1. Phase II Foundation Block Chronic Inflammation (ID # 2676) Wednesday 23-01-2013 Prof.T.A.Junaid Department of Pathology

2. Role in InflammationMediators VasodilationProstaglandins Nitric oxide Histamine Increased vascular permeabilityHistamine and serotonin C3a and C5a (by liberating vasoactive amines from mast cells, other cells) Bradykinin Leukotrienes C 4, D 4, E 4 PAF Substance P Chemotaxis, leukocyte recruitment and activation TNF, IL-1 Chemokines C3a, C5a Leukotriene B 4 (Bacterial products, e.g., N-formyl methyl peptides) FeverIL-1, TNF Prostaglandins PainProstaglandins Bradykinin Tissue damageLysosomal enzymes of leukocytes Reactive oxygen species Nitric oxide IL-1, interleukin-1; PAF, platelet-activating factor; TNF, tumor necrosis factor. Role of mediators in different reactions of Inflammation

3. Joint Bone Spine 2011

5. CytokinePrincipal Sources Principal Actions in Inflammation IN ACUTE INFLAMMATION TNFMacrophages, mast cells, T lymphocytes Stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effects IL-1Macrophages, endothelial cells, some epithelial cells Similar to TNF; greater role in fever IL-6Macrophages, other cellsSystemic effects (acute-phase response) ChemokinesMacrophages, endothelial cells, T lymphocytes, mast cells, other cell types Recruitment of leukocytes to sites of inflammation; migration of cells to normal tissues IN CHRONIC INFLAMMATION IL-12Dendritic cells, macrophagesIncreased production of IFN-γ IFN-γT lymphocytes, NK cellsActivation of macrophages (increased ability to kill microbes and tumor cells) IL-17T lymphocytesRecruitment of neutrophils and monocytes Cytokines in Inflammation

6. Chronic inflammation follows unresolved or disordered acute starts de novo of long duration (wks  months) Localised or Systemic Examples Chronic lung disease Rheumatoid arthritis Asthma Ulcerative colitis/ Crohn disease Chronic dermatitis Autoimmune diseases

7. Chronic Inflammation Consists of varying combinations of i.Inflammation ii.Tissue injury iii.Repair Caused by i.Persistent microbial infections a. mycobacteria b.viruses c.fungi d.parasites ii.Autoimmune disease iii.Prolonged exposure to toxic agents

8. Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (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.

9. Chronic Inflammation Cells involved Monocyte/macrophages Lymphocytes, T&B Plasma cells Dendritic cells Fibroblasts Eosinophils Neutrophils Mast cells

10. Chronic Inflammation Morphologic types i.Non-specific cellular patterns with fibrosis ii.Granulomatous The macrophage is the dominant player in chronic inflammation Monocyte Macrophage Epithelioid cell Giant cell

11. Maturation of mononuclear phagocytes.

12. The roles of activated macrophages in chronic inflammation. Activated by nonimmunologic stimuli such as endotoxin or by cytokines Activated macrophages cause tissue injury and fibrosis.

13. Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) and others that activate macrophages (IFNγ). Different subsets of T cells (called T H 1 and T H 17) may produce different sets of cytokines; Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (such as IL-12).

14. Chronic rheumatic endocarditis of aortic valve

15. Viral hepatitis.

16. Hashimoto’s thyroiditis A- The enlarged thyroid has a multinodular whitish appearance B – A lymphoid follicle with a germinal centre and diffuse lymphocytic infiltrate C – Thyroid follicles devoid of colloid, lined by oncocytic cells with eosinophilic granular cytoplasm and round vesicular nuclei

17. Chronic osteomyelitis; the bone appears sclerotic

18. Chronic Inflammation Granulomatous i.Distinct pattern of chronic inflammation ii.Induced by limited number of causative agents iii.Comprises aggregates of epithelioid cells iv.Often contain giant cells v.Surrounding lymphocytes & fibrosis vi.+ Necrosis Examples: tuberculosissarcoidosis leprosysyphilis brucellosiscat-scratch disease fungal infectionssilicosis berylliosislymphogranuloma inguinale insoluble indigestible bodies

19. Lung – Tuberculosis Caseation Necrosis

20. Necrosis Langhan’s type giant cell

21. Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes.

27. Nature 2008

28. Immunotherapy 2012

29. Nature 2008