Lecture 7 - Kapila - Chr Inf Iv - 11 Sep 2006

Inflammation IV – Chronic Kusum Kapila September 2006

Inflammation A dynamic continuum of change

Resolution

Resolution with scarring*

Inciting

Acute

Chronic-active

Chronic

Stimulus

Inflammation

Inflammation

Inflammation

Abscess

Resolution with scarring* *The longer the stimulus persists, the greater the scarring will be.

SUBACUTE INFLAMMATION: Transition period separating acute and chronic inflammation. -hyperaemia -edema is regressing -evidence of repair such as fibroplasia and angiogenesis is lacking. Occasional viral infections may result in primary lymphocytic accumulation often referred to as subacute Mixed inflammtory infiltrate

CHRONIC-ACTIVE INFLAMMATION:

Definition: Chronic inflammation accompanied by acute exacerbations in which the tissues exhibit all of the usual characteristics of chronicity, with superimposed features of acute inflam. Time: Long period with exacerbations Vascular Involvement: Same as with acute Inflammatory cells: Neutrophils and chronic inflammatory cells Lymphatics: May be inflamed Clinical Signs: Variable Repeated episodes of inflam overlap Host fails to contain the acute condition

Common causes of chronic inflammation: 1- Persistent acute inflammation a- Persistence of the agent b- Interference with normal healing 2- Persistent infections by organisms resistant to phagocytosis and intracellular killing -tuberculosis, -leprosy, -brucellosis, -viral

Survival of Phagocytosed Microorganisms Most bacteria are killed following phagocytosis.

some survive - either due to a disorder of the

host’s defense system – or due to their own specialized protective mechanisms. Organisms survive within phagolysosome - eg. Coxiella burnetti, some Mycobacterium Some escape phagolysosome and grow in cytoplasm - Eg. Listeria, Rickettsiae Some don’t allow lysosome to fuse with phagosome - Eg. Toxoplasma gondii - Mycobacterium tuberculosis

Inflammation Defects in Phagocytosis Congenital: 1. Chediak-Higashi Syndrome (autosomal recessive) Defective intracellular transport protein, inability to lyse bacteria

2. Job Syndrome (Hyper IgE) 3. Chronic granulomatous disease (x-linked) Neutrophils incapable of producing H2O2 during phagocytosis - No oxidative burst - Results in recurrent infections.

4. Myeloperoxidase deficiency

Inflammation Defects in Phagocytosis Acquired: • • • • •

Iatrogenic immunosuppression (most common) Overwhelming infections Severe trauma or burn Diabetes mellitus Chronic debilitating disease

Common causes of chronic inflammation: 3- Prolonged exposure to potentially toxic agents: Endogenous -necrotic bone, uric acid crystals Exogenous- silica,asbestos,prosthesis,suture material 4- Autoimmune diseases: Organ specific -Hashimoto’s Non –organ specific- Rheumatoid arthritis , Systemic lupus erythematosus (SLE) 5-Unknown aetiology- ulcerative colitis 6-Primary Granulomatous diseases-sarcoidosis

PATHOGENESIS – CHRONIC INFL Persistent release of chemical mediators induce - Tissue destruction -Persistent increase in blood flow -increased vascular permeability -Recruitment of inflammatory cells macrophages, lymphocytes, plasma cells - Proliferation -Parenchymal cells (epithelial) -Supportive cells (fibroblasts, capillary endothelial cells)

Chronic Inflammation Definition: Inflammation of prolonged duration (weeks to months to years), in which active inflammation, tissue injury and healing occur at the same time. Characteristics 1. Mononuclear inflammatory cells 2. Tissue destruction 3. Repair a. Fibroblasts b. Endothelial cell proliferation (angiogenesis)

CHRONIC INFLAMMATION: Inflammation which persists over a period of time. Chronic Mononuclear infiltration macrophages, lymphocytes, plasma cells Tissue Destruction Attempts of healing – fibrosis and angiogenesis Acute (often present as well) [chronic-active] -Vascular changes -Edema, haemorrhage -Neutrophilic infiltrate

Macrophage-prime cell in chr infl prominent role due the large repertoire of products it can produce when activated Tox. O2

Key macrophage events 1. Recruitment from circulation 2. Local Proliferation 3. Immobilization

Proteases Collagenases Chemotx factors Coag factors AA metabolites NO PDGF FGF TGF-β

4. Differentiation (microglia, kupffer, alveolar macrophage, osteoclasts).

Mononuclear Infiltration Macrophages A component of mononuclear phagocyte system (MPS) including: Blood monocytes Tissue macrophages a- liver (Kupffer’s cells) b- spleen (sinus histiocytes) c- lymph nodes (sinus histiocytes) d- lungs (alveolar macrophages) e- skin (melanophage) f- brain (microglia) g- bone (osteoclast) h- specialised macrophage- epithelioid cell

Chronic inflammation macrophage accumulation persists

1.Continued recruitment of monocytes from circulation 2.Production of adhesion molecules and chemotactic factors -C5a, IL-8, PDGF, TGF-ß, chemokines 3. Local proliferation and Immobilization of macrophages at the site 4. Recruitment of other lymphocytes 5.Destruction of target cells

Macrophage-lymphocytes interaction in chronic inflammation Lymphocytes activate macrophages - IFN Lymphocytes and macropahges constantly stimulate one another unless stimulus is removed

Note that the activated macrophage releases products that are similar to those released by PMNs

Macrophage- chr infl Biologically active substances produced by Macrophages cause: Tissue Injury: -Toxic oxygen metabolites -Proteases -Neutrophilic chemotactic factors -Coagulation factors -Arachidonic acid metabolites -Nitric oxide Fibrosis: -Growth factors (PDGF, FGF, TGFß) -Fibrogenic cytokines -Angiogenesis factors

Chronic inflammation Other types of cells present 1. B & T lymphocytes (antibody and cell mediated immunity) 2. Plasma cells (produce antibodies) 3. Eosinophils (contain major basic protein –MBP, toxic to parasites)

Macrophage – Tissue destruction

Macrophages can produce tissue destruction when inappropriately activated. -Explains why tissue destruction is one of the hallmarks of chronic inflammation. -also reason for seeing acute/active response in chronic inflammation

CHRONIC INFLAMMATION: Inflammation which persists over a period of time.

Lymphatics – involvement variable - +/proliferation and activation Clinical Signs: Primary dependent upon duration of the illness and inflammatory lesions NOTE: Many changes represented in chronic inflammation are also seen in areas of REPAIR.

Macroscopic appearance of chronic inflammation Chronic

ulcer Chronic abscess cavity Thickened wall –hollow viscus Granulomatous inflammation fibrosis

Chronic Peptic Ulcer

healing by fibrosis

Macroscopic appearance of chronic inflammation – chr abscess

Macroscopic appearance of chronic inflammation – hollow viscera

Chronic inflammation interstitial Certain etiologic agents such as viruses are more likely to lead to chronic inflammation, the inflammatory infiltrates of chronic inflammation are more likely to be interstitial (within tissues) rather than exudative (above surfaces or in spaces) like acute inflammation.

Granulomatous Inflammation Definition: Granulomatous response characterized by the presence of lymphocytes,macrophages, and plasma cells .Modified macrophages appear "epithelioid," and may be"multinucleated " Distinctive pattern of chronic inflammation TIME: always chronic Etiology: 1.some non-digestible organism or particle which serves as a chronic inflammatory stimulus, 2.delayed-type hypersensitivity is often required.

Granuloma: Focal area (often small 0.5 -2mm) of granulomatous inflammation, which is organised and comprises of epithelioid macrophages Usually surrounded by a collar of lymphocytes and occasionally plasma cells presence of fibrous connective tissue Presnce of Langhan’s or foreign body giant cells

Granuloma Epithelioid cells - more cytoplasm - look like epithelial cell - specialized for secretion of cytokines - Fewer receptors - Less phagocytic activity Multinucleated Giant cells - Coalescence of macrophages

granulomas There are two types of granulomas: 1- Foreign body granulomas Talc powder, Suture strings, etc 2- Immune granulomas Tuberculosis, Syphilis, Sarcoidosis, Brucellosis Cell Mediated Immunity accelerates development of granulomatous inflam and intensifies

Inflammation Granulomatous Inflammation Fibroblasts

Lymphocytes Macrophages, Epithelioid Cells, and Giant Cells Caseous Necrosis Caseating Granuloma

Non-caseating Granuloma

Secondary Tuberculosis

Granulomatous Inflammation Inflammatory Cells Epithelioid cells (epithelioid macrophages)

Multinucleated Giant cells T- lymphocytes ■Neutrophils - Pyogranulomatous inflammation

■Eosinophils - Eosinophilic granulomatous inflammation

Granulomatous Inflammation Etiology - Continued Bacteria - Mycobacterium sp - Actinomyces bovis Fungi - Blastomyces dermatitidis - Coccidiodes immitis - Aspergillus fumigatus Parasites

Granulomatous Inflammation Fungi Histoplasmosis Blastomycosis Metal/Dust Berylliosis Silicosis Foreign body Splinter Suture Graft material Sarcoidosis

Bacteria Tuberculosis Leprosy Parasites Schistosomiasis

Spectrum of Inflammatory Responses to Infection Inflammatory cell reaction depends on the host immune response to the organism Lymphocytes Granulomas brucella

Viruses Mycobacteria, fungal organisms,

Granulomas with necrosis M. Tuberculosis, Histoplasmosis Eosinophils + Granulomas Granulomas + Suppuration yersinia infection

Helminthes Plague, tularemia, listeria,

*Granulomas do not form in patients with cell-mediated immune deficiency.

Multinucleate Giant cells Normal tissues -osteoclasts (bone) -trophoblasts (placenta) -megakaryocytes (bone marrow) Giant cells in Inflammation -foreign body -Langhan’s -touton Giant cells in Tumour -Reed Sternberg cell -tumour giant cells

Giant cells in Inflammation

Langhan’s

Touton – at sites of lipid breakdown

Foreign body

Foreign body giant cells

Suture material

Silica

Cholesterol

Hair

Characteristics of acute and chronic inflammation ACUTE

CHRONIC

Vascular changes

Vasodilation and Increased permeability

Minimal

Cellular infiltrates

Polymorphs No replication

Mononuclear Replication

Minimal separation due to edema

Cellular proliferation Fibrosis

Stromal changes

exception Typhoid is an example of acute inflammation which induces leucopenia with relative lymphocytosis