen activator inhibitor-1.
• the widespread micro vascular thrombosis consumes platelets and
coagulation proteins initiating Fibrinolysis cascades hence DIC.

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 Compensatory-inflammatory response
syndrome:
• The body is equipped to reverse and counteract the acute
inflammatory response via CARS.
• IL-4 and IL-10 are cytokines responsible for decreasing the production
of TNF-α, IL-1, IL-6, and IL-8.
• The acute phase response also produces antagonists to TNF-α and
IL-1 receptors.
• These antagonists either bind the cytokine, and thereby inactivate it,
or block the receptors.
• The balance of SIRS and CARS helps determine a patient's outcome
after an insult.

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OVERVIEW OF OTHERS SYSTEMEIC EFFECTS
OF INFLAMMATION:
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 Sepsis:
• Refers to symptomatic presence of bacteria in the blood with or
without organ dysfunction.
• Its pathophysiology is the same as that of SIRS.

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• septic shock triad:
Due to production of TNF can be responsible of :
1-DIC,
2-metabolic disturbances including acidosis and
hypoglycemia.
3-cardiovascular failure e.g :hypotensive shock.

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 Acute respiratory distress syndrome
ARDS:
• clinical syndrome caused by diffuse alveolar capillary and epithelial
damage.
• The same physiopathology as in SIRS

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 Wasting syndrome:
• It is involuntary loss of weight, muscle atrophy ,fatigue, weakness.
• Its among chronic inflammation systemic effects.
• Results from TNF-mediated appetite suppression and mobilization of
fat stores.
• Altering circulating levels of hormones that regulate muscle growth
and affects tissue sensitivity to such factors.

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References
• Lewis J K. SIRS Medscape 2018.
• Cytokines in the systemic inflammatory response syndrome: a review
by U.Jaffer, R.G.Wade, T.Gourlay.
• Up-to-date.
• Robbins Basic Pathology 8th /9th edition.
• Harsh Mohan Text book of Pathology; 6th edition.
• Acute-phase proteins and other systemic responses to
inflammation.https://www.ncbi.nlm.nih.gov/pubmed/9971870
• Acute Phase Reactants
www.tip.hacettepe.edu.tr/actamedica/2013/Acta13(2).pdf

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Thank you