Roles of adhesion molecules ICAM-1 and alpha4 integrin in antigen-induced changes in microvascular permeability associated with lung inflammation in sensitized brown Norway rats.
Increased microvascular permeability and mucosal edema are pathological features of airway inflammation in asthma. In this study, we investigated the characteristics of the edema response occurring in a model of antigen-induced lung inflammation in sensitized brown Norway rats and examined the effects of monoclonal antibodies (mAbs) to adhesion molecules on this response. Ovalbumin (OA) challenge-induced increases in lung permeability were determined by the leakage of 125I-labeled bovine serum albumin (BSA) into the extravascular tissues of the lungs 24 h after challenge in animals intravenously injected (prechallenge) with this tracer. Inflammatory cell infiltration into the alveolar space was determined by bronchoalveolar lavage (BAL). Mean extravascular plasma 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 was 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 alpha4 integrin mAb TA-2 (2 mg/kg at 12 and 1 h before, and 7 h after, antigen challenge), significantly suppressed eosinophil infiltration into the alveolar space without inhibiting the enhanced microvascular leakage and lung edema. Determination of plasma antibody concentrations by ELISA of mouse IgG1 indicated that sufficient concentrations of the appropriate mAb were present to block alpha4- or ICAM-1-dependent adhesion. The results suggest that increases in microvascular permeability and plasma leakage occurred independently of eosinophil accumulation.
Taylor
B M
BM
Department of Cell Biology and Inflammation Research, Pharmacia and Upjohn, Incorporated, Kalamazoo, Michigan 49001, USA. Bruce.M.Taylor@am.pnu.com
Kolbasa
K P
KP
Chin
J E
JE
Richards
I M
IM
Fleming
W E
WE
Griffin
R L
RL
Fidler
S F
SF
Sun
F F
FF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D008168:Lung / Q000098:blood supply; D011654:Pulmonary Edema / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D003907:Dexamethasone