A small-molecule, tight-binding inhibitor of the integrin alpha(4)beta(1) blocks antigen-induced airway responses and inflammation in experimental asthma in sheep.
The leukocyte integrin very late antigen-4 (alpha(4)beta(1), CD49d/CD29) is an adhesion receptor that plays an important role in allergic inflammation and contributes to antigen-induced late responses (LAR) and airway hyperresponsiveness (AHR). In this study, we show that single doses of a new small-molecule, tight-binding inhibitor of alpha(4), BIO-1211, whether given by aerosol or intravenously, either before or 1.5 h after antigen challenge blocks allergen- induced LAR and post-antigen-induced AHR in allergic sheep. Multiple treatments with doses of BIO-1211 that were ineffective when given singly, were protective. BIO-1211 also provided dose-dependent inhibition of the early airway response (EAR) to antigen. In conjunction with the functional protection against the antigen-induced LAR and AHR, sheep treated with BIO-1211 before challenge showed significantly reduced: (1) numbers of eosinophils in bronchoalveolar lavage (BAL), (2) BAL levels of the inflammatory marker tissue kallikrein, and (3) numbers of inflammatory cells (lymphocytes, eosinophils, metachromatic staining cells, and neutrophils) in bronchial biopsies obtained after challenge when compared with corresponding biopsies after vehicle treatment. More importantly, we show for the first time that an inhibitor of alpha(4) was able to reverse post-antigen-induced AHR, thereby decreasing the time of recovery from the normal period of > 9 d to 3 d. Our results show that effective inhibition of antigen-induced airway responses can be achieved with single doses of a potent small-molecule inhibitor of alpha(4) and that such agents may be used therapeutically, as well as prophylactically, to alleviate allergen- induced inflammatory events. These data provide further support and extend the evidence for the role of alpha(4) integrins in the pathophysiologic events that follow airway antigen challenge.
Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida, USA. abraham@msmc.com
W M
WM
Abraham
A
A
Gill
A
A
Ahmed
M W
MW
Sielczak
I T
IT
Lauredo
Y
Y
Botinnikova
K C
KC
Lin
B
B
Pepinsky
D R
DR
Leone
R R
RR
Lobb
S P
SP
Adams
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002217:Carbachol / Q000008:administration & dosage; D004804:Eosinophils / Q000166:cytology; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000502:physiology*; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007610:Kallikreins / Q000032:analysis; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D016029:Receptors, Very Late Antigen / Q000502:physiology*; D012756:Sheep
D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D009842:Oligopeptides; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; C118154:BIO 1211; D002217:Carbachol; D007610:Kallikreins