Airway and tissue behavior during early response in sensitized rats: role of 5-HT and LTD4.

We have recently demonstrated that tissue resistance increases during the early response (ER) to antigen challenge in sensitized Brown-Norway rats. The purpose of the present study was to investigate the role of the potential ER mediators 5-hydroxytryptamine (5-HT) and leukotriene D4 (LTD4) in the airway and tissue response. We sensitized the rats with ovalbumin (OA) and performed experiments on anesthetized, open-chested, mechanically ventilated [breathing frequency = 1 Hz, tidal volume = 12 ml/kg, positive end-expiratory pressure (PEEP) = 3 cmH2O] animals. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the resistance of lung (RL), tissue (Rti), and airway (Raw). To assess the effects of LTD4 and 5-HT, we administered the antagonists methysergide (5-HT antagonist) and MK-571 (LTD4 antagonist) before challenge. To assess lung morphometry during the ER, the lungs of four animals from each group were frozen with liquid nitrogen (PEEP = 3 cmH2O). Airway constriction was assessed by measuring the ratio of the airway lumen to the ideally relaxed airway (Abm/Abm). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), an atelectasis index (ATI) derived by calculating the ratio of tissue to air space, and SD of the two (SD-Lm and SD-ATI). In all animals receiving OA but no antagonists, an ER was seen (RL, Rti, and Raw = 180.7 +/- 6.1, 155.4 +/- 8.2, and 223.1 +/- 14.0% of baseline, respectively). Methysergide significantly inhibited the ER (RL, Rti, and Raw = 117.0 +/- 5.9, 101.2 +/- 1.6, 133.7 +/- 10.2%, respectively), whereas MK-571 partially reduced the ER (RL, Rti, and Raw = 144.2 +/- 5.6, 132.9 +/- 5.7, and 155.5 +/- 9.2%, respectively). Abm/Abm was significantly decreased, and SD-Lm and SD-ATI were significantly increased in animals receiving OA alone and in those receiving MK-571 before OA challenge. These data suggest that alterations in both airways and tissues contribute to the ER and that 5-HT and, to a lesser degree, LTD4 are important mediators of the ER in this rat model of extrinsic asthma.