MECHANISMS OF PULMONARY NO2 ABSORPTION

Although NO2-induced cytotoxic responses have been well characterized, the specific mechanisms responsible for initiating toxicity remain equivocal. The inhomogeneous distribution of epithelial injury suggests that differential interactions between NO2 and the lung surfaces may contribute to the extent of regional responses. Consequently, we have initiated studies to characterize the mechanisms which govern NO2 absorption and the initiation of the toxic cascade. Due to limitations in whole animal models, we have utilized numerous in vitro exposure models. Herein we examine our recent investigations. In brief synopsis: NO2 uptake is governed by reaction between inhaled NO2 and constituents of the pulmonary surface lining layer (SLL). The predominant reaction pathway involves hydrogen abstraction producing HNO2 and an organic radical. NO2 uptake is first-order with respect to NO2 ([NO2] < 10 ppm), is aqueous substrate-dependent, and is saturable. Conditions at the gas/liquid interface proper modulate the rate of transfer into the aqueous phase. Most likely, NO2 does not diffuse unreacted through the SLL. Absorption is proportional to inspired dose. The clearance efficiency may be modulated by ventilation frequency and the effective surface area of the exposed air space surfaces. We propose that the profile and concentration of SLL constituents mediate both the dosimetry and the extent of epithelial responses. Due to differential lining layer conditions, the relationship between absorbed dose and response may be complex and may exhibit anatomic and host variability.