New insights in the regulation of leukocytosis and the role played by leukocytes in septic shock.

Leukocytosis is the result of white blood cell production in the bone marrow, margination onto the blood and lymph vessels and elimination of leukocytes in the peripheral tissues and the spleen. The regulation of the exit of leukocytes from the circulation at peripheral inflammatory sites is well known as the four-step paradigm of rolling, adhesion, diapedesis and chemotaxis. The entry of white blood cells into the circulation is less well studied. In the bone marrow, immature myeloid cells adhere to the stromal network by means of interactions between oligosaccharides and lectins and between adhesion molecules. During the maturation process, cell surface molecules are altered and the possibilities for multivalent binding to stroma components or cells are gradually lost. Mature cells produce matrix metalloproteinases (MMPs) that solubilise the basement membranes of the bone marrow sinuses. Hematogenic signals of inflammation activate mature granulocytes in the bone marrow and cause an increase in the circulating pool of leukocytes. The so-called shift-to-the-left, i.e. the presence of precursor forms of differentiating neutrophils, appears during full blown reactions. In the latter situation, immature cells, positive for the CD34 cell surface marker, enter the circulation. The activities of gelatinase B and integrin interactions are indispensable to induce leukocytosis and stem cell mobilization. Indeed, with the use of neutralizing antibodies against gelatinase B and against lymphocyte-associated functional antigen-1 (LFA-1), experimentally induced leukocytosis and stem cell mobilization were blocked. What is the role of adhesion molecules and proteases in septic shock syndromes? In the early phase of endotoxinaemia or bacteraemia, the bone marrow will be activated, which leads to leukocytosis. Neutrophils secrete considerable amounts of latent MMPs, including neutrophil procollagenase (MMP-8) and progelatinase B (MMP-9). In addition, these granulocytes activate the enzymes chemically and these cells are not able to produce tissue inhibitors of metalloproteinases (TIMPs). As a result, an intensive degradation of endothelial basement membranes occurs and results in vascular leakage and shock. These observations raise the hope that inhibition of proteases might constitute a new strategy for the treatment of septic shock.