Inflammation lecture

INFLAMMATION

Inflammation is a non specific, localized immune reaction of the organism, which tries to localized the pathogen agent. Many consider the syndrome a self-defense mechanism.

It consist in vascular, metabolic, cellular changes, triggered by the entering of pathogen agent in healthy tissues of the body.

In Cell Injury – various exogenous and endogenous stimuli can cause cell injury which involve the cells, nuclei and organelles of the cells.

In Vascularized Tissue – same exogenous and endogenous stimuli produce inflammation.

Role of tissue and cells in inflammationThe circulating cells are:

Neutrophils. Monocytes. Eosinophils. Lymphocytes. Basophils. Platelets.

Sign & Symptoms Of InflammationThese are:

Fever (increase temperature). Pain. Tissue damage. Swelling of tissue. Redness of tissue. Loss of movements or restricted

movement, if near joints.

Types Of Inflammation

Inflammation is divided into

I - Acute inflammation, which occurs over seconds, minutes, hours, and days.

II - Chronic inflammation, which

occurs over longer times, days & months.

Acute Inflammation

Acute inflammation, begins within seconds to minutes following the injury of tissues.

The damage may be purely physical, or it may involve the activation of an immune response.

Chronic Inflammation

Chronic inflammation is of longer duration and is associated histologically with the presence of:

Lymphocytes and macrophages. The proliferation of blood vessels. Fibrosis and tissue necrosis.

Response Of Inflammation

The main processes are:

I - Increased blood flow. II - Increased permeability.III - Migration of neutrophils.IV - Chemotaxis.V - Leucocytes recruitment &

activation.


The main processes are:

I - Increased blood flow due to dilation of blood vessels (arterioles) supplying the region.

II - Increased permeability of the capillaries, allowing fluid and blood proteins to move into the interstitial spaces


III - Migration of neutrophils (and perhaps a few macrophages) out of the venules and into interstitial spaces.


V - Leucocytes recruitment & activation.

This is the first step is the binding of the neutrophils to the endothelium of the blood vessels.

The binding is due to molecules, called cell adhesion molecules (CAMs), found on the surfaces of neutrophils and on endothelial cells in injured tissue.

Response of Inflammation V - Leucocytes recruitment &

activation (contd.)

The binding of leukocytes occur in two steps:

In the first step, adhesion molecules called selectins tightly gather the neutrophil to the endothelium, so that it begins rolling along the surface.

Response of Inflammation

V - Leucocytes recruitment & activation (contd).

In a second step, a much tighter binding occurs through the interaction of ICAMs on the endothelial cells with integrins on the neutrophil.

Response of Inflammation

Eosinophils. However, in some circumstances

eosinophils rather than neutrophils predominate in acute inflammation. This tends to occur with parasites (worms), against which neutrophils have little success.

Response of Acute Inflammation Increased Blood Flow, increased

permeability and Edema in Inflammation:

The increased blood flow & increased permeability are readily visible within a few minutes following a scratch that does not break the skin.

Response of Acute Inflammation At first, there is pale red line of

scratch. Later on there is accumulation of

inflammatory cells lead swelling, (inflammation).

Finally, there is accumulation of interstitial fluid cause edema.

Acute Inflammation(recruitment of neutrophils).

Acute Inflammation(Acute Bronchitis)

Acute Inflammation

Outcomes

Resolution The complete restoration of the inflamed tissue back

to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.

Fibrosis Large amounts of tissue destruction, or damage in

tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.

Outcomes

Abscess formation A cavity is formed containing pus, an opaque liquid

containing dead white blood cells and bacteria with general debris from destroyed cells.

Chronic inflammation In acute inflammation, if the injurious agent persists

then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.

Causes of Chronic inflammationI - Persistent infection:

Bacteria. Viruses. Fungi. Parasites

Causes of Chronic inflammationII - Prolonged exposure to

potentially toxic agents:

Endogenous, (atherosclerosis). Exogenous, ( particulate silica-

Silicosis).

Chronic inflammation

Lymphocyte, macrophage, plasma cell (mononuclear cell) infiltration

Tissue destruction by inflammatory cells

Attempts at repair with fibrosis and angiogenesis (new vessel formation)

When acute phase cannot be resolved Persistent injury or infection (ulcer, TB) Prolonged toxic agent exposure (silica) Autoimmune disease states (RA, SLE)

Morphological Features of

Chronic InflammationThese are characterized by:

I - Infiltration by mononuclear cells.

II - Tissue destruction.

III - Removal of damaged tissue, (healing).


Chronic InflammationI - Infiltration by mononuclear cells: The mononuclear cells are become

predominant after 48 hours.These include: Macrophages. Lymphocytes. Plasma cells. Eosinophils. Mast cells.


Chronic InflammationII - Tissue destruction Occur due to: Inflammatory cells. Persistent infecting material.

Granulomatous Inflammation Clusters of T cell-activated

macrophages, which engulf and surround indigestible foreign bodies (mycobacteria, H. capsulatum, silica, suture material)

Resemble squamous cells, therefore called “epithelioid” granulomas with peripheral lymphocytes, fibrosis & multinucleated giant cells.

Chronic Granulomatous Inflammation

Lymph Nodes and Lymphatics Lymphatics drain tissues

Flow increased in inflammation Antigen to the lymph node Toxins, infectious agents also to the

node Lymphadenitis, lymphangitis Usually contained there, otherwise

bacteremia ensues Tissue-resident macrophages must then

prevent overwhelming infection

Systemic effects

Fever One of the easily recognized cytokine-

mediated (esp. IL-1, IL-6, TNF) acute-phase reactions including Anorexia Skeletal muscle protein degradation Hypotension

Leukocytosis Elevated white blood cell count

Systemic effects (cont’d)

Bacterial infection (neutrophilia) Parasitic infection (eosinophilia) Viral infection (lymphocytosis)

Neutrophil is the main cell of chronic inflammation

Eosinophilia occurs in parasitic infection

Lymphocytes are dominant in viral infections

Abscess formation is indicator of acute inflammation

Interleukins causes fever

Vasodilatations is the first step in acute inflammation

Acute inflammation always leads to chronic inflammation

There is no nervous involvement in inflammation

TISSUE REPAIR AND REGENERATION

Skin Injuries

Skin is the body’s first layer of defense against injury

Most frequently injured body tissue Different Types of Skin Injuries

Abrasions Blisters Skin Bruises Incision Laceration Puncture Wound

After Tissue Injury…

1. Capillaries become very permeable Clotting proteins – form a clot / scab Nutrients – healing process

2. Granulation tissue forms New capillaries grow into area Phagocytes – consume blood clot Fibroblasts – collagen fibers (scar

tissue)

3. Regeneration and/or fibrosis Growth of replacement tissue Scab detaches Scar (fibrosis) may be visible

Tissue repair = restoration of tissue architecture and function after an injury

• Occurs in two ways:– Regeneration of injured tissue – Replacement by connective tissue (scarring)

• Usually, tissue repair involves both processes.

• Involves cell proliferation, and interaction between cells and extracellular matrix

Continuously dividing (labile) tissues

• Stable tissues

• Permanent tissues

Tissue response to injury. Repair after injury can occur by regeneration, which restores normal tissue, or by healing, which leads to scar formation and fibrosis.

Repair Involves

Regeneration of injured tissue by parechymal cells of the same type

Replacement by connective tissue (fibrosis), resulting in a scar

In most cases tissue repair involves both of these two processes.

Repair Involves

A complete restore is called complete regeneration

A repair with connective tissue is called incomplete regeneration (fibrous repair, scar repair)

Normal cell proliferation and cell cycle

1- Continuously dividing (labile) tissues

• Cells are continuously proliferating• Can easily regenerate after injury• Contain a pool of stem cells• Examples: bone marrow, skin, GI epithelium

2- Stable tissues

• Cells have limited ability to proliferate• Limited ability to regenerate (except liver!)• Normally in G0, but can proliferate if injured• Examples: liver, kidney, pancreas

3- Permanent tissues

• Cells can’t proliferate• Can’t regenerate (so injury always leads to scar)• Examples: neurons, cardiac muscle

The Extracellular Matrix

A dynamic, constantly, remodeling, macromolecular complex Interstitial matrix Basement membrane (BM)

Major components Collagens Elastic fibers Fibronectin Laminin Proteoglycans

Major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins. To simplify the diagram, many ECM components (e.g., elastin, fibrillin, hyaluronan, syndecan) are not included.

Fibrosis (scar formation)

Granulation tissue is the initial event in the repair of an injury, and consists of richly vascular connective tissue which contains capillaries, young fibroblasts, and a variable infiltrate of inflammatory cells

Do not confuse with GRANULOMA

Healing of Skin Wound

Primary intention: the usual case with a surgical wound, in which there is a clean wound with well-apposed edges, and minimal clot formation

Secondary intention: when wound edges cannot be apposed, (e.g., following wound infection), then the wound slowly fills with granulation tissue from the bottom up. A large scar usually results.

Factors that Influence Wound Healing

Type, size, and location of the wound Vascular supply (diabetics heal poorly) Infection - delays wound healing and

leads to more granulation tissue and scarring

Movement - wounds over joints do not heal well due to traction

Radiation - ionizing radiation is bad, UV is good

Factors that Influence Wound Healing

Overall nutrition: vitamin and protein deficiencies lead to poor wound healing, especially vitamin C, which is involved in collagen synthesis

Age: younger is definitely better! Hormones - corticosteroids

drastically impair wound healing, because of their profound effect on inflammatory cells

Complications of Wound Healing Defective scar formation Excessive scar formation (keloid) Contraction Defective scar formation

Dehiscence or ulceration is usually due to: Wound infection (common) Malnutrition (scurvy - rare) Hypoxia with ulceration, usually due

to inadequate vascularity in a skin flap (common).

Dehiscence

A, Keloid. Excess collagen deposition in the skin forming a raised scar known as keloid.

B, Note the thick connective tissue deposition in the dermis.

Scar contracture in a boy after scald

Cirrhosis (gross)

Inflammation lecture

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