Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-3 and tissue leukocyte apoptosis.
We have used two models of murine pulmonary inflammation to investigate the signals responsible for the resolution of bronchial hyperresponsiveness (BHR). Both protocols involved two sensitizations with OVA followed by serial aerosolized challenge with OVA. We determined that administration of the second sensitization by aerosol (model A) was associated with a transient response, whereas administration by the i.p. route (model B) induced a sustained response, in the form of BHR and eosinophilia. This difference in kinetics was due solely to the route of the second Ag administration and was not associated with Ag dose or adjuvant. Differences in kinetics of lung eosinophilia/BHR were shown to be independent of IgE levels and IL-4 or IL-5. However, IL-3 levels in model A closely correlated with the rate of leukocyte clearance by apoptosis and were observed concomitant with a decline in BHR. Blockage of IL-3 in model B increased leukocyte apoptosis but reduced tissue eosinophilia and BHR. The use of mouse models in which a single different administration of allergen is associated with a failure/success to resolve inflammation and BHR by 72 h postchallenge indicates a link between IL-3 production, leukocyte apoptosis, and BHR responses.
Lloyd
C M
CM
Millennium Pharmaceuticals Inc., Cambridge MA 02139. Division of Immunology, Children's Hospital, Boston, MA 02115.
Gonzalo
J A
JA
Nguyen
T
T
Delaney
T
T
Tian
J
J
Oettgen
H
H
Coyle
A J
AJ
Gutierrez-Ramos
J C
JC
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007377:Interleukin-3 / Q000276:immunology / Q000502:physiology*; D007700:Kinetics; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D007377:Interleukin-3; D007073:Immunoglobulin E