Chest
Volume 121, Issue 5, Supplement, May 2002, Pages 142S-150S
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Airways Inflammation and COPD: Epithelial-Neutrophil Interactions

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Neutrophils are recognized as major cellular mediators of inflammation. They contain specific and highly regulated mechanisms for controlling the expression of adhesion molecules that allow for their tethering and migration into inflammatory sites. These adhesion molecules not only are activated by exogenous pollutants but are regulated by endothelial and epithelial cell signals. Lipid mediators, such as platelet-activating factor, reactive oxygen and nitrogen species, and cytokines from airway epithelial cells, further control neutrophil functions such as infiltration and activation resulting in an increase in respiratory burst activity and release of granule enzymes, such as elastase. Furthermore, virus and bacteria products affect inflammation by increasing secondary epithelial mediators. However, once the endogenous or exogenous agents are expelled, neutrophil populations are programmed to die and are cleared by macrophage phagocytosis.

Section snippets

Adhesion Molecules

Leukocyte migration from the circulation into tissues is widely acknowledged to occur by a sequential activation of adhesive proteins and their ligands on leukocytes and endothelial cells.5,6,7,8,9 Monocytes, lymphocytes, and neutrophils all migrate using similar sequential mechanisms, although they differ in their responses to chemotactic and inflammatory signals, as well as in the qualitative and quantitative expression of adhesion molecules.10,11,12 Under normal conditions, circulating

Epithelial Signals

Deleterious environmental stimuli such as airborne pollutants, allergens and microbes cause the airway epithelium to alter defense mechanisms such as the secretion of mucus, the production of oxygen and nitrogen species, the efficiency of ciliary beating, the transport of ions for fluid absorption and secretion, and the influx of inflammatory cells. The epithelium is also a target for factors released by infiltrating inflammatory cells and serves as a major effector of inflammation.47,48,49 On

Lipid Mediators

Lipid mediators, including prostaglandins, leukotrienes (LTs), hydroxyeicosatetraenoic acids, and platelet- activating factor (PAF), are produced both by infiltrating inflammatory cells and by airway epithelial cells in response to various stimuli. These lipid mediators produced by the epithelium can act in an autocrine or paracrine manner to stimulate airway epithelial cells to produce other mediators. For example, PAF, which is a potent inflammatory mediator that is produced by a wide variety

ROS and RNS

Reactive species such as superoxide anion radicals (ie, O2•−), hydroxyl radicals (ie, OH•), hydrogen peroxide (ie, H2O2), nitric oxide, and peroxynitrite (ie, ONOO−) alter several cell functions. Although the release of oxidants from macrophages, eosinophils, and neutrophils is well-documented, only as recently as 1998 was the production of these species by airway epithelial cells examined.54 For example, bronchial and tracheal epithelial cells have been shown to release H2O2 in response to

Cytokines

Cytokines are pluripotent protein mediators of inflammation63 that are produced and secreted by a wide variety of cell types, including neutrophils,64 monocytes, macrophages, endothelial cells, and epithelial cells.65,66,67 The supernatants of cultured airway epithelial cells contain detectable amounts of cytokines such as IL-1, IL-6, IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor.49 On epithelial cell stimulation, the expression of

IL-8 and COPD

Several studies have suggested that the overexpression of IL-8 is central to pathophysiologic changes in the airways and to the severity of airflow obstruction that may ultimately lead to diseases such as COPD, asthma, and cystic fibrosis. For example, neutrophils, and not eosinophils, have been implicated in the creation of the symptoms of acute exacerbations of asthma.75,76 Likewise, in induced sputum samples from COPD patients, significant increases in the concentrations of IL-8, TNF-α, and

Viral and Bacterial Effects on Airway Inflammation

Airway epithelial cells serve as a barrier to invading allergens, and they produce enzymes and mediators that maintain normal airway homeostasis. They are also, however, the principal host cells for respiratory viruses, which can cause varying degrees of damage on infection. Respiratory viruses such as rhinovirus, respiratory syncytial virus, and influenza rapidly stimulate epithelial cells to secrete a wide range of proinflammatory mediators, including IL-6, IL-8, IL-11, and GM-CSF.70,94,95,96

Neutrophil Inflammatory Response

As neutrophils move to a site of inflammation or injury to remove invading particles such as bacteria and viral products, they degrade connective tissue, releasing peptides that may serve as chemoattractants. Similarly, the activation of the neutrophils results in the further release of the chemoattractants LTB4 and IL-8, thereby self-perpetuating the inflammatory response. Finally, the elastase released by neutrophils can activate complement factor 5, resulting in the release of C5a,112 which

Apoptosis

Aging neutrophils undergo spontaneous apoptosis or programmed cell death in the absence of cytokines or other proinflammatory agents prior to their removal by macrophages.130 This phagocytic removal of intact, apoptotic neutrophils prevents them from releasing their cytotoxic content into the extracellular space, as would occur if the cells died by necrosis. In patients with acute inflammation, neutrophil accumulation within tissues can be extremely high because of the targeted influx from the

Conclusion

In conclusion, it is important to understand the molecules and pathways involved in regulating and controlling neutrophil inflammation. Unfortunately, the current treatments for inflammation only control the influx of neutrophils to the site of injury. However, by better understanding all the mechanisms employed by the neutrophil, pharmacologic agents that will better control this universal and sometimes debilitating condition can be developed.

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