Chronic InflammationDefinition:

Inflammation of prolonged duration in which active inflammation, tissue injury and the healing proceed simultaneously

Causes:Persistent Infections

Ex. Treponema palladium (causative organism of syphilis)

Organism of low toxicity and evoke an immune reaction = delayed hypersensitivity

Prolonged Exposure to toxic AgentsAutoimmunity

Ex. Autoimmune diseases

Chronic InflammationMorphologic Features:

Infiltration with mononuclear cells (macrophages, lymphocytes & plasma cells) indicates persistent reaction to injury

Tissue destruction Done by way of Inflammatory cells

Repair involving angiogenesis and fibrosis Attempt to replace lost tissue

Chronic InflammationMononuclear Phagocyte System

Circulating blood monocytes →Tissue macrophages

↓Kupffer cells (liver)

Sinus Histiocytes (spleen)Microglia (CNS)Alveolar Macrophages (lung)

Maturation of Mononuclear Phagocytes

Mechanisms of macrophage accumulation during Chronic Inflammation

Continued recruitment of monocytes from the circulationMost important source for macrophages

Local proliferation of macrophages from the blood stream

Immobilization of macrophages within the site of inflammation Cytokines and oxidized lipids can cause

immobilization

Effects of Macrophage Activation

Other Cells of Chronic Inflammation

Infiltration with mast cells, lymphocytes and plasma cells

LymphocytesMobilization in antibody – mediated response

Mast CellsWidely distributed in connective tissues and participate

in both acute and persistent inflammatory reactionsBinds the Fc portion of the IgE antibody

Plasma CellsProduce antibody directed either against persistent

antigen in the inflammatory site or against altered tissue components

Eosinophilsparasitic infectionsMediated by IgEEotaxin – a chemokine that has the ability to prime

eosinophils for chemotaxis

Granulomatous inflammation

It’s a pattern of chronic inflammatory reaction in which the predominant cells are

Aggregations of macrophages having an enlarged, squamous cell-like appearance (called Epitheloid macrophages)

GRANULOMA = Nodular collection of Epitheloid macrophages surrounded by a rim of LYMPHOCYTESIt’s a focal area of Granulomatous inflammationIn an H&E stain can see:

Epitheloid cells have pale granular cytoplasm with indistinct boundaries

Giant cells = Epitheloid cells that fuse (Langhan’s) Can be found in the periphery or sometimes in the center

of the granuloma Have large mass of cytoplasm Have 20 or more small nuclei arranged in the periphery

or haphazardly

Granulomatous inflammationTypes of Granulomatous Inflammation1. Immune granulomas

Caused by insoluble particles that are capable of inducing a cell-mediated immune response

Macrophages are transformed into Epitheloid cells and multinucleate giant cells

Examples: Bacteria

Tuberculosis *** (high incidence due to drug resistant stains)

Leprosy Parasites

Schistosomiasis (3 types) Fungi

HistoplasmosisBlastomycosis

Granulomatous inflammation2.Foreign Body Granulomas

Don’t incite either an inflammatory or immune response.

Epitheloid cells and giant cells are apposed to the surface and encompass the foreign body.

The foreign body is usually found in the center of the granuloma.Examples:

Metal/DustBerylliosisSilicosis

Foreign bodySplinterSuture

Granulomatous inflammation 3 Sarcoidosis

Bad systemic disease, probably autoimmune disease

Etiologic agent is unknown

LYMPHATICS IN INFLAMMATION

Secondary line of defense Lymph flow is increased in

inflammation and helps drain the edema fluid

Lymphangitis Lymphadenitis

Third line of defense

organisms gain access to the vascular circulation- Bacteremia

next line of defensePhagocytic cells of the liver, spleen, and

bone marrow heart valves, meninges, kidneys, and

joints are favored sites of implantation for blood-borne organisms

Systemic Effects of Inflammation Infections→ reactions to cytokines

↓Acute phase response or the systemic

inflammatory response syndrome (SIRS)Acute phase response consists of

Acute phase response

Fever-elevation of body temperature by 1° to 4°Cpyrogens stimulate prostaglandin

synthesis in the vascular and perivascular cells of the hypothalamus exogenous pyrogens (LPS) endogenous pyrogens (TNF, IL-1)

1.Fever

PGE2 via neurotransmitters such as cyclic AMP

↓Reset the temperature set-point at a higher

level↓

Fever↓

Fever induce heat shock proteins that enhance lymphocyte responses to microbial antigens

2.Acute-phase proteins

C-reactive protein (CRP) Fibrinogen Serum amyloid A protein (SAA)

Synthesised by hepatocytesSynthesis is by upregulated by

cytokinesIL-6 (for CRP and fibrinogen) IL-1 or TNF (for SAA)

2.Acute-phase proteins

CRP and SAA act as opsonins helps in clearing

Necrotic cell nucleiMicrobial cell walls

Unlimited production of SAA - secondary amyloidosis in chronic inflammation

3.Leukocytosis

Common feature of inflammatory reactionsBacterial infectionUsually 15,000 or 20,000 cells/μl,

3.Leukocytosis contd…

A) Accelerated release of cells from the bone marrow post - mitotic reserve pool

↓

(shift to the left) by cytokinesB) Colony stimulating factors cause

increase production of WBC

3.Leukocytosis contd…

Most bacterial infections induce Neutrophilia

Viral infections-LymphocytosisTyphoid fever , Rickettsiae-Leukopeniabronchial asthma, hay fever, and parasitic

infestations- Eosinophilia

Other features of APR

Effects of cytokines on brain cellsIncreased pulse and blood pressureDecreased sweating, Rigors (shivering)Chills (search for warmth)AnorexiaMalaise

Sepsis Sepsis ;- severe bacterial infection Large amounts of LPS & TNF Multiple small thrombi by expressing

Tissue Factor (TF) on Endothelial cells (EC) Septic shock – Triad

1. Liver failure – no Gluconeogenesis (Hypoglycemia)

2. Loss of perfusion pressure & heart failure – hemodynamic shock

3. Disseminated Intravascular Coagulation (DIC) – Multiple Thrombi in circulation & Fibrin split products

Multi Organ Failure Mainly Lung , Liver also Kidney & Bowel

Consequences of impaired inflammation Defective

inflammation↑ susceptibility to

infectionDelay in wound

healingTissue damage

Excess InflammationAllergiesImportant in

CancerAtherosclerosisFibrosis as a sequel

of chronic infections, metabolic conditions