Inflammation

Question 1

Explain the pathology and histological features of acute inflammation

Answer 1

Inflammation: reactions of living vascularized tissue to sub-lethal cellular injury

• A protective response geared towards removing the cause and consequences of the injury
• Sets stage for potential healing
• Tightly regulated process consisting mainly of leukocyte and vascular responses
• Triggered by various cell types and soluble mediators

Acute inflammation is a rapid non-specific response to cellular injury

Key Features

• Histamine release
• Hours/days
• May be prominent necrosis

Histology

• Lots of neutrophils
• May also be mast cells and eosinophils

Recognised on examination by the cardinal signs:

• Rubor (Redness)
• Calor (Heat)
• Tumor (Swelling)
• Dolor (Pain)

•Rapid delivery of leukocytes and plasma proteins to the site of injury

•Three main components:

1. Alteration in the calibre of blood vessels to increase flow
2. Structural changes to the microvasculature to allow proteins and leukocytes to leave the circulation
3. Emigration, accumulation and activation of leukocytes at the focus of injury

Vasodilation

• Vasodilation is one of the earliest manifestations
• May be preceded by brief arteriolar constriction
• Causes the heat and redness of acute inflammation
• Induced by several mediators including histamine and nitric oxide
• Affect vascular smooth muscle
• Quickly followed by increased permeability of microvasculature
• Increased diameter and loss of fluid slow down flow and lead to stasis
• Histamine is a major vasoactive amine
• Richest source is mast cells
• Preformed and released as the cell degranulates
• Triggered by binding of surface IgE, trauma, heat, cold, complement C3a/C5a, cytokines IL-1 / IL-8
• Leads to vasodilation and also increased vascular permeability
• Dysregulation can be seen in allergic reactions
• Type 1 Hypersensitivity

Increased Vascular Permeability

• Endothelial cells contract; increased interendothelial spacing
• Immediate Transient Response
• Histamine and Nitric Oxide

Exudate:

• Result of increased vascular permeability
• High protein content (fibrin, antibodies)
• High specific gravity
• Contains cells and cell debris
• May be purulent (leukocyte-rich)

Exudate serves to:

• Dilute pathogens
• “Wall off” pathogens
• Permit spread of soluble inflammatory mediators
• Provide substrate for inflammatory cell migration
• Intravascular fluid losses can be very high
• Life threatening in severe burns

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Transudate:

• Ultrafiltrate of blood plasma caused by increased hydrostatic pressure or decreased osmotic pressure
• Low protein content (albumin)
• Low specific gravity
• Low cell content

Leukocyte Response:

• The most important leukocytes in the initial phase of typical acute inflammation are those capable of phagocytosis
  
  • Neutrophils
  • Macrophages
• Kill bacteria and eliminate foreign and necrotic material
• Produce multiple factors and mediators that interact with other cells
• Overactivation may prove harmful in the long term

Neutrophils

• Neutrophils are produced in bone marrow
• Circulate in blood and migrate towards damaged tissues
• Often the first cell into a damaged area
• Rapid response
• Main roles are to kill bacteria and recruit additional cells
• Phagocytosis
• Degranulation – enzymes, free radicals, soluble mediators

Leukocyte Response

• Leukocytes first need to be recruited to the site of injury
• The process of exiting the vessel lumen (extravasation) has the following steps:

1. Margination
2. Rolling
3. Adhesion to activated endothelium
4. Transmigration (diapedesis) across endothelium through vessel wall
5. Migration through tissues towards chemotactic stimulus

• Once recognised, microbes and necrotic tissues need to be destroyed
• Phagocytosis requires:
• Attachment
• Engulfment and formation of phagocytic vacuole
• Degradation by various substances
• Reactive oxygen species; myeloperoxidase (neutrophils)
• Lysozyme (antibacterial)
• Lactoferrin (iron binding; prevents bacterial reproduction)
• Major Basic Protein (produced by eosinophils; antiparasitic)

Termination of the Acute Inflammatory Response

• Inflammatory mediators and neutrophils have a short half life
• Macrophages release a number of anti-inflammatory products
• Mast cells and lymphocytes produce anti-inflammatory products
• Lipoxins
• The cause of the injury (e.g. bacteria) is removed
• Under normal conditions, process comes to a stop

Question 2

Explain the pathology and histological features of chronic inflammation

Answer 2

Chronic inflammation is a persistent inflammatory response

• Ongoing inflammation and repair over weeks to years
• May arise form acute inflammation

Key Features

• Cytokines
• Caused by persistent damage (e.g. persistent infection, autoimmunity)
• Form granulation tissue

Histology

•Lots of macrophages, lymphocyes and plasma cells

Granulomatous inflammation is a specific subtype of chronic inflammation

Characterised by:

• Mononuclear cell infiltrate (macrophages, lymphocytes, plasma cells)
• Tissue destruction, induced by persistent inflammatory agent or by the inflammatory cells themselves
• Attempts at healing by replacement of damaged tissue with connective tissue
• Accomplished by fibrosis and accompanied by angiogenesis
• “Granulation tissue”

Macrophages

• In the acute phase of inflammation macrophages destroy the offending agent either directly or by stimulating other pathways that do so
• When the offending agent is cleared, the macrophages fade away
• In chronic inflammation macrophages persist and cause significant tissue destruction
• Ongoing tissue destruction can trigger the inflammatory cascade in of itself
• Acute and Chronic inflammation may co-exist

A number of other cell types are also involved:

• T-Lymphocytes (can be stimulated by macrophages; regulated immune reaction and can be cytotoxic)
• Plasma cells (develop from activated B-lymphocytes and produce antibodies)
• Eosinophils (in response to parasites or IgE mediated inflammation)
• Mast cells
• Neutrophils if co-existing acute inflammation
• There is prominent angiogenesis
• VEGF from macrophages and endothelial cells

Question 3

Explain the pathology and histological features of granulomatous inflammation

Answer 3

Granulomatous inflammation:

• Distinctive pattern of chronic inflammation showing granuloma formation
• A granuloma is an aggregate of activated macrophages; an attempt to eliminate a resistant offending agent
• Triggered by strong and specific T-lymphocyte reaction
• Several causes
• Infections (TB, leprosy, syphilis, fungi)
• Foreign material (foreign body granuloma)
• Tumour reaction
• Granulomatous diseases (Sarcoidosis, Crohn’s disease)

Histology

• Granuloma: ball of activated lymphocytes and macrophages
• Giant cells: fused macrophages with horseshoe-shaped nuclei

Question 4

List the sequelae of inflammation

Answer 4

Positive outcomes:

• Removal of offending agent
• Cessation of the inflammatory response
• Healing of tissue damage with preservation of integrity and function (resolution)

Undesirable Outcomes

• Excessive tissue damage and scarring
• Possibly with detrimental effect on adjacent tissue
• Systemic involvement with multiorgan failure
• Septic shock, amyloid

Inflammation cuts both ways

Question 5

Wound healing: explain the sequential changes in wound healing

Answer 5

Wounds may heal either by resolution or scarring

Resolution

• involves regeneration of parenchymal cells with restoration of function
• Only occurs if tissue can regenerate and there is little structural damage
• Example: lobar pneumonia

Repair by scarring

• involves angiogenesis, migration and repair of fibroblasts, scar formation and connective tissue remodelling
• Occurs when there is significant tissue loss and tissue is unable to regenerate; results in loss of function

Process

• Fibroblasts lay down collagen
• Collagen is remodeled for maximal tensile strength
• Normal tissues is replaced by non-functional scar tissue

Wound healing may be impaired by:

1. Poor nutrition (protein, energy)
2. Vitamin deficiency (Vitamin C, Vitamin A)
3. Mineral deficiency (Zinc)
4. Suppressed inflammation (Steroids, Old Age)
5. Poor local blood supply (Peripheral vascular disease)
6. Persistent foreign body
7. Movement

Complications of Wound Healing

Keloid

•Due to excess collagen deposition

Contracture

• Fibrous tissue contracts
• Can cause reduced joint mobility

Impaired Organ Function

•Due to replacement of functional parenchymal tissue by scar tissue