Effects of steroid treatment on lung CC chemokines, apoptosis and transepithelial cell clearance during development and resolution of allergic airway inflammation.
BACKGROUND
Steroid treatment of allergic eosinophilic airway diseases is considered to attenuate cell recruitment by inhibiting several chemokines and to cause eosinophil clearance through inducement of apoptosis of these cells. However, roles of these mechanisms in the actions of steroids in vivo have not been fully established. Also, as regards clearance of tissue eosinophils other mechanisms than apoptosis may operate in vivo.


OBJECTIVE
This study explores anti-inflammatory effects of steroids instituted during either development or resolution of airway allergic inflammation.


METHODS
Immunized mice were subjected to week-long daily allergen challenges (ovalbumin). Steroid treatment was instituted either amidst the challenges or exclusively post-allergen challenge. CC chemokines, goblet cell hyperplasia, occurrence of eosinophil apoptosis, and airway tissue as well as lumen eosinophilia were examined at different time-points.


RESULTS
Daily steroids instituted amid the allergen challenges non-selectively attenuated a range of chemokines, permitted egression of tissue eosinophils into airway lumen to increase, and reduced development of lung tissue eosinophilia. Steroid treatment instituted post-challenge selectively inhibited the CC-chemokine regulation upon activation, normal T cell expressed and secrted (RANTES), permitted continued egression of eosinophils into airway lumen, and resolved the tissue eosinophilia. Eosinophil apoptosis rarely occurred at development and resolution of the allergic eosinophilic inflammation whether the animals were steroid treated or not. However, anti-Fas monoclonal antibodies given to mice with established eosinophilia post-challenge produced apoptosis of the tissue eosinophils indicating that apoptotic eosinophils, if they occur, are well detectible in vivo.


CONCLUSIONS
Airway tissue eosinophils are likely eliminated through egression into airway lumen with little involvement of apoptosis and phagocytosis. Our data further suggest that therapeutic steroids may resolve airway inflammation by permitting clearance of tissue eosinophils through egression and inhibiting RANTES-dependent cell recruitment to lung tissues.
Uller
L
L
Department of Experimental Medical Science, Lund University, Lund, Sweden. Lena.Uller@med.lu.se
Lloyd
C M
CM
Rydell-Törmänen
K
K
Persson
C G A
CG
Erjefält
J S
JS
D000485:Allergens; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019819:Budesonide / Q000494:pharmacology*; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000032:analysis / Q000235:genetics / Q000276:immunology; D019742:Chemokines, CC / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D004804:Eosinophils / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology*; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology*; D015848:Interleukin-5 / Q000032:analysis / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010047:Ovalbumin; D012333:RNA, Messenger / Q000032:analysis; D013194:Staining and Labeling
D000485:Allergens; D015415:Biomarkers; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D005938:Glucocorticoids; D015848:Interleukin-5; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D019819:Budesonide; D010047:Ovalbumin