Inflammation: response of vascularized tissue that delivers leukocytes and molecules of host defense from the circulation to the sites of and cell damage in order to eliminate the offending agents

Cells of Acute Inflammation

1. Polymorphneuclear leukocytes (PNL) or neutrophils:

   • migrate from the blood

   • Function: phagocytosis

   • characteristic cells of acute inflammation

2. Pus cells (dead polymorph nuclear leukocytes)

   • release lysosomal enzymes which liquefy necrotic tissues, forming pus

Three Major Components

1. Vascular dilation leading to an increase in blood flow

2. Increased permeability of the microvasculature allowing plasma proteins and leukocytes to leave the circulation

3. Emigration of leukocytes from blood vessels, their accumulation in the focus of injury and activation to eliminate the offending agent

Reaction of Blood Vessels

Edema: excess fluid in interstitial tissue or body cavities.

• Can either be:

  • Exudate: inflammatory extravascular fluid with cellular debris and high protein concentration

    • presence reflects increased vascular permeability

  • Transudate: excess extravascular fluid with low protein content

    • an ultrafiltrate of blood plasma resulting from elevated fluid pressures or diminished plasma osmotic forces

Pus: purulent inflammatory exudate rich in neutrophils and cell debris

Changes in Vascular Flow and Caliber

Begins immediately after injury

• Vasodilation: increases flow into areas of injury = increasing hydrostatic pressure

• Increased vascular permeability causes exudation of protein-rich fluid

• Vasodilation + fluid loss = increased blood viscosity and increased concentration of red blood cells = stasis

• with stasis, leukocytes (mostly neutrophils) accumulate along endothelium (marginate) and are activated by mediators to increase adhesion and migration through vessel wall

Increased Vascular Permeability (Vascular Leakage)

Increased vascular permeability can be induced by:

• Contraction of venule endothelium to form intercellular gaps

  • most common mechanism

  • evoked by chemical mediators (histamine, bradykinin, leukotrienes (LTs))

  • occurs rapidly

• Direct endothelial injury

  • severe necrotizing injury (e.g. burns) causes endothelial cell necrosis and detachment that affects blood vessels

  • recruited neutrophils may contribute to injury (e.g. through reactive oxygen species)

  • immediate and sustained endothelial leakage

• Increased transcytosis

  • transendothelial channels form by:

    • interconnection of vesicles derived from the vesiculo-vacuolar organelles (VVO)

    • Vascular endothelial growth factor (VEGF) and other factors

Responses of Lymphatic Vessels and Lymph Nodes

• represent a secondary line of defense

• in inflammation, lymphatic flow is increased to drain edema fluid, leukocytes, and cell debris from extravascular space

• in severe injuries, drainage may also transport the offending agent

  • lymphatics may becomes inflamed

    • lymphangitis

    • manifest grossly as red streaks

  • draining lymph nodes may becomes inflamed

    • lymphadenitis

    • manifest as enlarged, painful nodes

    • usually due to lymphoid follicle and sinusoidal phagocyte hyperplasia (reactive lymphadenitis)

Leukocyte Recruitment to Site of Inflammation

• recognize invading pathogens and necrotic debris, eliminate them, and produce growth factors to facilitate repair

• type of leukocyte depends on the original stimulus and duration of inflammatory response

  • Bacterial infections: neutrophils

  • Viral infections: lymphocytes

  • Allergic reactions: increased eosinophils

  • Hypersensitivity reactions: mixed

  • Necrosis: neutrophils (6 to 24 hours), replaced by monocytes (24 to 48 hours)

• Leukocyte movement:

  • Margination and rolling

  • Adhesion and transmigration

  • Chemotaxis and activation

  • Phagocytosis and degranulation

Margination

In normally flowing blood in venules red blood cells are confined to a central axial column

• as blood flow slows (stasis), leukocytes accumulate at the periphery of vessels along the endothelial surface

Rolling

• tumbling of leukocytes on the endothelial surface, transiently sticking along

• Mediated by: selectin molecules

  • 3 types:

    • L-selectin: expressed on leukocytes

    • E-selectin: expressed on endothelium

    • P-selectin: expressed on platelets and endotheium

  • bind via lectin domains to oligosaccharides on cell-surface glycoproteins

  • regulated by cytokines produced in response to infection and injury

  • P-selectin activated by: histamine and thrombin

  • E-selectin activated by: IL-1 and tumor necrosis factor (TNF)

Mechanism of Rolling

• leukocytes express L-selectins at the tips of their microvilli and also express ligands for E-selectin and P-selectin, all of which bind to the complementary molecules on the endothelial cells

• low affinity interactions with a fast off-rate

  • easily disrupted by flowing blood

• leukocytes bind, detach and bind again

• roll along the endothelial surface

Adhesion

• firm adhesion of leukocyte to endothelial cell surface

• mediated by:

  • integrins on leukocytes

  • immunoglobulin superfamily on endothelial cells: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)

  • immunoglobulin molecules on endothelial cells that bind integrins on leukocytes

    • lymphocyte function associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) bind ICAM-1

    • very late antigen-4 (VLA-4) binds to VCAM-1

Chemoattractants (chemokines) and cytokines affect adhesion and transmigration

• after histamine exposure, P-selectin is rapidly translocated to the cell surface

• TNF and IL-1 induce endothelial expression of E-selectin, ICAM-1, and VCAM-1

• integrins are converted from low-affinity to high-affinity forms by chemokines

Transmigration

Transmigration (diapedesis): crawling of leukocytes between endothelial cells and squeezing along the intercellular junctions and through basement membrane into extracellular space

• occurs mainly in postcapillary venules

• mediated by: homotypic interactions of platelet endothelial cell adhesion molecules (PECAM-1 or CD 31)

  • cell-cell adhesion molecule of immunoglobulin superfamily

• secrete collagenase and degrade basement membrane

  • after leukocytes pass through the basement membranes become continuous again

• migrate toward chemotactic gradient

Chemotaxis

Chemotaxis: movement of leukocytes towards the site of inflammation

• coordinate by chemotactic factors (chemotaxins)

Chemotactic factors: certain chemical substances and certain bacterial products that are able to attract leukocytes towards the site of inflammation

Include:

1. Endogenous factors

   • complement system components (C5a)

   • Arachidonic acid metabolites (leukotriene B4 (LTB4))

   • cytokines, especially chemokines (interleukin-8 (IL-8))

2. Exogenous factors

   • soluble bacterial products

Activation of leukocytes through:

• chemotactic factors

• degranulation and secretion of lysosomal enzymes

• generation of oxidative burst

• arachidonic acid metabolites production (LTB4)

• modulation of leukocyte adhesion molecules

Phagocytosis and Degranulation

Phagocytosis (to eat and destroy): engulfment of foreign materials by phagocytic cells

Two major phagocytes:

• neutrophils

• macrophages

Phagocytosis involves:

1. Recognition and attachment of a particle

2. Engulfment

3. Killing and degradation of the ingested material

Killing and degradation mechanisms:

• oxygen-dependent mechanisms (oxidative burst)

  • inside phagolysosome

  • production of free oxygen radicals

  • uses: NADPH oxidase, MPO in azurophilic granules

• oxygen-independent mechanisms

  • leukocyte granules contains substance capable of damaging and killing bacteria:

    • bactericidal permeability increasing protein

    • lysosomal enzyme, able to liquefy necrotic materials

    • major basic protein

    • defensins

General Signs of Acute Inflammation

1. Fever

2. Leukocytosis

3. C-reactive protein positive

4. Cloudy swelling of parenchymatous organs