Introduction

He Endothelium

The endothelium is a monolayer of cells covering the inside of the entire vascular tree. It is also a semipermeable barrier that, by modulating its intercellular junctions, allows the transmigration of various blood constituents (Figure 1). Morphologically, three types of organelles constitute endothelial cell junctions. At the apical side of the cells, tight junctions seal the cells. Gap junctions, which are sometimes intercalated with tight junctions, allow the exchange of ions and small molecules between adjacent cells. Adherens junctions, located at a more basal position, mediate the physical contacts between cells and are anchored in the actin cytoskeleton.

The endothelium is also the point of entry of circulating leukocytes into inflamed tissue. The mechanism of leukocyte entrance into tissues is a complex, multistep event involving leukocyte adhesion to the endothelium and subsequent migration across the blood vessel wall [1]. Whereas the early steps leading to leukocyte adhesion are well understood, it is still unclear how leukocytes actually crawl

* Current address: European Molecalar Biology Laboratory (EMBL), Grenoble, France through the endothelial wall. A recent study suggested that leukocytes could pass across the body of endothelial cells using a transcellular route, but it is generally accepted that most leukocyte transendothelial migration occurs via para-cellular rather than transcellular routes.

Neutrophils

Leukocytes are circulating blood cells involved in defending the body against infective organisms and foreign substances. During normal immunosurveillance, leukocytes circulate in search of foreign antigens. Injury or infections cause inflammatory responses that lead to the recruitment of granulocytes, monocytes, and T cells to the sites of inflammation. Responding to the signals induced by infections or tissue damages, sentinel cells stationed in the tissues, mast cells and macrophages, release histamine, eicosanoids, and chemokines, which cause vasodilatation of blood vessels and consequently a decrease of the blood flow. This facilitates the capture of leukocytes on the surface of the endothelium. In parallel, inflammatory cytokines such as TNFa stimulate the endothelium to express adhesion receptors on its apical surface with which leukocytes can interact.

Following transmigration into the tissue, leukocytes undergo directed migration through a concentration gradient of chemotactic cytokines to the site of inflammation. According to their type and their specialized function, leukocytes release different inflammatory cytokines that, in turn, activate other white blood cells and enhance leukocyte recruitment to the inflammatory site.

Neutrophils form the primary defense against bacterial infections. Similarly to the other cells of the immune

Figure 1 VE-cadherin is involved in the maintenance and restoration of the endothelium integrity. The endothelium is made up of a monolayer of endothelial cells (A) that separates blood components from underlying tissues (B). VE-cadherin is expressed at the lateral junctions between endothelial cells (C). Different types of leukocytes and tumor cells transmigrate at the intercellular junctions where VE-cadherin is expressed (C).

Figure 1 VE-cadherin is involved in the maintenance and restoration of the endothelium integrity. The endothelium is made up of a monolayer of endothelial cells (A) that separates blood components from underlying tissues (B). VE-cadherin is expressed at the lateral junctions between endothelial cells (C). Different types of leukocytes and tumor cells transmigrate at the intercellular junctions where VE-cadherin is expressed (C).

system, they are produced in the bone marrow and circulate in the bloodstream. However, they can move out of blood vessels into infected tissue where they attack the foreign substances mainly through phagocytosis which allows them to "eat" other cells and foreign substances. Both the transmigration of neutrophils across the endothelium and the intracellular degradation of antigens are at least in part mediated by proteases, of which there are four classes: serine proteases, metalloproteases (MMPs), thiol proteases, and aspartate proteases. The first two classes play a critical role in the degradation of extracellular components, whereas the two others are involved in the intracellular degradation of antigens. Serine proteases, characterized by the presence of a catalytic triad made of histidine, aspartic acid, and serine, are packed into the azurophil granules of neutrophils. They include elastase, cathepsin G, proteinase 3, and Cap37, the last being enzymatically inactive. Upon stimulation of neutrophils by proinflammatory mediators, the content of the azurophil granules is translocated toward the external membrane of neutrophils. These surface-bound proteases are catalytically active and remarkably resistant to naturally occurring protease inhibitors [2].

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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