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INTRODUCTION

The normal development of organ systems—including the lungs in utero, their subsequent maturation to adulthood, and maintenance of health throughout life—requires intricate signals to be exchanged among various tissues, capable of permitting diversity and adaptation in differing cellular and extracellular contexts, while being robust to onslaughts from ever-changing environmental stimuli. Among the mediators involved in such complex cellular signaling, and relevant in the setting of many pulmonary disorders, are chemokines and growth factors. There has been further complexity added with increasing recognition of adipose tissue as a source of systemic bioactive mediators, called adipokines, that impact on lung health. While some of these mediators are implicated in the development of disease states, they are more often than not also critical to tissue homeostasis and are challenging target systems for therapeutic manipulation. Nonetheless, we are now in an era of exciting developments in targeted biologic therapies that offer the potential for substantial progress in the fight against difficult-to-treat pulmonary disorders characterized by pathogenic processes including acute and chronic inflammation, fibrosis, vascular remodeling, and neoplasia.

CHEMOTACTIC CYTOKINES AND THE INFLAMMATORY RESPONSE

The salient feature of inflammation is leukocyte infiltration. These recruited leukocytes contribute to the pathogenesis of chronic inflammation and promote fibrosis via the elaboration of a variety of cytokines. Maintenance of leukocyte recruitment during inflammation requires the expression of cell-surface adhesion molecules, and the production of chemotactic molecules, such as chemokines.1 The chemokines can be divided into four families—CXC, CC, C, and CXXXC—which behave as potent chemotactic factors for neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells, NK cells, and T and B lymphocytes (Table 24-1). There is approximately 20% to 40% homology between the members of the four chemokine families.2 Chemokines are produced by an array of cells, including monocytes, alveolar macrophages, neutrophils, platelets, eosinophils, mast cells, T- and B-lymphocytes, NK cells, and various structural cells, including keratinocytes, mesangial cells, epithelial cells, hepatocytes, fibroblasts, smooth muscle cells, mesothelial cells, and endothelial cells. Specific chemokines can form heterodimers that differentially dictate their functional activity, for example, obligate CC-type heterodimers can drive acute lung injury.3 Production of chemokines by both immune and nonimmune cells supports the contention that these cytokines may play a pivotal role in orchestrating chronic inflammation.4

TABLE 24-1The Human C, CC, CXC, and CXXXC Chemokine Families of Chemotactic Cytokines

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