INFLAMMATION

Manar hajeer, MD

Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult.

Inflammation accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes and toxins). It then sets into motion the events that eventually heal and repair the sites of injury.

Inflammation is part of a broader protective response that immunologists refer to as innate immunity .

Pathology may even become the dominant feature if the reaction is:

1. very strong (e.g., when the infection is severe)

2. prolonged (e.g., when the eliciting agent resists eradication).

3. inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases or against usually harmless environmental antigens in allergic disorders)

Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage.

The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various cells.

COMPONENTS OF INFLAMMATION

Inflammatory responses involve an interaction of: Blood vessels (endothelial cells and smooth muscles of vessels) White blood cells and platelets

Neutrophils, monocytes, basophils lymphocytes, eosinophils. Plasma proteins and chemical mediators:

Coagulation / fibrinolytic system, kinin system, complement system• Extracellular matrix and stromal cells

Mast cells, fibroblasts, macrophages & lymphocytes. Structural fibrous proteins, adhesive glycoproteins, proteoglycans,

basement membrane.

Inflammation and repair may have potentially harmful outcomes such as digestion of normal tissues, and inappropriate inflammatory response:

Rheumatoid arthritis. Life threatening hypersensitivity reactions. Some forms of fatal renal diseases. Fibrous scarring after pericarditis

ACUTE VS CHRONIC INFLAMMATION

Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation.

Chronic inflammation may be more insidious, is of longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring).

Acute inflammation

CAUSES OF ACUTE INFLAMMATION

Infections (bacteria, fungal, viruses, and parasites). Physical agents (heat, cold, burns, radiation, and trauma). Chemicals (acids, alkali, bacterial toxins, metals, and

caustic substances). Necrotic tissue (infarction) All types of immunologic reactions, i.e., hypersensitivity

(contact with some substances), autoimmune reactions

LOCAL SIGNS OF ACUTE INFLAMMATION

Hottness. Redness. Swelling. Pain. Loss of function.

COMPONENTS OF ACUTE INFLAMMATION

Vascular changes: Alterations in vessel caliber resulting in increased

blood flow (vasodilation) and structural changes that permit plasma proteins to leave the circulation (increased vascular permeability).

Cellular events: Emigration of the leukocytes from the

microcirculation and accumulation in the focus of injury (cellular recruitment and activation).

The principal leukocytes in acute inflammation are neutrophils.

NORMAL

VASCULAR CHANGES

1- Changes in Vascular Caliber and Flow: Transient vasoconstriction (lasting only for seconds) Arteriolar vasodilation. Capillary and venular vasodilatation increased blood

flow and engorgement of the down-stream capillary beds. Slowing of the circulation and stasis. Leukocyte margination.

Red blood cells become more concentrated, thereby increasing blood viscosity and slowing the circulation (stasis),,,,,,,,NET RESULT HOTTNESS AND REDNESS.

VASCULAR CHANGES

Transient vasoconstriction of arterioles disappears within 3-5 seconds in mild injuries may last several minutes in more severe injury (like burns).

Vasodilatation:: first involves the arterioles thus leading to increasing blood flow.

Increased blood volume lead to increased local hydrostatic pressure leading to transudation of protein -poor fluid into the extravascular space (in early phase).

Transudate results from hydrostatic imbalances between vessel and extravascular tissues, vascular permeability is normal, has a low protein content (ultrafiltrate of blood plasma)

Persistence of stasis leads to peripheral orientation of leukocytes (mainly neutrophils) along the vascular endothelium [leukocytic margination].

leukocytes first stick transiently then more avidly, then they migrate through the vascular wall into the interstitial tissue [emigration]..

NEUTROPHIL MARGINATION

2 - Increased Vascular Permeability: increasing vascular permeability that allows the movement of

protein-rich fluid and even cells (exudate)………..NET RESULT IS EDEMA.

Components of exudate Fluid: contains nutrients, mediators, immunoglobulins,

complement Fibrin (insoluble): derived from the plasma protein fibrinogen

(soluble), also important in clotting Cells: neutrophils predominate (6-72 hours), also macrophages

(involved slightly later: 48+ hours)

MECHANISMS OF INCREASED VASCULAR PERMEABILITY IN ACUTE INFLAMMATION

Endothelial cell contraction (most common), in post capillary venules .

Others:. Endothelial cell retraction. Direct endothelial injury. Leukocyte-mediated endothelial injury . Increased transcytosis of proteins . Leakage from new blood vessels.

Immediate transient response Begins directly after injury, peaks in 5-10 min., phases out in 15-30

min. Elicited by histamine and other chemical mediators Affects small & medium size venules, increasing gaps between

endothelial cells (contraction of endothelial cells).

Immediate sustained reactions: leakage starts immediately after injury and sustained at high level for

several hours, lasts for several days (until damaged vessels thrombosed or repaired)

It is caused by direct severe endothelial cell injury and necrosis. e.g. severe burns and infections.

Arterioles, capillaries and venules are all affected..

Delayed prolonged leakage: Begins after a delay (2 to 12 hours) and lasts for hours or days, e.g. mild

to moderate thermal injury, x-ray or ultraviolet irradiation (sunburn).

Involves venules and capillaries.

Induced by direct cell injury.

LEUKOCYTE CELLULAR EVENTS

Margination, rolling and adhesion.

Transmigration between endothelial cells.

Migration in the interstitium toward the site of stimulus (chemotaxis and

activation) Phagocytosis and degranulation (Release of leukocyte products.)

Rolling, adhesion, and transmigration are mediated by the binding of complementary adhesion molecules between leukocytes and endothelial surfaces.

Chemical mediators (chemoattractants) affect these processes by modulating the surface expression of the adhesion molecules and by stimulating directional movement of the leukocytes.

Different molecules play predominant roles in different steps of this process:

Selectins in rolling. Chemokines in activating the neutrophils to

increase surface affinity of integrins. Integrins in firm adhesion. CD31 (PECAM-1) in transmigration

1- MARGINATION AND ROLLING

This process of leukocyte accumulation at the periphery of vessels is called margination.

Subsequently, leukocytes tumble on the endothelial surface, transiently loose sticking along the way, a process called rolling.

The weak and transient adhesions involved in rolling are mediated by the selectin family of adhesion molecules.

The three members of this family are E-selectin expressed on endothelial cells; P-selectin present on endothelium and

platelets; L-selectin on the surface of most

leukocytes

SELECTINS

The endothelial selectins are typically expressed at low levels or not present at all on normal cells.

They are up-regulated after stimulation by specific mediators.

In nonactivated endothelial cells, P-selectin is found primarily in intracellular Weibel-Palade bodies; however, within minutes of exposure to chemokines, P-selectin is distributed to the cell surface.

E-selectin, which is not expressed on normal endothelium, is induced after stimulation by inflammatory mediators such as IL-1 and TNF.

2- FIRM ADHESION

This adhesion is mediated by integrins expressed on leukocyte cell surfaces interacting with their ligands on endothelial cells.

Integrins are normally expressed on leukocyte plasma membranes in a low-affinity form and do not adhere to their appropriate ligands until the leukocytes are activated by chemokines.

The ligands for integrins found on endothelial cell surface include: ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), which bind to their corresponding integrins.

The net result is stable adhesion of leukocytes to endothelial cells at sites of inflammation.

EFFECTS OF CHEMOTACTIC FACTORS ON ENDOTHELIAL CELLS

Effects of Chemotactic Factors on Leukocytes

3- TRANSMIGRATION OF LEUKOCYTES

leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions (diapedesis).

Migration of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate movement of the leukocytes toward their chemical gradient.

PECAM-1 (platelet endothelial cell adhesion molecule 1, also called CD31), mediates the binding events needed for leukocytes to traverse the endothelium.

After passing through the endothelium, leukocytes cross vascular basement membranes.

Diapedesis

4- CHEMOTAXIS

Both exogenous and endogenous substances can be chemotactic for leukocytes:

(1) bacterial products, particularly peptides with N-formylmethionine termini

(2) cytokines, especially those of the chemokine family like IL-8.

(3) components of the complement system, particularly C5a

(4) products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)

LEUKOCYTE CELLULAR EVENTS

LOBAR PNEUMONIA

NATURE OF LEUKOCYTE INFILTRATES IN ACUTE INFLAMMATORY REACTIONS

In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours.

Neutrophils are short-lived-they die by apoptosis and disappear within 24 to 48 hours-while monocytes survive longer.

5-LEUKOCYTE ACTIVATION

Leukocytes express on their surface different kinds of receptors that sense the presence of microbes by recognizing the endotoxin (LPS) and many other bacterial and viral products

LEUKOCYTE ACTIVATION

1- Phagocytosis of particles, an early step in the elimination of harmful substances.

2- Production of substances that destroy phagocytosed microbes and remove dead tissues; these leukocyte products include lysosomal enzymes and reactive oxygen and nitrogen species.

3- Production of mediators that amplify the inflammatory reaction, including arachidonic acid metabolites and cytokines.

4- Modulation of the numbers and affinity of leukocyte adhesion molecules

LEUKOCYTE ACTIVATION

PHAGOCYTOSIS

The process of ingestion and digestion by cells of solid substances, e.g., other cells, bacteria, necrotic tissue or foreign material.

Steps of phagocytosis:Recognition, attachment and binding to cellular receptors.Engulfment.Fusion of phagocytic vacuoles with lysosomes.Killing or degradation or ingested material.

PHAGOCYTOSIS

KILLING OF INFECTIOUS AGENTS Oxygen burst products (free radical) Lysosomal enzymes Bactericidal permeability increasing protein lysozyme Major basic protein (in eosinophils) Defensins

OUTCOMES OF ACUTE INFLAMMATION

Complete resolution Healing by scarring or fibrosis Abscess formation Progression to chronic inflammation

OUTCOME OF ACUTE INFLAMMATION

OUTCOMES OF ACUTE INFLAMMATION

Complete resolution Occurs when the injury is limited or short-lived and when the tissue is

capable of regeneration: Neutralization and removal of chemical mediators Normalization of vascular permeability Halting of leukocyte emigration Clearance of edema (lymphatic drainage) , inflammatory cells and

necrotic debris (macrophages).

OUTCOMES OF ACUTE INFLAMMATION

Scarring or fibrosis Occurs when

There is substantial tissue destruction.When the inflammation occurs in tissue not capable

of regeneration.There is extensive fibrinous exudate that cannot

comlpetely absorbed.

OUTCOMES OF ACUTE INFLAMMATION Abscess formation:

may occur in the setting of certain bacterial or fungal infection (pyogenic or “pus forming”)

Progression to chronic inflammation in cases of persistent infections or autoimmune diseases.

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

1. Serous inflammation :

- Characterized by a watery, protein-poor fluid - Example is the skin blisterفقاعة resulting from a burn or viral

infection2. Fibrinous inflammation :

- Is characteristic of inflammation in meninges, pericardium, and pleura

BURN BLISTER

FIBRINOUS PERICARDITIS

3. Suppurative (purulent) inflammation

- Means collection of large amounts of pus consisting of many neutrophils, necrotic cells, and edema

- Organisms (such as staphylococci) cause suppuration and are referred to as pyogenic (pus-forming )

Abscesses الدمل أو . means cavities filled with pusالخراج

SUBCUTANEOUS ABSCESS

LUNG ABSCESS

CHRONIC INFLAMMATION

a. Inflammation of prolonged duration (weeks to years) b. In which continuing inflammation, tissue injury, and healing by

fibrosis, proceed simultaneously .

c. Characterized by infiltration with macrophages, lymphocytes, and plasma cells.

-Chronic inflammation occurs in: 1. Persistent infections by microbes that are difficult to

eradicate such as Mycobacterium tuberculosis, 2. Immune-mediated diseases (hypersensitivity diseases and

immune reactions against the affected person's own tissues, leading to autoimmune diseases)

3. Prolonged exposure to toxic agents. a. Exogenous materials such as inhaled silica. b. Endogenous agents such as cholesterol which may contribute

to atherosclerosis.

- Autoimmunity plays an important role in several chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis الصدفية

- Immune responses against common environmental substances are the cause of allergic diseases, such as bronchial asthma

CHRONIC INFLAMMATORY CELLS

1. Macrophages

- Are the dominant cells of chronic inflammation- Are tissue cells derived from circulating blood monocytes- They migrate to a site of injury within 24 to 48 hours after the

onset of acute inflammation

2. Lymphocytes

- Are the major cells of inflammation in many autoimmune and other chronic inflammatory diseases

3- Eosinophils:

- Are characteristic of

A. Parasitic infections

B. Allergic diseases such as asthma

4. Mast cells:

Source of histamine early in allergic reactions

CHRONIC GRANULOMATOUS INFLAMMATION

Granulomatous inflammation is a specific type/pattern of chronic inflammation characterised by the presence of activated macrophages that either become ‘epithelioid’ in appearance or become giant multinucleate cells.

Tuberculosis, leprosy, schistosomiasis, sarcoidosis, Crohn’s disease, reactions to foreign material (e.g. suture).

THE ACUTE-PHASE RESPONSE OF INFLAMMATION

A. Fever,:

- Elevation of body temperature, - Is produced by substances called pyrogens that act by

stimulating prostaglandin synthesis

- NSAIDs (non-steroidal anti-inflammatory drugs), including aspirin, reduce fever by blocking prostaglandin synthesis.

B- Elevated plasma levels of acute-phase proteins.

- These proteins are synthesized in the liver,

- Examples

1. C-reactive protein (CRP)

Elevated serum levels of CRP are now used as a marker for increased risk of myocardial infarction or stroke in patients with atherosclerotic vascular disease

2. Fibrinogen, Fibrinogen binds to erythrocytes and causes them to form stacks

that sediment more rapidly than individual erythrocytes and this is the basis for measuring the erythrocyte sedimentation rate (ESR)

- ESR is a simple test for the systemic inflammatory response,

C. Leukocytosis:

- Is a common feature of inflammatory reactions, especially those induced by bacterial infection

- The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some cases it may reach 40,000 to 100,000 cells/mL. called leukomoid reaction

a. Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia

b. Viral infections, such as infectious mononucleosis, and mumps associated with increase numbers of lymphocytes (lymphocytosis).

Note: Typhoid fever and certain viruses are associated with leukopenia

c. Bronchial asthma and parasite infection cause increase in the number of eosinophils,

D Rigors (shivering)

E. Chills (perception of being cold )