Comparative Analysis of Pulmonary Irritation by Measurements of Penh and Protein in Bronchoalveolar Lavage Fluid in Brown Norway Rats and Wistar Rats Exposed to Irritant Aerosols

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Abstract
The object of this study was to compare in two strain of rats (Brown Norway and Wistar) that were acutely exposed (1 x 6 hrs) to aerosols of polymeric methylenediphenyl-4,4'-diisocyanate (MDI), the relative sensitivity of the functional endpoint "enhanced pause (Penh)" with endpoints in bronchoalveolar lavage fluid (BALF) indicative of lower respiratory tract irritation. This approach included an analysis of both the concentration-response and the time-course of effects. Penh was measured repeatedly prior to (baseline) and during a stepped methacholine (MCh) bronchoprovocation challenge in barometric plethysmographic chambers on postexposure days 1, 3, and 7. Results show that total protein in BALF was a sensitive endpoint to probe early effects caused by exposure to irritant polyisocyanate aerosol. Baseline Penh increased in a concentration-dependent manner and paralleled closely the magnitude of increased BALF-protein on postexposure day 1. The time-course of changes in Penh complemented those of BALF-protein observed in previous studies. The incremental increase of Penh during a stepped MCh-challenge was attenuated with increasing baseline Penh values. In summary, these data show that the exposure to irritant concentrations of this aerosolized polyisocyanate caused a transient perturbation of the blood/air-barrier, which can suitably be probed by measurements of protein in BALF. Although Penh appears to parallel these changes, it displays substantially greater variability. The increase in Penh is apparently more related to changes in breathing patterns either caused by stimulation of receptors or changes in the mechanical properties of lung parenchyma. In regard to Penh and BALF-protein, both strains of rats were equally susceptible, although some endpoints displayed a higher variability in Brown Norway rats when compared to Wistar rats. This supports the conclusion that Wistar rats afford a higher diagnostic resolution than BN rats.

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