No abstract

We studied the magnitude and the time course of changes in pulmonary resistance (RL) after aerosol challenge with chicken ovalbumin (OA) of 15 sensitized, highly inbred Brown-Norway (BN) rats. Animals were actively sensitized and 2 wk later were challenged through the airways. Airway responses of sensitized animals were compared to those of 6 control animals challenged with sufficient methacholine (MCh) to at least double RL and to 4 unsensitized control rats challenged with OA. Ten of 15 rats in the experimental group displayed an early response (ER), defined as an increase in RL of at least 50% within 1 h of challenge. A late response (LR) was considered to have occurred when the value of RL exceeded the mean plus 2 standard deviations of all the measurements taken from 1 h after challenge to the end of the experiment. Two rats died less than 240 min after OA challenge with RL greater than 200% baseline. The remaining 13 were studied for a total duration that ranged from 390 to 720 min and of these animals 10 demonstrated LRs. Maximal RL during the LR after OA was 287 +/- 49% (SE) baseline (range, 129 to 760) versus 115 +/- 15% (75 to 176) for control animals after MCh (p less than 0.01) and 52 +/- 3% (51 to 142; p less than 0.01) for unsensitized control animals after OA. There was no correlation between the magnitude of ER and LR; 3 LRs occurred in the absence of detectable ERs. The median time to the peak of the LR was 450 min; median duration of LRs was 90 min (range, 30 to 135 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

The purpose of this study was to evaluate the possible role of the quantity of airway smooth muscle (AWSM) as a determinant of differences in responsiveness between inbred rat strains. To do this, we studied several batches of 8- to 10-wk-old Lewis and Fisher 344 rats. Animals were anesthetized intraperitoneally with pentobarbital (30 mg/kg) and xylazine (7 mg/kg). The peak value of pulmonary resistance (RL) was measured after progressively doubling concentrations of inhaled aerosolized methacholine (MCh). The MCh concentration required to double RL (EC200RL) was calculated as an index of airway responsiveness. Fisher rats were significantly more responsive than Lewis, and the interstrain variability in responsiveness was significantly greater than the intrastrain variability. Additional animals from the less responsive Lewis strain (n = 8) and the more responsive F344 strain (n = 11) were killed immediately after measurement of responsiveness, and AWSM was quantitated as a fraction of total lung tissue using a point-counting technique. F344 rats were again significantly more responsive than Lewis rats (EC200RL geometric mean: 0.72 versus 2.16 mg/ml, p less than 0.005). F344 rats also had significantly more AWSM than did Lewis rats (3.22 +/- 0.176 versus 2.48 +/- 0.185%, mean +/- SE, p less than 0.001). We conclude that highly inbred Fisher rat strains characteristically exhibit a degree of airways responsiveness greater than that of the Lewis strain and that the quantity of AWSM may be an important determinant of interstrain differences.

We measured airway responsiveness to methacholine (MCh) of highly inbred rats before and after six inhalational challenges with antigen. Ten Brown-Norway rats (130-216 g) that were actively sensitized to ovalbumin (OA) received six challenges with OA at 5-day intervals beginning 19 days after sensitization. An aerosol of OA (5% wt/vol) was inhaled for 1, 2, 5, and 10 min or until pulmonary resistance (RL) increased by at least 50%. Challenges with aerosolized MCh were performed immediately before and 14 days after sensitization, 2 days after the 3rd OA exposure, and 2, 7, 12, and 17 days after the 6th OA challenge. Four unsensitized rats underwent inhalational challenges with MCh over an equivalent time period. Responsiveness to MCh was calculated as the concentration of MCh required to increase RL to 200% of the control value (EC200RL). Seven out of 10 rats in the experimental group reacted to the first OA challenge with an immediate increase in RL of greater than 50% of control (range 70-550%). Three animals were unreactive to OA. Base-line EC200RL for all rats undergoing sensitization was 2.13 mg/ml (geometric mean), and it did not change significantly after sensitization (2.05 mg/ml). However, EC200RL of the rats that reacted to OA (n = 7) decreased significantly after 3 (1.11 mg/ml; P less than 0.005) and 6 OA exposures (0.96 mg/ml; P less than 0.005). The increase in responsiveness to inhaled MCh was present 17 days after the last OA exposure (EC200RL = 1.40 mg/ml; P less than 0.05). EC200RL of neither the unreactive sensitized rats (n = 3) nor the control rats (n = 4) changed after OA challenges.(ABSTRACT TRUNCATED AT 250 WORDS)