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.
Highlights
Mechanisms active in development of cell-mediated airways disease such as asthma and chronic obstructive pulmonary disease (COPD) may differ from mechanisms involved in exacerbations of these diseases
We have found three clinical experimental studies where both airway wall and lumen eosinophils have been determined during the resolution phase
We have argued here that the occurrence of eosinophils, neutrophils, lymphocytes, and mast cells in the bronchial lumen can reflect their successful and non-injurious elimination away from cell-mediated disease areas in the airway wall
Summary
Mechanisms active in development of cell-mediated airways disease such as asthma and chronic obstructive pulmonary disease (COPD) may differ from mechanisms involved in exacerbations of these diseases. A seminal supporting study demonstrated FAS ligand-induced eosinophil apoptosis and reduced airway lumen eosinophilia in mice with allergic inflammation [92] We asked whether these effects in the airway lumen involved anti-inflammatory actions in the airway wall? Caution is advised in interpretation of sputum data since airway tissue and lumen may differ as to which granulocyte, eosinophil or neutrophil [81,82], and which T lymphocyte, especially Tc1 or Tc2 [116,142,143,144], is predominant Irrespective of such differences, it is commonly assumed that numbers of leukocytes in sputum samples reflect intensity of cell-mediated inflammatory processes in diseased bronchial tissues. As a bonus this work could lead to discovery of interventions that will speed up resolution of airway wall inflammation
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