Resolution of airway disease: removal of inflammatory cells through apoptosis, egression or both?

Pathogenic granulocytes (eosinophils and neutrophils) infiltrate airway tissues in asthma and chronic obstructive pulmonary disease. Granulocytes release tissue-toxic and inflammatory mediators, making their removal an important pharmacological goal. Removal is thought to be accomplished through apoptosis followed by engulfment by macrophages. Thus, the molecular mechanisms of granulocyte apoptosis have been unravelled and pro-apoptotic actions that target granulocytes have been proposed as desirable features of future airway drugs. However, observations in vitro and in airway lumen that support this role of granulocyte apoptosis translate poorly to airway tissues in vivo. Either apoptosis cannot be demonstrated, even at the resolution of airway inflammation, or, when significant granulocyte apoptosis is induced in airway tissues in vivo, there is insufficient engulfment of apoptotic granulocytes. Therefore, apoptotic eosinophils and neutrophils in airway tissues undergo secondary necrosis, causing inflammation. As an alternative or complement to the apoptosis hypothesis, in vivo work indicates that egression to the airway lumen can produce swift non-injurious removal of tissue granulocytes. Once in the airway lumen, granulocytes can undergo apoptosis and engulfment, be trapped by secretions and plasma exudates and be removed by mucocillary escalator mechanisms. In this article, we propose that egression into the airway lumen is an effective mode of inflammatory cell disposal that connotes novel drug opportunities.