Chronic Inflammation: Causes and Processes

• Chronic inflammation is a prolonged process, tissue destruction and inflammation occurs simultaneously with healing attempts.

Causes of Chronic Inflammation

• Can follow acute inflammation or arise distinctly.

Following Acute Inflammation

• Acute inflammation doesn't resolve normally.
• Factors include inciting stimulus persistence, interfered healing, or repeated acute bouts.
• Results in continued inflammation, leading to repair with fibrous scarring.
• Examples of unresolved acute inflammation can become chronic osteomyelitis or chronic abscess.
• Repeated acute inflammation includes conditions like chronic pyelonephritis (urinary tract infection), chronic cholecystitis (gallstones repeatedly injuring mucosa).

Distinct Process from the Outset

• Initiated by viral infections, persisting microorganisms with low toxicity, insoluble particles, or a persistent hypersensitivity state.
• Non-infective or autoimmune conditions may cause it. Aetiology can be unknown.
• Begins as a low-grade, smoldering response without an acute phase.
• Viral infections can lead to Hepatitis B.
• Persistent infections include TB, syphilis, and fungal infections.
• Insoluble particles may include silica, asbestos, or other foreign bodies.
• Hypersensitivity can manifest as allergic contact dermatitis or autoimmune conditions like rheumatoid arthritis.
• Sarcoidosis has an unknown aetiology
• Crohn’s disease (IBD) can arise.

Histological Hallmarks of Chronic Inflammation

• Proliferative changes and a mononuclear inflammatory cell infiltrate is present.

Mononuclear Inflammatory Cell Infiltrate

• Characterized by macrophages, lymphocytes, and plasma cells.
• Macrophages are derived from circulating monocytes recruited by chemotaxis, transforming into macrophages; their activation can result in local proliferation and immobilzation.
• Lymphocytes mediate antibody and cell-mediated immune reactions.
• Plasma cells can arise.
• Plasma cells have abundant cytoplasm, with the nucleus pushed to the side, presence of a blue nucleus, and a "clockface" nucleus.
• Eosinophils are abundant in IgE-mediated immune reactions and parasitic infections.
• Mast cells respond in allergic reactions.
• Neutrophils are present from repeated acute inflammation induced by persistent microbes or mediators from activated macrophage/t-cells.

Granulation Tissue & Function

• Granulation tissue grows from connective tissue, contains thin-walled capillaries and potentially pus-filled cavities.
• Involved in healing process, regeneration, and repair.

Tissue Destruction and Fibrosis (Scarring)

• Can lead to ulcer formation -> bleeding.
• Can cause narrowing of hollow lumens
• Can cause adhesions in serous cavities.

Regeneration

• Epithelial Overgrowth
• Endarteritis obliterans
• Narrowing of small artery lumen (surrounded by ground substances)

Effects of Chronic Inflammation

• Includes fever, acute phase protein production, and increased leukocytes.
• Can cause hyperplasia of the lymphoid system.
• A immune response and reactive systemic amyloidosis with formation of AA protein may be initiated.

Granulomatous Inflammation

• A distinct chronic inflammation pattern characterized by activated macrophages with an epithelioid arrangement.
• Formation is induced by T cell and macrophage activation against agents resistant to eradication.

Structure of Granuloma

• Modified macrophages are collected and surrounded by a rim of lymphocytes, with possible central necrosis.

Types of Granuloma

• Includes foreign body and immunologic granulomas.
• Foreign body granulomas can be incited by talc or sutures.
• Lipid or cholesterol presence leads to cholesterol granuloma.
• Immunologic granulomas are incited by insoluble particles and cause an immune response.
• Can be infective, with TB, leprosy, or fungal/parasitic infections, or related to tumours, e.g. seminoma.

Mycobacterium Tuberculosis

• Classified as acid-fast bacilli, leading to the characteristic tubercle formation.

Primary TB

• Infection of an individual that lacks previous contact with tubercle bacilli.

Secondary TB / Post primary TB

• Arises in previously sensitised individual
• Reactivation of asymptomatic primary disease

Miliary TB

• Develops when mycobacterium gain access to lymphatics and blood to seed distant organs.

Chronic vs. Acute Inflammation

• Acute inflammation is initial and transient, lasting days.
• Chronic inflammation is subsequent and prolonged, lasting weeks/months.
• Acute inflammation exhibits exudative properties.
• Chronic inflammation exhibits proliferative features.
• Acute inflammation leads to the restoration of tissue.
• Chronic inflammation causes destruction or fibrosis.

Acute Inflammation Process

• Tissue damage results in released chemical dilators, increased vascular permeability, and attracts.
• Necrosis (cell death) occurs; the organ loses function, and molecules leak into bloodstream.
• Results in Scarring or dystrophic calcification.
• Vasodilation leads to increased blood flow.
• Leakage of plasma proteins occurs.
• Neutrophil emigration takes place.

Hallmarks and Pathological Basis of Acute Inflammation

• Include redness, swelling, heat, and pain.
• Redness results from dilated blood vessels in injured tissue.
• Swelling due to fluid and cell movement to the injury site.
• Heat is caused by increased blood flow.
• Pain results from oedema pressing on pain receptors.

Pathological Features of Acute Inflammation

• Involved processes are neutrophil margination, diapedesis, and chemotaxis.
• Neutrophils migrate through vessel walls.
• Tissue injury results in chemical attractants that attract the neutrophils.

Neutrophil Chemotaxis attractants

• Bacterial products
• Cytokines
• Complement factors (C5a) -Cause mast cells to release histamine for vasodilation -Neutrophil migration -C3b receptor (act as opsonin) on neutrophil binds to antigen
• Leukotrienes
• Neutrophils recognize the concentration gradient of chemoattractants.

Phagocytosis

• Involves Ab binding to an antigen, forming complex.
• Pseudopodia engulf complexes to form the phagosome.
• Lysosomes fuse and initiate intracellular destruction.
• Destruction is completed through self-suicidal and oxygen dependent mechanisms.

Chemical Mediators

• Released by damaged tissues.
• Can be cell-derived (amines, cytokines, chemokines, arachidonic acids, NO)

Vasoactive amines

• Histamine causes vasodilation and increases vascular permeability.
• 5-hydroxytryptamine (5-HT, serotonin) causes vasodilation and increases vascular permeability.

Cytokines and Chemokines

• Tumour necrosis factor alpha (TNF-a) promotes neutrophil adhesion.
• Interleukin-1 (IL-1) promotes neutrophil adhesion.
• Chemokines attract neutrophils to sites of tissue damage.

Arachidonic Acid Metabolites and Nitric Oxide

• Prostaglandins cause vasodilation and increase permeability.
• Leukotrienes cause vasodilation and increase permeability.
• Nitric oxide (NO) increases vascular permeability.

Histamine

• found in mast cells
• released from mast cell degranulation during physical injuries or binding of antibodies, initiating vasodilation and increased vascular permeability.

Arachidonic acid

• an omega-6 polyunsaturated fatty acid (FA)
• converted to prostaglandins and inflammatory mediators.

Blood Vessels and Vasodilation

• Vasodilation is initiated by chemical mediators.
• includes histamine, prostaglandins, complements or Brady kinin
• Causes laminar flow with the central system (axial flow)

Increased Vascular Permeability Stages

Transudate

• initially, only low molecular weight proteins exit through small pores. Exudate
• pores become larger.
• higher molecular weight proteins and cells exit.

Physiological effects

Immunoglobulins

• move into damaged tissue to help destroy microorganisms Coagulation proteins
• move into tissue to help blood clot formation

Outcomes of Acute Inflammation

• Resolution involves a Usual Result
• Excessive Exudate/Necrosis and Suppuration cause Discharge of Pus.
• Repair and Organisation leads to Fibrosis and Chronic Inflammation
• Persistent causal agent involves the Systemic effects

The systemic effects, symptoms, and additional outcomes

Can be caused by

• Due to PGE2 & PGH2, Cytokines spilling into the systemic Blood Circulation.

Symptoms

• Fever, Tiredness, Loss of Appetite, and Leukocytosis

Outcomes

• Suppuration and Repair/Fibrosis can both occur, separately or in conjunction.

Effects of Acute Inflammation

• Beneficially destroys invading microorganisms and delivers much needed oxygen to the injured zone or the infection site.
• Can negatively impact by also destroying normal cells and causing inflammation in the local swellings.

Acute Appendix

• White areas on the appendix signify accumulation of cells.
• Brown areas on the appendix signify haemorrhage and oedema.
• Vascular dilation and a high neutrophil count are indicators.

Clinical Significance of Acute Inflammation - Lymphangitis

• It can also be detected through the secondary inflammation of lymphatics.

Clinical Significance of Acute Inflammation - Recurrent or Chronic

• Is due to genetic or acquired deficiences in leukocytes and adhesion.

Anti-inflammatory significance

• Antiinflamatories: agents block action of COX 1,2
• Proteases released by neutrophils can excess tissue destruction if not properly regulated.