Resolution of cell-mediated airways diseases

Abstract

"Inflammation resolution" has of late become a topical research area. Activation of resolution phase mechanisms, involving select post-transcriptional regulons, transcription factors, 'autacoids', and cell phenotypes, is now considered to resolve inflammatory diseases. Critical to this discourse on resolution is the elimination of inflammatory cells through apoptosis and phagocytosis. For major inflammatory diseases such as asthma and COPD we propose an alternative path to apoptosis for cell elimination. We argue that transepithelial migration of airway wall leukocytes, followed by mucociliary clearance, efficiently and non-injuriously eliminates pro-inflammatory cells from diseased airway tissues. First, it seems clear that numerous infiltrated granulocytes and lymphocytes can be speedily transmitted into the airway lumen without harming the epithelial barrier. Then there are a wide range of 'unexpected' findings demonstrating that clinical improvement of asthma and COPD is not only associated with decreasing numbers of airway wall inflammatory cells but also with increasing numbers of these cells in the airway lumen. Finally, effects of inhibition of transepithelial migration support the present hypothesis. Airway inflammatory processes have thus been much aggravated when transepithelial exit of leukocytes has been inhibited. In conclusion, the present hypothesis highlights risks involved in drug-induced inhibition of transepithelial migration of airway wall leukocytes. It helps interpretation of common airway lumen data, and suggests approaches to treat cell-mediated airway inflammation.

Figure 1

"Schematic representation of trans-epithelial loss of leukocytes into airway lumen". Modified from references [61,16,112]. This scheme identifies some of the steps where future research is warranted to delineate mechanisms involved in the trans-epithelial elimination of inflammatory cells from the airway wall. 1 After cell-to-cell contact at the epithelial base paraepithelial crawling of the leukocyte may begin by integrin binding to desmosomal junction adhesion molecules. 2 Several binding interactions and cellular signalling events including cytosolic Ca++ fluxes may be involved as the leukocyte continues to migrate between juxtapositioned epithelial cells. 3 Binding interactions involving junction adhesion-like proteins and receptors such as the coxsackie and adenovirus receptor may be involved in protein-tight passage of the leukocyte through the tight apical junction complex. 4 After its elimination from the airway wall the leukocyte mixes with epithelial lining fluids and is finally eliminated by mucociliary clearance.