**2. Evolutionary origin of neutrophils**

The evolutionary origins of the human neutrophil lie in phagocytic cells found in simple organisms. These evolutionary precursors to the human PMNs, originally studied in star‐ fish, were first observed migrating to a site of injury over a century ago. Since the semi‐ nal immunological discovery of cells that attack invading pathogens, various phagocytic immune cells along the evolutionary continuum have been described. Phagocytic cells with functions and signaling mechanisms similar to mammalian neutrophils have been described in organisms as simple as the slime mold *Dictyostelium discoideum*. [1] Phago‐ cytes containing bactericidal granules analogous to those in the human neutrophil are

© 2013 Guess et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

found in insects. Although functionally similar, these immune cells differ from their hu‐ man counterparts significantly in lifespan and nuclear morphology, suggesting that a short-lived, multi-lobed phagocyte is a more recent evolutionary development. [2] This trend continues with non-mammalian vertebrates. Both amphibians and bony fish have granulocytic phagocytes with multi-lobed nuclei that are genetically and morphologically similar to the human PMN. [3] Although the structure, morphology, function, and genet‐ ic make-up of neutrophils is highly conserved within mammals, the percentage of total immune cells represented by neutrophils varies significantly. Even within primates neu‐ trophil counts vary a great deal; neutrophils represent approximately 50% of chimpan‐ zee's circulating immune cells, whereas the human neutrophil accounts for almost 70% of white blood cells. [4],[5] The commonality of PMNs and PMN-like cells make it clear that the neutrophil is an ancient player on the immunological stage.

the bone marrow, activation of CXCR2 promotes their release into circulation. Under ho‐ meostatic conditions a normal human adult produces 1 - 2 X 10[11] neutrophils per day. The rate of neutrophil production and release is dictated largely by G-CSF in a negative feedback mechanism whereby an increasing number of apoptotic neutrophils decreases the amount of G-CSF. The apoptotic neutrophils are phagocytosed by tissue macrophages, which decrease their release of interleukin-23 (IL-23). IL-23 stimulates the release of IL-17 by helper T (TH) cells. [13] IL-17 is in turn the primary stimulus for the release of G-CSF. Thus, increased con‐ trolled destruction of neutrophils leads to decreased levels of macrophage derived IL-23 re‐ leased by macrophages, IL-17 released by TH17 cells, G-CSF released by osteoblasts, and thus a decrease in neutrophil synthesis and release. Conversely, IL-17 has been shown to act through p38 MAPK to augment IL-8 release from pulmonary epithelial cells. This mecha‐ nism, ideally, allows the body to rapidly speed neutrophil production and release during in‐ fection in a regulated fashion to minimize potential damage to the host. [10],[14]Another method by which the host regulates circulating neutrophil numbers is through the phenom‐ enon of margination and demargination. Margination occurs when resting neutrophils trav‐ el at a significantly slower pace along the endothelium of the blood vessels. The expression of previously mentioned adhesion molecules creates distinct organ-specific (marginated) pools of cells. Exercise induced stress, infection, or other sources of systemic stress leads to an increase in blood flow, a release of epinephrine and demargination of the neutrophil into

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Although the rate of neutrophil production and release may increase during an immunolog‐ ical challenge, as the most populous circulating white blood cells, neutrophils serve as first line responders to injury and infection. During the course of their 6 to 8 hour life span in circulation, neutrophils tend to remain near the vascular endothelium. PMNs constitutively express two glycoprotein ligands, PSGL-1 and L-selectin, allowing neutrophils to detect in‐ flamed or injured endothelium. At sites of inflammation, bacterial peptides such as lipopo‐ lysaccharide (LPS), and f-Met-Leu-Phe (fMLP), along with host pro-inflammatory cytokines (i.e., tumor necrosis factor-α [TNF-α]) stimulate the vascular endothelium to produce to ad‐ hesion molecules such as lymphocyte function antigen (LFA) and the immunoglobulin-de‐

The adhesive force between the endothelial adhesion molecules and neutrophil selectins produces a Velcro®-like action that slows the neutrophil down, a process known as rolling. Rolling also prompts the neutrophil to express surface molecules known as β-integrins, which further slow the neutrophil. It is at this early stage that PMNs have already begun to become activated and are preparing the intracellular machinery necessary to combat the in‐ vading pathogens. Slow rolling is followed by arrest and firm adhesion via clustering of β2 integrins. Arrest initiates actin polymerization vital to migration across the endothelial surface via a G-protein coupled receptor (GPCR) signaling cascade. [16],[17] Transendothe‐ lial migration, or exocytosis, begins as the adhesive force between the neutrophil and endo‐

the general circulation.[15]

**5. Response to infection/smoking**

rived intercellular adhesion molecule (ICAM). [4],[15]
