Development and Resolution of Allergic Airway Inflammation in vivo: effects of therapeutic intervention

Eosinophils, containing tissue toxic granule proteins, are regarded a culprit cell in asthma pathogenesis. Using animal and human experimental models of asthma effects on eosinophilic airway inflammation were investigated in vivo. The current research paradigm regarding spontaneous and steroid-induced clearance of airway tissue eosinophils exclusively involves death through apoptosis followed by phagocytosis of the apoptotic eosinophils. Since this paradigm is based on observations in vitro and in airway lumen, in vivo studies on occurrence of eosinophil apoptosis in airway tissues are urgently warranted. Using well-validated techniques we demonstrated that eosinophil apoptosis may not occur, not even at spontaneous or steroid-induced resolution of airway eosinophilic inflammation. Yet, by Fas-receptor stimulation in mouse allergic airways, we could for the first time produce apoptotic eosinophils in lung tissues. However, instead of being phagocytosed most apoptotic eosinophils underwent secondary necrosis. Fas-receptor stimulation also induced direct cytolysis of non-apoptotic eosinophils, a mode of death and degranulation that also occurs in asthma. Consequently, airway inflammation was greatly aggravated. Indeed, our in vivo studies involving Fas-induced eosinophil apoptosis turned a promising asthma treatment modality? into a mechanism causing exacerbation of airway inflammation. Furthermore, we demonstrated that eosinophil cell clearance in vivo involved trans-epithelial migration of cells into the airway lumen. This luminal entry mechanism allowed 350 000 eosinophils/cm2 airway mucosal surface to be cleared from the airway tissue each minute without affecting the epithelial integrity. Once in the lumen some eosinophils underwent apoptosis before being removed, likely by mucociliary clearance or coughing. Hence, we suggest that facilitating cell clearance by luminal entry may constitute an important characteristic of future treatments that shall resolve airway inflammatory conditions. Interestingly, we discovered that steroid treatment permitted luminal entry of eosinophils while it inhibited selectively the CC-chemokine RANTES. These data suggest that inhibiting RANTES-dependent cell recruitment and promoting clearance of inflammatory cells into the airway lumen are significant components of the pharmacology of therapeutic steroids.