**5. Response to infection/smoking**

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.

100 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

disease will be addressed below.

**4. Release and homeostasis**

**3. Hematopoietic origin, differentiation/maturation of neutrophils**

Neutrophil biogenesis occurs in the bone marrow from an undifferentiated hematopoietic stem cell. Regulation of transcription factors through cytokine and growth factor signaling dictates neutrophil differentiation, a process called granulopoiesis. Granulopoiesis is the successive differentiation of a pluripotent hematopoietic stem cell, to a multipotent commit‐ ted myeloid progenitor cell (myeloblast), to a bipotent granulocyte-macrophage progenitor cell (metamyelocyte) and finally to a unipotent committed granulocyte. The final stage of PMN maturation, or terminal granulopoiesis, is characterized morphologically by the ap‐ pearance of a multi-lobed granulated nucleus. On a molecular level, granule protein synthe‐ sis and granule packaging mark neutrophil maturation. These granules and their cargo proteins are among the primary weapons in neutrophils' antimicrobial arsenal. [6]-[8]Syn‐ thesis of granules and granule proteins progresses concurrently with granulopoiesis. Gran‐ ules are traditionally classified as primary, secondary and tertiary according to the stage of differentiation during which they are formed. This is important because the granules formed at different stages of differentiation exhibit drastically different protein cargo and thus play different roles in the immune and inflammatory response. [9]The array of neutro‐ philic granule cargo might include myeloperoxidase, lactoferrin, haptoglobin and alpha-1 antitrypsin. [10] Specific granule proteins and their respective roles in neutrophilic lung

Once mature, neutrophils are released from the bone marrow. Locally, release of neutrophils into circulation is governed by cytokine signaling. Toll like receptors (TLRs) and granulo‐ cyte colony stimulating factor (G-CSF) receptors are crucial in neutrophil production, but CXCR2 and CXCR4 appear to be the primary receptors involved in neutrophil release into the circulation. [11],[12] Whereas activation of CXCR4 favors retention of mature PMNs in

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

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‐ thelium increases and the neutrophil "crawls" in search of a suitable route to cross the vessel wall, either paracellular or transcellular. At this point the neutrophil extends pseudopodlike surface projections that penetrate the endothelium. Upon penetration the neutrophil in‐ creases expression of surface integrins and releases proteases that function to break through the vascular basement membrane and into the inflamed tissue. [16]

demiology, cellular pathophysiology, diagnosis and current treatment of each condition will be discussed briefly. Following each disease will be a discussion of recent advancements in the understanding of the disease and advancements in therapeutics directed toward each

New Frontiers in the Diagnosis and Treatment of Chronic Neutrophilic Lung Diseases

http://dx.doi.org/10.5772/53834

103

**Figure 1.** Neutrophils in both normal and chronic inflammatory responses. Neutrophils are recruited into the airway in nor‐ mal acute information through the release of chemokines such as IL-8, IL-17 and LTB4. Once in the airway they release pro‐ teases and reactive oxygen species (ROS) to combat bacteria (shown in red). After the infection in resolved, the neutrophils undergo apoptosis and prevent destructive release of their proteases and ROS into the interstitium. (A) In chronic inflam‐ mation, neutrophils continue to release harmful proteases with no pathogen presence. Eventually the neutrophils under‐

Chronic obstructive pulmonary disease (COPD) is marked by progressive and irreversible airway limitation, chronic bronchitis, pulmonary hypertension and emphysema. These tis‐

go necrosis which futher damages the epithelium and creates a feed-forward process of disease. (B)

condition.

**6. COPD**

**6.1. Overview and epidemiology**

Once in the interstitium, PMNs must target the specific site of infection amidst large number of healthy cells. This is accomplished by a two pronged method of sensing inflammatory chemoattractant gradients. PMNs sense a chemoattractant gradient of IL-8 produced by damaged host cells and resident monocyte/macrophages through CXCR1 and CXCR2 (both GPCRs), and also detect fMLP (FPR1 receptor) LPS (TLR4), flagellin (TLR5), through pattern recognition receptors. [18] Although PMNs have been traditionally thought to promulgate an active innate immunity with little regulation, more recent evidence suggests that PMNs carefully coordinate a well-tailored immune response. A classic example of this regulated coordination is the elegant response of PMNs to IL-8. [19] As PMNs travel along the IL-8 gradient activation and release of microbicidal molecules occurs in a step-wise manner. With increasing concentrations of IL-8, neutrophils first produce more β-integrins, subse‐ quently begin the oxidative burst, and finally degranulate potent proteases into the intracel‐ lular space. [20] The trafficking of neutrophils to sites of inflammation is with dual purpose: 1) to release their antimicrobial arsenal, and 2) to recruit more neutrophils and other innate immune cells to the site of inflammation.

The neutrophil's arsenal includes the following weapons with which the neutrophil attacks pathogens: release of aforementioned granules with their anti-microbial contents, synthesis and release of anti-microbial peptides, production of reactive oxygen species (ROS) during the respiratory/oxidative burst, phagocytosis (mainly utilized to remove debris) and the re‐ lease of neutrophil extracellular traps (NETs), composed of DNA material that entraps in‐ vading pathogens. The second objective is accomplished through the release soluble mediators such as IL-12 and IFN-gamma that form a complex network of recruitment of oth‐ er neutrophils, dendritic cells, natural killer cells and macrophages. [21] Neutrophils can al‐ so act as antigen presenting cells in communication with CD8+ T cells, thus forming a link between innate and adaptive immunity. Such a potent response to injury and inflammation depends on negative feedback mechanisms, the short life span of neutrophils and the clear‐ ance of apoptotic neutrophils by macrophages. If left unchecked, the inflammatory response mediated by neutrophils can be a major contributor to chronic disease. 4 (Fig. 1)

Neutrophils are capable of responding to a number of inflammatory stimuli other than in‐ fection. Cigarette smoking has been shown to be a primary stimulus for the activation and migration of neutrophils into the tissues. Neutrophil treatment with cigarette smoke induces β2-integrin activation and firm adhesion to fibrinogen. Increased levels of neutrophil elas‐ tase, and matrix metalloproteases has been demonstrated with exposure to cigarette smoke. Furthermore, there is a decrease in superoxide production in the presence of cigarette smoke, indicating that smoking may lead to an impaired response to bacterial challenge.

It is with this potential for destructive dysregulation that we provide the following review of selected neutrophil mediated, inflammatory lung diseases. The definition, etiology, epi‐ demiology, cellular pathophysiology, diagnosis and current treatment of each condition will be discussed briefly. Following each disease will be a discussion of recent advancements in the understanding of the disease and advancements in therapeutics directed toward each condition.

**Figure 1.** Neutrophils in both normal and chronic inflammatory responses. Neutrophils are recruited into the airway in nor‐ mal acute information through the release of chemokines such as IL-8, IL-17 and LTB4. Once in the airway they release pro‐ teases and reactive oxygen species (ROS) to combat bacteria (shown in red). After the infection in resolved, the neutrophils undergo apoptosis and prevent destructive release of their proteases and ROS into the interstitium. (A) In chronic inflam‐ mation, neutrophils continue to release harmful proteases with no pathogen presence. Eventually the neutrophils under‐ go necrosis which futher damages the epithelium and creates a feed-forward process of disease. (B)
