Chronic Inflammation Monday, January 27, 2003

1. Chronic InflammationMonday, January 27, 2003 Plasma RBC Platelet WBC

2. Chronic Inflammation Overall concept of inflammation is relatively straightforward: --host-defense __________ to invading substance; --excluding autoimmune events, inflammation occurs due to some kind of _________________; --if the cause is not removed, inflammation becomes chronic and can persist for months, years, a lifetime! The inflammatory process goes from the "fire" of the cardinal signs of inflammation to now become a "simmer": --that is, the two signs that relate to "flames", redness and heat, are toned down but and remain.

3. Chronic vs. Acute Inflammation--A Few “Differences” Microscope will tell you what’s going on when inflamed tissue is examined: --it can tell us why the inflammatory response is not turned off by showing us that the offending agent is still there. --in acute inflammation the hallmark cell is the polymorphonuclear leukocyte (__________), while in chronic inflammation, __________ leukocytes are predominant.

4. Chronic vs. Acute Inflammation--A Few “Differences” (cont’d) The initial event of inflammation is the local recruitment of ________________: --the acute response takes place almost immediately, seconds or minutes after the injury- --fluids pour out and then the neutrophils. --the response then takes over if the injurious agent is not immediately removed. Its function is a more ___________ defense than phagocytosis alone.

5. Chronic vs. Acute Inflammation--A Few “Differences” (cont’d): Acute Inflammation Bruised tissue with a blood vessel in the middle Neutrophils and smooth muscle cells- ruptured Appendix

6. Chronic vs. Acute Inflammation--A Few “Differences” (cont’d): Chronic Inflammation Two pulmonary __________, which typically consists of epithelioid , giant cells, lymphocytes, and fibroblasts.

7. Acute Inflammation vs. Chronic Inflammation May have one of four outcomes: 1. Complete ________- restoration of the site of acute inflammation to normal: --outcome when the injury is mild (superficial cut, burn or trauma, little tissue injury); 2. Healing by __________- substantial tissue destruction, or when inflammation occurs in non-regenerating tissues; 3. _________ formation- occurs in infections with pyogenic organisms; 4. _________ to chronic inflammation.

8. End Results of Acute-Chronic Inflammation Cellulitis- rapidly spreading acute inflammation. Note the redness and edema of the skin. Abscess, brain- well developed with fibrous connective tissue and scarring

9. End Results of Acute-Chronic Inflammation Chronic inflammation- viral encephalitis in brain, inflammation that arises with an initial lymphocyte response. Burn, from extensive damage to skin, and the attempt to healing led to large-scale scarring.

10. Causes of Chronic Inflammation Clinically, chronic inflammation arises in various organs: 1. It may __________ acute inflammation- persistence of the inciting stimulus, or interference in the normal process of wound healing: --example, lung infections that persists and leads to tissue destruction, and a chronic lung abscess. 2. _____________ of acute inflammation- the patient shows successive attacks of fever, pain, and swelling: --occurs in recurrent infections in major organs.

11. Causes of Chronic Inflammation (cont’d) 3. More curiously, chronic inflammation may begin ________ -a ________ smoldering response that does not follow classic symptoms of acute inflammation. --This includes some very disabling human diseases: rheumatoid arthritis; tuberculosis; and chronic lung disease.

12. Causes of Chronic Inflammation (continued) These diseases mentioned above occur in the following setting: a. infection by intracellular microorganisms --tubercle bacilli, viral infections, which are of low toxicity but evoke an immunological reaction;

13. Causes of Chronic Inflammation (continued) b. prolonged to non-degradable but potentially toxic substances (e.g., silicosis and asbestosis); reactions, particularly those perpetuated against the individual's own tissues (autoimmune diseases, such as rheumatoid arthritis).

14. Definition of Chronic Inflammation Chronic inflammation is an inflammatory response of prolonged duration, which is provoked by of the causative stimulus to inflammation in the tissue. The inflammatory process inevitably causes tissue _______ and is accompanied by simultaneous attempts at healing and repair. The exact nature, extent and time course is _________, and depends on a balance between the causative agent and the attempts of the body to remove it.t.

15. Cells and Mediators The histological hallmarks of chronic inflammation are: 1) infiltration by cells, principally monocytes/ macrophages and lymphocytes; 2) proliferation of , and in many instances, small blood vessels (endothelial cells); 3) increased connective tissue (); and 4) tissue .

16. Mononuclear Cells Monocyte/Macrophage Pivotal cell in regulating the reactions that lead to chronic inflammation Lymphocyte Also prominent and vital function in both humoral and cell-mediated immune response, macrophage activation and recruitment of specific mediators (lymphokines)

17. Mononuclear Cells (cont’d) Plasma Cell Primary source of antibodies, important for antigen neutralization, clearance of foreign antigens, particles and Ab-dependent cell cytotoxicity Eosinophil Allergic-type reactions and parasitic infections, contain unique basic proteins that are toxic to certain parasites.

18. Development of Monocytes/Macrophages

19. Development of Monocytes/Macrophages

20. CD4+ CD8+ Development of Lymphocytes

21. Chronic Injury • Bacteria and tissue- Activated Tissue-derivedmonocyteT-lymphocytes derived mitogen • chemotaxins • ___________ • Recruitment of circulating Proliferation of • monocytes tissue macrophages • _______ macrophages

22. Monocytes/Macrophages in Chronic Inflammation Does about everything a ___________ can, but can also initiate the immune system, recruit lymphocytes, activate fibroblasts, and induce new blood vessels. Macrophage is “ ” to organize an impressive second line of defense.

23. Types of Chronic Inflammatory Cells 1. Lymphocytes and macrophages: This illustration shows a mixed chronic inflammatory cell infiltrate containing mainly lymphocytes and macrophages. The __________ have small, round, very darkly staining nuclei and little surrounding cytoplasm; the ___________ have larger, paler, oval or bean shaped nuclei and a somewhat larger amount of cytoplasm. Plasma cells are not obvious in this field.

24. Types of Chronic Inflammatory Cells 2. Lymphocytes around a blood vessel: Perivascular cuffing is a common pattern of lymphocytic _________ in chronic inflammatory reactions. Lymphocytes emerge from the circulating _______ mostly through the walls of small venules and tend to aggregate around the vessels. This example is from an inflammatory disease of the brain- multiple sclerosis.

25. Types of Chronic Inflammatory Cells 3. Macrophages in infarcted brain: Macrophages are very ________, and engulf and degrade all sorts of debris in damaged areas. This example shows macrophages that have phagocytosed lipid from broken-down myelin in an area of ________ brain. The macrophage cell bodies are large and round, distended with pale, foamy looking lipid-filled vacuoles (lysosomes).

26. Types of Chronic Inflammatory Cells These distinctive looking cells have an eccentrically placed nucleus with coarse, blotchy staining of the chromatin, said to resemble a clock face. The cytoplasm is rather blue staining (_________), reflecting its high content of rough ER. There is also a prominent pale area of cytoplasm next to the nucleus- Golgi apparatus. Plasma cells are _______, end-stage cells of the B-_________ lineage, specialized for antibody production and secretion. 4. Plasma cells:

27. Types of Chronic Inflammatory Cells A lymphoid follicle producing lymphocytes in thyroid tissue during the _________ inflammatory process, which destroys the gland in Hashimoto's Disease. Inflammation is triggered and maintained against its own thyroid tissue, i.e., an _________ disease. The follicle is a structured aggregate of lymphoid cells, with a central region of large, pale-staining precursor cells and a zone of closely packed mature lymphocytes recognizable by their small, intensely blue/black nuclei. 5. Lymphoid follicles:

28. Granulomatous Inflammation When a substance cannot easily be digested by neutrophils, this leads to a vicious cycle of ____________. Failure of digestion, neutrophil death, release of the undigested material and then the cycle starts over again, and again.  inflammation is our mechanism for dealing with indigestible substances. Macrophages and lymphocytes are the principal cell types.

29. Granulomatous Inflammation Macrophages ____ _____ than neutrophils, so they store the undigested material longer in their cytoplasm, thus, stopping the continuous acute inflammatory response. Upon ingesting indigestible agent, macrophages lose their motility, and accumulate at the site of injury- undergo a into epithelioid cells. A is a collection of epithelioid cells frequently surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.

30. Structure of a Granuloma Granulomas are aggregates of particular typesof chronic inflammatory cells, which form _________. The essential components of a granuloma are collections of modified macrophages, termed epithelioid cells, usually with a surrounding ________ of lymphocytes. Epithelioid cells are less phagocytic than other macrophages and appear to be modified for secretory functions. The full extent of their functions is still unclear.

31. Structure of a Granuloma Macrophages in granulomas are modified to form giant cells. These arise by fusion of epithelioid macrophages without division forming huge single cells. In some circumstances the nuclei are arranged round the periphery of the cell, termed a Langhans-type giant cell (characteristically seen in ). Areas of granulomatous inflammation commonly undergo necrosis- here is necrosis in tuberculosis.