ROLES OF ADHESION MOLECULES ICAM-1 AND ALPHA(4) INTEGRIN IN ANTIGEN-INDUCED CHANGES IN MICROVASCULAR PERMEABILITY ASSOCIATED WITH LUNG INFLAMMATION IN SENSITIZED BROWN-NORWAY RATS

Increased microvascular permeability and mucosal edema are pathologica l features of airway inflammation in asthma. In this study, we investi gated the characteristics of the edema response occurring in a model o f antigen-induced lung inflammation in sensitized brown Norway rats an d examined the effects of monoclonal antibodies (mAbs) to adhesion mol ecules on this response. Ovalbumin (OA) challenge-induced increases in lund permeability were determined by the leakage of I-125-labeled bov ine serum albumin (BSA) into the extravascular tissues of teh lungs 24 h after challenge in animals intravenously injected (prechallenge) wi th this tracer. Inflammatory cell infiltration into the alveolar space was determined by bronchoalveolar lavage (BAL). Mean extravascular pl asma volume in the lung increased 233% as compared with control (P < 0 .005) at 24 h and increased to 517% by 72 h. The 24-h edema response w as completely inhibited by two oral doses (0.1 mg/kg) of dexamethasone 1 h before, and 7 h after, challenge. Intraperitoneal administration of the anti-rat ICAM-1 mAb 1A29, or anti-rat alpha(4) integrin mAb TA- 2 (2 mg/kg at 12 and 1 h before, and 7 h after, antigen challenge), si gnificantly suppressed eosinophil infiltration into the alveolar space with out inhibiting the enhanced microvascular leakage and lung edema . Determination of plasma antibody concentrations by ELISA of mouse Ig G(1) indicated that sufficient concentrations of the appropriate mAb w ere present to block alpha(4)- or ICAM-1-dependent adhesion. The resul ts suggest that increases in microvascular permeability and plasma lea kage occurred independently of eosinophil accumulation.