Mediators produced during inflammatory/immune responses dictate the severity and intensity of pulmonary disease. The profile of inflammatory leukocyte populations accumulating in inflamed tissues is initiated by cytokine-induced expression of adhesion molecules on the vascular endothelium. Endothelial adhesion molecules include intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), as well as E- and P-selectins that initiate, and in some cases, mediate the migration of leukocytes into tissues. Subsequently, leukocyte adherence to the endothelium is followed by leukocyte migration into the inflamed tissue, directed by chemotactic molecules at the site of the inflammatory/immune response. Upregulation of these early response mediators is crucial for the initiation of early events that regulate the inciting agent, whether it is infectious or noninfectious in nature. However, the continuous over-production of these mediators can lead to destructive, pathologic consequences due to the continued recruitment and activation of disease-specific leukocyte populations. In human lung, inflammation-induced damage can be observed in numerous inflammatory diseases, including both acute and chronic disease settings. In this chapter, we will examine the mediators that promote inflammatory diseases in lung and outline how specific leukocyte populations can contribute to pulmonary pathology.
Leukocyte Adhesion and Migration into the Lung
Important considerations in the biology of leukocyte adhesion and migration into the lung are discussed below.
Selectin and Adhesion Molecules in Lung Inflammation
The release of early response mediators leads to the upregulation of selectins (E and P) and other adhesion molecules (ICAM-1, VCAM-1, etc.) on surfaces of vascular endothelial cells within the site of inflammation.1–7 Initially, selectin molecules (P and E) are quickly upregulated on the vascular endothelium and initiate “rolling” of leukocytes on activated endothelium through Ca2+-dependent recognition of cell surface carbohydrates of the sialyl Lewis X family and related oligosaccharides. Initial and rapid expression of selectin molecules results in a slowing of leukocyte velocities in the circulatory flow, allowing additional interactions to proceed.8–11 However, such interactions are required to ultimately allow firm adhesion of leukocytes to endothelial cells. Once the leukocytes have begun the selectin-mediated rolling process, they must next go through a series of activation events to allow them to firmly adhere to other adhesion molecules. Leukocytes ultimately bind firmly to the vascular endothelium via β-integrin receptors on leukocyte surfaces, resulting in a very rapid increase in binding affinity, and engagement of other molecules that are upregulated during inflammatory responses on the vascular endothelium. A number of β-integrin adhesion molecules play a role in the migration process, and they are differentially expressed on subsets of leukocytes.12–14 The β1α4 integrins (VLA-4), expressed primarily on mononuclear cells and eosinophils, have been shown to bind to vascular cell adhesion molecule-1 (VCAM-1), while β2-integrins (CD11/CD18) are expressed on all leukocytes and bind varyingly to intracellular adhesion molecules-1,2,3 (ICAM-1,2,3), the first of which is highly expressed on endothelial cells. These families of adhesion molecules are ...