In order to investigate whether bronchopulmonary hyperresponsiveness represents a unique property of sensitized lungs, we examined the responses of lungs from either actively sensitized, passively sensitized, or nonsensitized (control) guinea pigs to in vitro bronchoconstriction (BC) and release of thromboxane (Tx) B₂, 6-keto-PGF_1α, and histamine induced by platelet-activating factor (PAF-acether) or leukotriene (LT) D₄. Guinea pigs were actively sensitized with 10 µg of either ovalbumin or Dermatophagoides farinae extract in Al(OH)₃ injected intraperitoneally twice at a 2-wk interval. Seven days after the second injection (booster injection), the lungs were removed, ventilated, and perfused via the pulmonary artery with Krebs solution containing 2.5 g/L bovine serum albumin. In lungs from actively sensitized animals, BC was induced by significantly lower doses of PAF-acether and LTD₄ than those required to elicit the same response in control preparations. In addition, sensitized lungs released more TxB₂, 6-keto-PGF_1α, and histamine in response to PAF-acether and LTD₄ than did control lungs. Increased mediator release was also observed upon challenge of lungs from actively sensitized animals with arachidonic acid and histamine. Lungs from guinea pigs passively sensitized with serum from actively sensitized animals did not exhibit increased responsiveness to PAF-acether as compared to control lungs. The hyperresponsiveness induced after booster injection of the antigen occurred concomitantly with an increase in the homocytotropic antibody titer (as measured by passive cutaneous anaphylaxis) and persisted for 3 months after sensitization, when the levels of circulating antibodies and lung response to antigen challenge returned to control values. The hyperresponsiveness to PAF-acether in lungs from actively sensitized guinea pigs was unaffected by the addition of 0.1 mM aspirin, 3 µM mepyramine, or 0.1 mM of the cyclooxygenase and lipoxygenase inhibitor BW 755C to the perfusion medium. By contrast, when mepyramine and BW 755C were added together, BC but not histamine release was suppressed, suggesting a participation of leukotrienes in this process. These results are at variance to those observed with control lungs, for which PAF-acether-induced BC was totally inhibited by aspirin. Thus, active sensitization modifies mediator-induced responses of lung tissue, and this may provide a novel basis for understanding the immunologic mechanisms involved in the development of bronchopulmonary hyperreactivity.