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Chemokines in the Lung

2003 Edition, January 22, 2003

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Active, Most Current

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ISBN: 978-0-8247-0858-0
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Product Details:

  • Revision: 2003 Edition, January 22, 2003
  • Published Date: January 22, 2003
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 426
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


The hallmark of an inflammatory response in the lung is the presence of infiltrating leukocytes. This process can occur in the context of a variety of disorders, including trauma, infection, autoimmune diseases, idiopathic interstitial pneumonias, asthma, chronic bronchitis, acute respiratory distress syndrome (ARDS), exposure to environmental/occupational noxious agents, cancer, allograft rejection, and ischemia–reperfusion injury. The course of inflammation in these disease states is defined by the delicate balance and nature of inflammatory mediators expressed in the context of lung inflammation, and the specific leukocyte populations recruited in response to lung injury.

The resolution of pulmonary inflammation is determined by whether or not the inciting factor(s) persist. For example, in response to a bacterial challenge such as Streptococcus pneumoniae, there is an exuberant inflammatory reaction characterized by tissue injury, deposition of fibrin, extravasation of neutrophils, and eventual elimination of the offending bacteria, leading to resolution of inflammation and reestablishment of normal lung function. In contrast, chronic lung inflammation in association with interstitial lung disorders is often manifested by a neutrophilic alveolitis and an intense mononuclear leukocyte infiltration within the pulmonary interstitium, a process that results in tissue destruction, loss of the integrity of the alveolar–capillary basement membrane, fibroproliferation , and exaggerated extracellular matrix deposition. This type of inflammation often fails to resolve and, ultimately, progresses to end-stage pulmonary fibrosis. Although the specific molecular mechanisms that induce an acute inflammatory reaction or perpetuate chronic inflammation have not been fully elucidated, it is now clear that leukocytes, mesenchymal-derived cells, and parenchymal cells produce a variety of molecules that regulate leukocyte recruitment during the inflammatory response.

The recruitment of specific leukocyte subpopulations in response to lung injury is a fundamental mechanism of pulmonary inflammation. The elicitation of leukocytes is dependent on a complex sequence of events, including: (1) endothelial cell activation and expression of endothelial cell-derived leukocyte adhesion molecules; (2) leukocyte activation and expression of leukocyte-derived adhesion molecules; (3) leukocyte–endothelial cell adhesion; (4) leukocyte transendothelial migration; and (5) leukocyte migration beyond the endothelial barrier along established chemotactic gradients. This last event is dependent on the presence of chemotactic factors. Although the events of leukocyte extravasation may appear intuitive, it has taken over 150 years of research to elucidate the cellular and molecular steps involved in the process of leukocyte migration.

In the last two and one-half decades there has been an explosion of interest in a group of chemotactic cytokines that have chemotactic activity for leukocytes. Indeed, there have been more than 16,000 publications related to chemokines since 1975. The human chemokine families are referred to as CXC, CC, C, and CX3C chemokines. These four closely related polypeptide families generally behave as potent chemotactic factors for neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells, NK cells, and T and B lymphocytes. Chemokines in their monomeric form have a molecular mass of 7–10 kDa and are characteristically basic heparin-binding proteins, which facilitates binding to cells and matrix components within the lung. The chemokines have in common highly conserved cysteine amino acid residues. The CXC chemokine family has the first two NH2-terminal cysteines separated by a single, nonconserved amino acid residue, the CXC cysteine motif; whereas the CC chemokine family has the first two NH2-terminal cysteines in juxtaposition, the CC cysteine motif. The C chemokine lymphotactin has a lone NH2-terminal cysteine amino acid, the C cysteine motif; and the CX3C chemokine fractalkine has the first two NH2-terminal cysteines separated by three nonconserved amino acid residues. Interestingly, CXC chemokine genes are, in general, clustered on human chromosome 4, and the proteins exhibit between 20% and 50% homology on the amino acid level; whereas CC chemokine genes are generally clustered on human chromosome 17, and the proteins exhibit between 28% and 45% homology on the amino acid level. The gene that encodes lymphotactin is located on human chromosome 1, and the gene encoding fractalkine is located on human chromosome 16. Overall, there is approximately 20–40% homology among the members of the four chemokine families.

Although there has been tremendous interest in chemokines for their ability to recruit specific subpopulations of leukocytes, it is becoming increasingly clear that the function of these cytokines goes well beyond leukocyte trafficking. For example, chemokines are involved in regulating angiogenesis and have direct stimulatory effects on mesenchymal and parenchymal-derived cells, and some members of the chemokine family can exert direct antimicrobial properties similar to those mediated by human defensins. The varied function and biology of chemokines can be best exemplified in the lung. Therefore, these chapters reflect the breadth and depth of our current knowledge regarding the role chemokines play in the lung. The aims and structure of this volume are designed to expose a diverse audience of clinicians and clinical and basic science researchers to the field of chemokine biology, and how these molecules participate in immune response within the lung. This volume will complement other texts focused on pulmonary inflammation and repair. We sincerely hope that our readers will have a heightened appreciation for the importance of chemokines in the lung, and will recognize these cytokines as natural targets for novel intervention that may ultimately impact on diseases that affect the lung.