1. Chronic inflammation
Dr. Mamlook Elmagraby

2. Objectives of the lecture:
Upon completion of this lecture, students should be able to:
Define chronic inflammation with emphasis on causes, nature of the inflammatory response, and tissue changes
Compare and contrast the clinical settings in which different types of inflammatory cells (eosinophils, macrophages, lymphocytes) accumulate in tissues
Describe the systemic manifestations of inflammation and their general physiology, including fever, leukocyte left shift, and acute phase reactants

3. Overview
Chronic inflammation is a prolonged process in which destruction and inflammation are proceeding at the same time as attempts at healing
This type of inflammation is characterized by an insidious onset and long duration
Manifestations are NOT as dramatic as those of acute inflammation
Chronic inflammation is characterized by:
Infiltration with mononuclear cells
Tissue destruction
Repair
Dramatic an event sudden and striking (attracting attention by reason of being extreme or prominent)

4. The evolution of Chronic inflammation (Causes)
Acute inflammation may progress to chronic inflammation :
The persistence of the injurious agent
The interference with the normal process of healing
Insidiously or de novo
Persistent infection
Prolonged exposure to non-degradable substances
Immune reactions against common environmental substances
Immune reactions develop against the individual's own tissues
Insidious proceeding in a gradual, subtle way, but with harmful effects
Evolution the gradual development of something, especially from a simple to a more complex form

5. Chronic Inflammatory Cells

6. Macrophages
Macrophages are tissue cells derived from circulating blood monocytes after their emigration from the bloodstream The dominant cells in most chronic inflammatory reactions are macrophages The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair Excessively activated macrophages can induce considerable tissue destruction (one of the characteristics of chronic inflammation)

7. Maturation of mononuclear phagocytes.
During inflammatory reactions, the majority of tissue macrophages are derived from hematopoietic precursors.
Some long-lived resident tissue macrophages are derived from embryonic precursors that populate the tissues early in development.
(B)The morphology of a monocyte and activated macrophage

9. Mechanisms of macrophage accumulation in tissues
Mechanisms of macrophage accumulation in tissues. The most important is continued recruitment from the microcirculation
Macrophage Migration Inhibitory Factor

10. The roles of activated macrophages in chronic inflammation.
Macrophages are activated by cytokines from immune-activated T cells (particularly IFN-γ) or
by nonimmunologic stimuli such as endotoxin.
The products made by activated macrophages that cause tissue injury and fibrosis are indicated.
AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFβ, transforming growth factor β.

11. T Lymphocytes
T Lymphocytes emigrate from blood vessels late in an inflammatory reaction Activation of T cells is effected by cytokines (from macrophages) and directly by antigens Once activated, lymphocytes can react with certain antigens destroying them They also secrete cytokines that stimulate macrophages

12. The other Cells of Chronic Inflammation:
B-Lymphocytes (Plasma Cells)
Eosinophils
Fibroblasts and Collagen
Multinucleated Giant Cells

13. Macrophage–lymphocyte interactions in chronic inflammation
Lymphocytes and macrophages interact in a bidirectional way:
Macro­phages
Display antigens to T cells
Express membrane molecules (costimulators)
produce cytokines (IL-12) that stimulate T-cell responses
Activated T lymphocytes
produce cytokines (IFN-γ which activate macrophages,
promoting more antigen presentation and cytokine secretion)
These interactions play an important role in generating sustained chronic inflammation
Bidirectional functioning in two directions
Interaction reciprocal action

14. Macrophage–lymphocyte interactions in chronic inflammation.
Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines)and others that activate macrophages (IFN-γ)
Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines such as IL-12

15. Histological features of chronic inflammation
Infiltration of mononuclear cells
Tissue destruction
Granulation tissue formation (fibroblasts and small blood vessels)
Increased connective tissue (fibrosis)

16. Outcome of chronic inflammation
Resolution: restoration of normal structure and function
Healing by connective tissue (fibrosis or scarring)
It can continue indefinitely
Some disease processes are capable of continuing indefinitely such as rheumatoid arthritis

17. Acute inflammatory cells –
Chronic
Flush, Flare & Weal
Little signs
Acute inflammatory cells –
Neutrophils
Chronic inflammatory cells –Mononuclear cell
Vascular damage
Neo-vascularisation
More exudation
No/less exudation
Little or no fibrosis
Prominent fibrosis
Comparison between acute and chronic inflammation

18. A, Chronic inflammation in the lung, showing all three characteristic histologic features:
collection of chronic inflammatory cells (*),
(2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads)
(3) replacement by connective tissue (fibrosis, arrows).
B, By contrast, in acute inflammation of the lung (acute bronchopneumonia),
neutrophils fill the alveolar spaces and
blood vessels are congested

19. Types Of Chronic Inflammation
Histological features are used for classifying chronic inflammation into two types:
Chronic non-specific inflammation
It is characterized by non-specific inflammatory cell infiltration e.g. chronic osteomyelitis
Chronic granulomatous inflammation
It is characterized by formation of granulomas e.g. tuberculosis

20. Systemic Effects of Inflammation

21. Systemic Effects of Inflammation
The cytokines TNF, IL-1, and IL-6 are the most important mediators of these systemic effects These cytokines are produced by leukocytes and released systemically In severe bacterial infections, the large amounts of organisms stimulate the excessive production of these cytokines, leading to septic shock Systemic effects of Inflammation consist of several clinical and pathologic changes

22. Fever (An elevation of body temperature)
The most prominent signs especially when there is infection Exogenous pyrogens stimulate leukocytes to release endogenous pyrogens that increase the levels of cyclooxygenases Cyclooxygenases convert AA into prostaglandins (PG) In the hypothalamus the PGE2 stimulate the production of neurotransmitters Neurotransmitters reset the temperature set point at a higher level

23. Acute-phase proteins
Plasma proteins, synthesized in the liver, whose concentrations increase as a response to inflammatory stimuli
The most common acute-phase proteins are:
C-reactive protein (CRP)
Fibrinogen
Serum amyloid A (SAA) protein
Synthesis of these molecules by hepatocytes is up-regulated by cytokines (IL-6)
Many acute-phase proteins, may act as opsonins, thus promoting the elimination of the microbes

24. Acute-phase proteins Fibrinogen
Fibrinogen binds to erythrocytes and causes them to form masses that sediment more rapidly at than do individual erythrocytes
This difference in erythrocyte sedimentation is the basis for measuring the erythrocyte sedimentation rate (ESR)

25. Leukocytosis
A common feature of inflammatory reactions (especially those induced by bacterial infection) In the beginning of inflammatory response, the leukocytosis occurs due to accelerated release of cells from the bone marrow reserve This initial leukocytosis is usually associated with a rise in the number of more immature neutrophils in the blood (shift to the left) Later, colony-stimulating factors leads to increased bone marrow output of leukocytes
Bone marrow reserve a storage pool of mature neutrophils in the bone marrow, which can be released as necessary
shift to the left:
 a marked increase in the percentage of immature cells in the circulating blood, based on the premise in hematology that the bone marrow with its immature myeloid cells is on the left, whereas the circulating blood with its mature neutrophils is on the right

26. Leukocytosis
Most bacterial infections induce neutrophilia Viral infections induce lymphocytosis Allergic diseases and parasite infestations induce eosinophilia