α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep

William M. Abraham, Marek W. Sielczak, Ashfaq Ahmed, Alejandro Cortes, I. T. Lauredo, Jacqueline Kim, Blake Pepinsky, Christopher D. Benjamin, Diane R. Leone, Roy R. Lobb, Peter F. Weller

Research output: Contribution to journalArticle

191 Scopus citations

Abstract

Eosinophils and T lymphocytes are thought to be involved in allergic airway inflammation. Both cells express the α4β1-integrin, very late antigen-4 (VLA-4, CD49d/CD29); α4-integrins can promote cellular adhesion and activation. Therefore, we examined the in vivo effects of a blocking anti-α4 monoclonal antibody, HP 1/2 bronchial responses, airway hyperresponsiveness, inflammatory cell influx, and peripheral leukocyte counts in allergic sheep. Sheep blood lymphocytes, monocytes, and eosinophils expressed α4 and bound HP 1/2 . In control sheep, Ascaris antigen challenge produced early and late increases in specific lung resistance of 380±42% and 175±16% over baseline immediately and 7 h after challenge, respectively, as well as airway hyperresponsiveness continuing for 14 d after antigen challenge. Treatment with HP 1/2 (1 mg/kg, i.v.) 30 min before antigen challenge did not affect the early increase in specific lung resistance but inhibited the late-phase increase at 5-8 h by 75% (P < 0.05) and inhibited the post-antigen-induced airway hyperresponsiveness at 1, 2, 7, and 14 d (P < 0.05, for each time). Intravenous HP 1/2 given 2 h after antigen challenge likewise blocked latephase airway changes and postchallenge airway hyperresponsiveness. Airway administration of HP 1/2 (16-mg dose) was also effective in blocking these antigen-induced changes. Response to HP 1/2 was specific since an isotypic monoclonal antibody, 1E6, was ineffective by intravenous and aerosol administration. Inhibition of leukocyte recruitment did not totally account for the activity of anti-α4 antibody since HP 1/2 neither diminished the eosinopenia or lymphopenia that followed antigen challenge nor consistently altered the composition of leukocytes recovered by bronchoalveolar lavage. Because airway administration of HP 1/2 was also active, HP 1/2 may have inhibited cell activation. Reduction of platelet- activating factor-induced eosinophil peroxidase release from HP 1/2 -treated eosinophils supports such a mechanism. These findings indicate a role for α4-integrins in processes that lead to airway late phase responses and persisting airway hyperresponsiveness after antigen challenge.

Original languageEnglish (US)
Pages (from-to)776-787
Number of pages12
JournalJournal of Clinical Investigation
Volume93
Issue number2
DOIs
StatePublished - Feb 1994

    Fingerprint

Keywords

  • adhesion molecules
  • asthma
  • bronchoprovocation
  • eosinophils
  • inflammation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abraham, W. M., Sielczak, M. W., Ahmed, A., Cortes, A., Lauredo, I. T., Kim, J., Pepinsky, B., Benjamin, C. D., Leone, D. R., Lobb, R. R., & Weller, P. F. (1994). α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. Journal of Clinical Investigation, 93(2), 776-787. https://doi.org/10.1172/JCI117032