This document outlines the systemic effects of inflammation, including fever, elevated acute phase proteins, anemia, leukocytosis/leukopenia, sepsis, ARDS, and wasting syndrome. It provides details on the mechanisms and clinical presentations of each effect. For example, it explains that fever occurs due to the effects of pyrogens like prostaglandins on the hypothalamus, while elevated acute phase proteins like C-reactive protein and serum amyloid A are produced in the liver in response to cytokines. Sepsis can lead to disseminated intravascular coagulation, hypoglycemia, and cardiac failure.

2. OBJECTIVES
 At the end of this presentation, one should be able
to:
 Mention systemic effects of inflammation
 Explain different systemic effects of inflammation

3. OUTLINE
 Introduction
 Systemic effects of inflammation
 Fever
 Elevated acute phase proteins
 Anaemia
 Leukocytosis
 Leukopenia
 Sepsis
 ARDS
 Wasting syndrome
 References

4. Introduction
 The effects of inflammation can be both local and
systemic .
 The effects are usually clearly beneficial (crp-opsonin)
or may be harmful
 Are chemical and pathological changes due to
inflammation process
 Known also as systemic inflammatory syndrome

5. Introduction…
 Mediated by pyrogens
 Produced by Leukocytes in response to infection or
immune reaction
 Released systemically
 Other pyrogens are pathogens LPS

6. Systemic effects of inflammation
 Fever
 Elevated levels acute phase proteins
 Anaemia
 Leukocytosis
 Leukopenia
 Sepsis
 ARDS (acute respiratory distress syndrome)
 Wasting syndrome

7. Fever
 Elevation of body temperature ; usually by
1°C t0 4°C
 Especially when inflammation is due to
infection
 Produced in response to substances called
pyrogens

8. Fever…
 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.

9. Fever…
 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.

11. Fever…
 NSAIDS ; like Aspirin, Ibuprofen, reduce fever by
inhibiting Cyclooxygenases thus blocking the
Prostaglandins synthesis
 An elevated body temperature has been shown to help
amphibians to ward off microbial infections
 Is assumed to do so in mammals though the
mechanism is not known

12. Fever
CELL MEMBRANE PHOSPHOLIPIDS
Phospholipases Steroids
ARACHIDONIC ACID
Cyclooxygenases NSAIDS
(COX 1 and COX 2)
PROSTAGLANDINS
(PGE2) FEVER

13. Elevated acute phase proteins
 These are plasma proteins synthesized in the liver,
 Their plasma concentrations may increase several
hundred-fold as part of the response to
inflammatory stimuli.
 Three of the best-known examples of these
proteins are
 C-reactive protein (CRP),
 Fibrinogen,
 Serum Amyloid A protein (SAA).

14. Elevated acute phase proteins…
 C reactive protein:(CRP)
 Pentameric polypeptide produced by the
hepatocytes in response to inflammatory
cytokines such as IL-6,
 Involved in variety of disorders which mediated by
inflammatory process;

15. Elevated acute phase proteins…
 Stimulate secretion of proinflamatory cytokines e.g.
IL-6,TNF,adhesion molecule, endothelin 1, by
endothelial cells
 Can bind to apoliprotein B contain lipoprotein and
opsonize LDL for uptake by monocyte-derived
macrophages (useful to show increased risk of
cardiovascular disease)
 CRP bind to microbial cell walls, and they may act as
opsonins and fix complement

16. Elevated acute phase proteins…
 Synthesis of these molecules by hepatocytes is up
regulated by cytokines, especially IL-6 (for CRP and
fibrinogen) and IL-1 or TNF (for SAA).
 CRP bind to microbial cell walls, and they may act as
opsonins and fix complement
 Thus promoting the elimination of microbes

17. Elevated acute phase proteins…
 Fibrinogen (factor I) is
a glycoprotein in vertebrates that helps in the
formation of blood clot.
 Is converted 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

18. Elevated acute phase proteins…
 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

19. Elevated acute phase proteins…
 Serum amyloid A (SAA)
 Are secreted dug the acute phase of inflammation
 Have several roles including recruitment of immune
cells to inflammatory sites, induction of enzymes that
degrade extracellular matrix
 Also acute phase marker that respond rapidly,
associated more with joint disease early inflamation.eg
rheumatoid arthritis

20. Anaemia
 Due to increases levels of Hepcidin
 Peptide hormone regulating Fe metabolism in the
body
 It controls absorption Fe from the gut and release from
macrophages
 It binds ferroportin which leads to its degradation
then reduce Fe release from cells
 The net effect is Anaemia

21. 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]
 These extreme elevations are referred to as
leukemoid reactions because they are similar to the
white cell counts obtained in leukemia.

22. Leukocytosis…
 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.

23. Leukocytosis…
 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.
 Neutrophilia refers to an increase in the blood
neutrophil count. Most bacterial infections

24. Leukocytosis..
 Lymphocytosis ;Viral infections such as
infectious mononucleosis, mumps, and German
measles produce a leukocytosis by virtue of an
absolute increase in the number of lymphocytes
 Eosinophilia ; the group of disorders, which
includes bronchial asthma, hay fever, and parasitic
infestations, there is an absolute increase in the
number of eosinophills

26. Leukopenia
 Decreased number of white blood cells
 Seen in certain infections like typhoid fever; and
infections caused by viruses, rickettsiae, and certain
protozoa
 is also encountered in infections that overwhelming
and in patients debilitated by disseminated cancer or
rampant tuberculosis.
 Likely because of cytokine-induced sequestration of
lymphocytes in lymph nodes.

27. Sepsis
 In severe bacterial infections (sepsis), the large amounts of
organisms and LPS in the blood stimulate the production
of large quantities of several cytokines, notably TNF , IL-1
and IL-12
 As a result, circulating levels of these cytokines increase
and the form of the host response changes.
 High levels of TNF cause disseminated intravascular
coagulation (DIC).
 Thrombosis results from two simultaneous reactions:

28. Sepsis…
 LPS and TNF induce tissue factor (TF) expression
on endothelial cells, which initiates coagulation;
the same agents inhibit natural anticoagulation
mechanisms, by decreasing the expression of
tissue factor pathway inhibitor (TFPI) and
endothelial cell thrombomodulin.

29. Sepsis…
 Hypoglycemia; cytokines cause liver injury and
impaired liver function, resulting in a failure to
maintain normal blood glucose levels due to a
lack of gluconeogenesis from stored glycogen.
 Cardiac failure; Overproduction of NO by
cytokine-activated cardiac myocytes and vascular
smooth muscle cells leads to heart failure and loss
of perfusion pressure, respectively, resulting in
hemodynamic shock.
 The clinical triad of DIC, hypoglycemia, and
cardiovascular failure is described as septic
shock.

30. ARDS
 Lung damage in the systemic inflammatory
response
 Commonly called the adult respiratory distress
syndrome (ARDS)
 Results when neutrophil-mediated endothelial
injury allows fluid to escape from the blood into
the airspace.

31. ARDS…
 Tissue injury in response to LPS (exogenous
pyrogen) can also result from the activation of
neutrophils before they exit the vasculature
 Thus causing damage to endothelial cells and
reduced blood flow.

32. Wasting syndrome
 It is a loss of weight, muscle atrophy ,fatigue,
weakness in someone who is not actively trying to
lose weight
 It is mainly the results of 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

33. References
 Acute Phase Reactants
www.tip.hacettepe.edu.tr/actamedica/2013/Acta13(
2).pdf
 Kumar, V., Abbas, A. K., Fausto, N., & Aster, J. C.
(2009, June 10). Robbins & Cotran Pathologic Basis
of Disease E-Book. Elsevier Health Sciences.
 Mohan, H. (2018, November 30). Textbook of
Pathology. Jaypee Brothers Medical Publishers.

34. THANK YOU