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 language | English |
|---|---|
| Pages (from-to) | 776-787 |
| Number of pages | 12 |
| Journal | Journal of Clinical Investigation |
| Volume | 93 |
| Issue number | 2 |
| State | Published - Feb 1 1994 |
| Externally published | Yes |
Fingerprint
Keywords
- adhesion molecules
- asthma
- bronchoprovocation
- eosinophils
- inflammation
ASJC Scopus subject areas
- Medicine(all)
Cite this
α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. / Abraham, William M.; Sielczak, Marek W.; Ahmed, Ashfaq; Cortes, Alejandro; Lauredo, I. T.; Kim, Jacqueline; Pepinsky, Blake; Benjamin, Christopher D.; Leone, Diane R.; Lobb, Roy R.; Weller, Peter F.
In: Journal of Clinical Investigation, Vol. 93, No. 2, 01.02.1994, p. 776-787.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep
AU - Abraham, William M.
AU - Sielczak, Marek W.
AU - Ahmed, Ashfaq
AU - Cortes, Alejandro
AU - Lauredo, I. T.
AU - Kim, Jacqueline
AU - Pepinsky, Blake
AU - Benjamin, Christopher D.
AU - Leone, Diane R.
AU - Lobb, Roy R.
AU - Weller, Peter F.
PY - 1994/2/1
Y1 - 1994/2/1
N2 - 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.
AB - 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.
KW - adhesion molecules
KW - asthma
KW - bronchoprovocation
KW - eosinophils
KW - inflammation
UR - http://www.scopus.com/inward/record.url?scp=0028177035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028177035&partnerID=8YFLogxK
M3 - Article
VL - 93
SP - 776
EP - 787
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 2
ER -