Dr. Hiba Wazeer Al Zou’bi Acute Inflammation 1 Dr. Hiba Wazeer Al Zou’bi

The survival of all organisms requires that they eliminate foreign invaders, such as infectious agents, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response that is intended to eliminate the initial cause of cell injury, the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair. The inflammatory reaction and the subsequent repair process can themselves cause considerable harm. The components of the inflammatory reaction are also capable of injuring normal tissues.

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 Acute inflammation Chronic inflammation Onset: Fast: minutes to hours Duration: Short, from minutes to days Cellular infiltrate: Mainly neutrophils Tissue injury, fibrosis: usually mild and self limited Local and systemic signs: Prominent Chronic inflammation Onset: Slow: days Duration: Long: days to years Cellular infiltrate: Monocytes/ macrophages and lymphocytes Tissue injury, fibrosis: Often severe and progressive Local and systemic signs: Less prominent, may be subtle

External manifestation of Inflammation Heat . Redness . Swelling. Pain. Loss of function.

The five classic signs of acute inflammation Heat Redness Swelling Pain Loss Of Function.

Acute inflammation

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

Stimuli for Acute Inflammation Infections (bacteria, fungal, viruses, and parasites). Trauma,various chemichal and physical agents (heat, cold, burns, radiation). Chemicals (acids, alkali, bacterial toxins, metals, and caustic substances). Tissue necrosis (from any cuase) Foreign bodies Immunologic reactions (hypersensitivity reactions)

The steps of the inflammatory response can be remembered as the five Rs: (1) recognition of the injurious agent (2) recruitment of leukocytes (3) removal of the agent (4) regulation (control) of the response (5) resolution (repair).

Recognition of Microbes, Necrotic Cells, and Foreign Substances Phagocytes, dendritic cells ,and many other cells, such as epithelial cells, express receptors that are designed to sense the presence of infectious pathogens and substances released from dead cells. These receptors have been called “pattern recognition receptors” because they recognize structures (i.e., molecular patterns) that are common to many microbes or to dead cells.

The two most important families of these receptors are the following: 1- Toll-like receptors (TLRs): Microbial sensors, recognize products of bacteria (such as endotoxin and bacterial DNA), viruses (such as double-stranded RNA), and other pathogens. Located in plasma membranes and endosomes, so they are able to detect extracellular and ingested microbes. Recognition of microbes by these receptors activates transcription factors that stimulate the production of mediators of inflammation, and antiviral cytokines (interferons).

2- The inflammasome: Multi-protein cytoplasmic complex recognizes products of dead cells, such as uric acid and extracellular ATP, crystals and some microbial products. Triggering of the inflammasome results in IL-1 production.

Vascular Changes 1- Changes in Vascular Caliber and Flow: Transient vasoconstriction (lasting only for seconds) Arteriolar vasodilation, the cause of erythema and warmth. Increased vascular permeability: protein- rich fluid moves outside the cell, more concentrated blood, slowing of the circulation (Stasis) Leukocyte margination: Accumulation of leukocytes (Mainly neutrophius), along vascular endothelial surfaces.

Normal

Neutrophil Margination

Vascular Changes 2- Increased Vascular Permeability Leads to the movement of protein-rich fluid and even blood cells into the extravascular tissues . This in turn increases the osmotic pressure of the interstitial fluid, leading to more outflow of water from the blood into the tissues. Protein-rich fluid accumulation is called an exudate. Fluid accumulation in extravascular spaces produces tissue edema.

Edema in Inflammation TRANSUDATE Mechanism: Hydrostatic pressure imbalance across vascular endothelium Fluid of low protein content (ultrafiltrate of blood plasma) Typical in noninflammatory conditions EXUDATE Mechanism: Alteration in normal permeabiltiy of small blood vessels in area of injury Fluid of high protein content (>3g/dl) & increased cellular debris Typical in inflammation

Mechanisms of increased vascular permeability in acute inflammation Endothelial cell contraction (most common cause), formation of intercellular gaps in post capillary venules Endothelial injury: vascular leakage by cuase endothelial cell necrosis and detachment. Increased transcytosis of proteins: By way of an intracellular vesicular pathway augments venular permeability, especially after exposure to certain mediators such as vascular endothelial growth factor (VEGF). Transcytosis occurs through channels formed by fusion of intracellular vesicles. Leakage from new blood vessels.

Cellular Events An important function of the inflammatory response is to deliver leukocytes to the site of injury and to activate them. Leukocytes ingest offending agents, kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. A price that is paid for the defensive potency of leukocytes is that once activated, they may induce tissue damage and prolong inflammation, since the leukocyte products that destroy microbes can also injure normal host tissues.

Leukocyte Recruitment Leukocytes normally flow rapidly in the blood, and in inflammation, they have to be stopped and brought to the offending agent or the site of tissue damage, which are typically outside the vessels. The sequence of events in the recruitment of leukocytes consists of : (1) margination and rolling along the vessel wall. (2) firm adhesion to the endothelium. (3) transmigration between endothelial cells (4) migration in interstitial tissues toward a chemotactic stimulus

The Process of Extravasation of 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.

Upregulation of Selectins

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) VCAM-1 (vascular cell adhesion molecule 1), 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

Firm Adhesion via Integrin -ICAM Interactions

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 secrete collagenase that enable them to cross vascular basement membranes.

Diapedesis

Endothelial and Leukocyte Adhesion Molecule Interactions ENDOTHELIUM WBC FUNCTION P & E-selectins Sialyl-Lewis X Rolling GlyCAM-1, CD34 L-selectin Rolling VCAM-1, ICAM1 Integrin Adhesion CD31 (PECAM-1) CD31(PECAM1) Transmigrat

4- Migration in interstitial tissue toward chemotactic stimulus After extravasating from the blood, leukocytes move toward sites of infection or injury along a chemical gradient by a process called chemotaxis . Both exogenous and endogenous substances can be chemotactic for leukocytes: (1) bacterial products, particularly peptides with N-formyl-methionine termini (2) cytokines, especially those of the chemokine family. (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

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.