Cytokinetic and morphological changes in the lungs and lung-associated lymph nodes of rats after inhalation of fly ash

Fischer-344 rats (male and female) were exposed to 36 mg/m³ of fluidized bed coal combustion fly ash or sham-exposed for 7 hr/day, 5 days/week for 4 weeks, and sacrificed after 2 or 4 weeks of exposure and at 2, 22, and 42 weeks after the end of exposure. Animals were injected with tritiated thymidine 2 hr before sacrifice and autoradiographs prepared from 1-μm sections of lung and lymph node tissue embedded in glycol methacrylate plastic. Differences in labeling indices of pulmonary epithelial cells, alveolar macrophages, airway epithelial cells, and cells of the lung-associated lymph nodes between the exposed and control animals were maximal after 2 and 4 weeks of exposure. Labeling indices for lung epithelial cells were about the same in control and exposed animals at 2, 22, and 42 weeks after the end of exposure. However, these values were elevated relative to earlier control levels. In contrast, morphological changes in the fly ash-exposed animals were most prominent after the end of the exposure. These changes included thickening of the alveolar walls, clusters of particle-filled macrophages in the alveolar region, and perivascular inflammation. Additionally, there were small granulomas in the alveolar region at 42 weeks after the end of exposure. Granulomas were also formed in the lung-associated lymph nodes and bronchus-associated lymphoid tissue. We conclude that the inhalation of fly ash alone had little detrimental effect upon the rat lung. However, the increases in proliferation indicate the potential for fly ash combined with a carcinogen to enhance the carcinogen's effect.     

Pulmonary aerosol actions of LY188695 (KB2413), a new potent H1-receptor antagonist

The new potent H₁ receptor antagonist, LY188695 (KB2413), was delivered to guinea pigs as a pulmonary aerosol and its ability to inhibit histamine-induced airway obstruction examined. Aerosol LY188695 was more effective than inhaled chlorpheniramine or clemastine in reducing the pulmonary gas trapping produced by histamine challenge. Lung antihistamine effects occurred within minutes of a brief, low concentration aerosol exposure and persisted for at least 1 hour. LY188695 aerosol treatment did not produce significant inhibition of methacholine-induced gas trapping. Although systemic antihistamine effects occurred 50 minutes after LY188695 inhalation, aerosol administration produced an enhanced local (i.e., lung) action compared to intravenous delivery.     

Mechanisms of gas loss from normal and hyperinflated excised guinea pig lungs

Increased pulmonary gas trapping was produced by in vivo inhalation exposures of guinea pigs to bronchoconstrictive aerosols. Both normal (filtered air-exposed) and hyperinflated excised lungs lost about 20% of their initial volume by 4 h; gas loss was more rapid during the first 60 min (early period) than the following 180 min (late period). During both periods, absolute rates of gas loss were positively correlated (P less than 0.001) with initial excised lung gas volumes (ELGVs). Tracheal foam movement was observed in most of the hyperinflated lungs, but only during the early period. Occlusion of the trachea reduced gas loss during the early period, but not the late. Gas volumes increased in lungs of animals exposed to SF6:O2 (tracheas tied), and decreased most rapidly in lungs of animals exposed to He:O2 (tracheas tied). Our results suggest that a major part of the early gas loss from excised guinea pig lungs occurs via the trachea and may be influenced by airway foam or menisci formation. After 60 min, airways may be closed and gas loss may occur via transpleural diffusion.     

Age-related changes in conditioned flavor preference in rats

Age-related changes have been documented in regions of the brain shown to process reward information. However, few studies have examined the effects of aging on associative memory for reward. The present study tested 7- and 24-month-old rats on a conditioned flavor preference task. Half of the rats in each age group received an unsweetened grape-flavored solution (CS-) on odd-numbered days and a sweetened cherry-flavored solution (CS+) on even-numbered days. The remaining rats in each age group received a sweetened grape-flavored solution (CS+) on odd-numbered days and an unsweetened cherry-flavored solution (CS-) on even-numbered days. During the acquisition phase of testing, the designated solution (CS+ or CS-) was presented to each rat for 15 min daily across six consecutive days. On the preference phase, each rat received unsweetened cherry and unsweetened grape-flavored solutions simultaneously for 15 min daily across four consecutive days. The 7-month-old rats showed a significant preference for the flavor that was previously sweetened during the acquisition phase (CS+) compared to the previously unsweetened solution (CS-) when the two unsweetened solutions were presented simultaneously during the preference phase of testing. In contrast, the 24-month-old rats did not show a preference and consumed roughly equal amounts of the previously sweetened (CS+) and unsweetened (CS-) solutions. Thus, the data suggest that the ability to form flavor-reward associations declines with increasing age, resulting in impaired conditioned flavor preference.     

Pulmonary responses of the guinea pig to inhaled A23187: a brief review.

The pulmonary effects of inhaled A23187 are reviewed. Guinea pigs challenged with this divalent cationic ionophore rapidly develop airway obstruction, which is maintained for at least 4 h. Pulmonary inflammation and increased airway responsiveness are also observed. Pharmacologic manipulations suggest that these actions are due to the release of multiple mediators. We have found A23187 challenge to be valuable as an approach for testing potential asthma drugs.     

Effects of ozone and sulfuric acid aerosol on gas trapping in the guinea pig lung

Four groups of 20 guinea pigs were sequentially exposed by inhalation to either air followed by sulfuric acid aerosol, ozone followed by sulfuric acid aerosol, ozone followed by air, or air followed by air to determine whether ozone preexposure sensitizes guinea pigs to the airway constrictive effects of sulfuric acid aerosol. All first exposures to ozone or air were 2 h in duration; all second exposures to sulfuric acid or air were for 1 h. All ozone and sulfuric acid exposures were 0.8 ppm and 12 mg/m3, respectively. Animals were observed for respiratory distress during exposure, and excised lungs were quantitated for trapped gas and wet/dry ratios. None of the guinea pigs developed dyspnea, and wet/dry ratios were not altered. Ozone significantly (p less than 0.05) increased trapped gas volumes, which were 44% (ozone-acid) to 68% (ozone-air) greater than in the air-air group. Trapped gas volume was 23% greater in the ozone-acid group than in the air-acid group, but the difference was not statistically significant (p less than 0.20). Thus, ozone increased gas trapping but did not significantly sensitize guinea pigs to the bronchoconstrictive action of sulfuric acid.     

Effect of acute carbon monoxide exposure on cardiopulmonary function of the awake rat

Unanesthetized male Sprague-Dawley rats were exposed for 20 min to 0 (control), 2000, or 4000 ppm carbon monoxide, and cardiopulmonary responses were evaluated. Venous blood samples were taken prior to exposure and at 2, 4, 7, 11, 15, and 20 min during exposure. Responses for CO-exposed animals were compared at 20, 30, 40, 50, and 60% carboxyhemoglobin (COHb), and these values were compared to control values at similar times during exposure. Fifty percent COHb was attained within 4 to 8.5 min at 4000 ppm and 11 to 14 min at 2000 ppm. For both CO exposure groups, mean arterial pressure first decreased at 40% COHb and fell to 69% of baseline at 60% COHb. Tidal volume and breathing frequency increases resulted in minute volume elevations of 52 (2000 ppm) and 77% (4000 ppm) at 60% COHb. Minute volume was elevated at 50 and 60% COHb at 4000 ppm, but was not elevated until 60% COHb for 2000-ppm exposures. The earlier ventilatory stimulation at 4000 ppm may have been a by-product of increased agitation observed in rats exposed to the higher concentration.     

Sulfuric acid induces airway hyperresponsiveness to substance P in the guinea pig

We investigated whether sulfuric acid inhalation would cause hyperresponsiveness to substance P. Guinea pigs became dyspneic during a 1 h sulfuric acid exposure, but recovered by 24 h when they were challenged with substance P or histamine aerosols. Eight minutes after the start of challenge, animals were killed and excised lung gas volumes measured. Sulfuric acid slightly increased histamine responsiveness compared to controls. However, sulfuric acid caused a much more pronounced leftward shift in the dose response to substance P. Coadministration of the neutral endopeptidase (NEP) inhibitor, thiorphan, did not reduce sulfuric acid-related hyperresponsiveness to substance P. By 72 h, sensitization to substance P was absent. Histological evaluation of sulfuric acid-treated lungs revealed mild alveolitis at 24 h, but not at 72 h. We conclude that sulfuric acid produces a marked sensitization to substance P. Inactivation of NEP does not appear to account for this effect.     

Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist.

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.0, respectively. In the functional correlate of the binding studies, LY255283 competitively reduced contractile responses of lung parenchyma to LTB4 (pA2 = 7.2). LTB4 produced airway obstruction which was reduced by LY255283 administered i.v. (ED50 = 2.8 mg/kg) or orally (ED50 = 11.0 mg/kg). Contractile responses to histamine, LTD4 and the thromboxane mimetic, U46619, were not reduced by LY255283. The compound also did not inhibit cyclooxygenase or 5-lipoxygenase enzymes. We conclude that LY255283 selectively antagonized pharmacologic responses to LTB4 on lung tissue and appears to be a useful tool to investigate the role of LTB4 in pulmonary disease.     

Sulfuric acid induces airway hyperresponsiveness to substance P in the guinea pig

We investigated whether sulfuric acid inhalation would cause hyperresponsiveness to substance P. Guinea pigs became dyspneic during a 1 h sulfuric acid exposure, but recovered by 24 h when they were challenged with substance P or histamine aerosols. Eight minutes after the start of challenge, animals were killed and excised lung gas volumes measured. Sulfuric acid slightly increased histamine responsiveness compared to controls. However, sulfuric acid caused a much more pronounced leftward shift in the dose response to substance P. Coadministration of the neutral endopeptidase (NEP) inhibitor, thiorphan, did not reduce sulfuric acid-related hyperresponsiveness to substance P. By 72 h, sensitization to substance P was absent. Histological evaluation of sulfuric acid-treated lungs revealed mild alveolitis at 24 h, but not at 72 h. We conclude that sulfuric acid produces a marked sensitization to substance P. Inactivation of NEP does not appear to account for this effect.