Chemokines in acute respiratory distress syndrome

Abstract

A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.

Fig. 1.

Polymorphonuclear leukocyte (PMN) chemotaxis into the lung in acute respiratory distress syndrome (ARDS). Chemokines are secreted at the site of inflammation by resident tissue cells, leukocytes, and cytokine-activated endothelial and epithelial cells. Chemokines are locally retained by matrix heparan sulphate proteoglycans, establishing a chemokine gradient surrounding the inflammatory stimulus. PMNs roll over the endothelium in a selectin-mediated process. Chemokine signaling activates leukocyte integrins, leading to firm adherence and extravasation. The PMNs then pass out of the blood vessel and move up the concentration gradient of the chemotactic peptides towards the site of inflammation. The Duffy antigen receptors for chemokines (DARC) functions as a sink removing the chemokines from circulation and thus helping to maintain the tissue blood stream gradient. In ARDS the capillary endothelium and alveolar epithelium have separate injuries. Activated alveolar macrophages release TNF-α and IL-1β, and in response to this other cells of the alveolar environment produce α- and β- chemokines, which in turn activate the inflammatory cascade resulting PMNs migration into the lungs.

Fig. 2.

Ribbon diagram illustrating the monomer 3-dimensional structure of IL-8. The NH₂ and COOH termini and the secondary structure elements are labeled in the IL-8 structure (5). [Image prepared using Protein Explorer 1.982 by Eric Martz (http://proteinexplorer.org).]

Fig. 3.

Chemokine receptors and their ligands. CCR, CC receptor; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted; HCC, hemofiltrate CC chemokine; TARC, thymus- and activation-regulated chemokine; DC-CK, dendritic cell CC chemokine; SLC, secondary lymphoid-tissue chemokine; MDC, macrophage-derived chemokine; MPIF, myeloid progenitor inhibitory factor; TECK, thymus-expressed chemokine; CTACK, cutaneous T cell-attracting chemokine; MEC, mucosal cell epithelial chemokine; XCR1, lymphotactin receptor; CXCR1, fractalkine receptor; SCM, single C motif chemokine; GRO, growth-related oncogene; ENA, epithelial neutrophil-activating protein; GCP, granulocyte chemotactic protein; NAP, neutrophil attractant-activation protein; MIG, monokine induced by IFN; IP-10, 10-kDa IFN-γ-inducible protein; I-TAC, IFN-γ-inducible T cell α-chemoattractant; SDF, stromal cell-derived factor; BCA, B cell attracting chemokine; BRAK, breast and kidney cell expressed chemokine.