Biomedical subjects

N H Solliday

Publications and source records attributed to N H Solliday.

At least 19 recordsLinked to original sources

PubMed1989

Monocrotaline pneumotoxicity in mice.

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.

Animals↗

PubMed1988

Radiation-induced pulmonary endothelial dysfunction in rats: modification by an inhibitor of angiotensin converting enzyme.

The ability of the angiotensin converting enzyme (ACE) inhibitor Captopril to modify radiation-induced pulmonary endothelial dysfunction was determined in male rats sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays to the right hemithorax. Half of each dose group consumed feed containing 0.12% w/w Captopril (60 mg/kg/day) continuously after irradiation, and half consumed control feed. Four markers of endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. All data were plotted as dose-response curves, and subjected to linear regression analysis. The Captopril modifying effect was expressed as the ratio of isoeffective doses at a common intermediate response (DRF), or as the ratio of the response curve slopes. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. Captopril exhibited DRF values of 1.4-2.1, and slope ratios of 1.4-5.1 for all four functional markers (p less than 0.05). Thus, the ACE inhibitor Captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months postirradiation. Although the mechanism of Captopril action is not clear at present, these data suggest a novel application for this class of compounds as injury-modifying agents in irradiated lung.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1987

Brain surface exposure to CO2 and NdYag laser application: effect on pulmonary endothelium response in the rat.

Pulmonary endothelial cells and the renin-angiotensin-aldosterone (RAA) system respond to different types of injury (direct or indirect) with variations in their functions. These variations influence the regulatory mechanisms of pulmonary and systemic blood pressure, electrolyte balance and fibrinolysis. Concentration changes of some components of the RAA system and lung plasminogen activator were observed following NdYag laser application to the brain surface in rats. These changes were similar to those observed in cutaneous burn and haemorrhagic hypotension. CO2 laser application did not cause the same changes.

Aluminum Silicates↗

PubMed1987

Functional responses of the pulmonary endothelium to thoracic irradiation in rats: differential modification by D-penicillamine.

Male rats were sacrificed 2 or 6 months after a range of single doses of gamma rays (0-30 Gy) to the right hemithorax. Half of each dose group consumed control feed continuously after irradiation, and half consumed feed containing the collagen antagonist D-penicillamine (10 mg/rat/day). Four markers of pulmonary endothelial function were monitored: angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Bronchoalveolar lavage (BAL) fluid also was obtained from the right lung, and was analyzed for macrophage number, and PGI2 and TXA2 concentration. Right lung ACE and PLA activities decreased linearly with increasing dose at both 2 and 6 months postirradiation, and penicillamine had no significant effect on either response. In contrast, PGI2 and TXA2 production by the right lung increased linearly with increasing radiation dose at both autopsy times. Penicillamine significantly ameliorated the increase in PGI2 production at 2 months, and the increase in TXA2 production at both 2 and 6 months postirradiation. Penicillamine dose-reduction factors (DRF) for PGI2 and TXA2 production were 1.3-1.4, and the response curve slope ratios were 1.7-2.5 (p less than 0.05). Penicillamine also ameliorated the dose-dependent increase in TXA2 concentration in the BAL fluid at 2 months. These data indicate that the four "markers" of radiation-induced pulmonary endothelial dysfunction do not respond identically to penicillamine dose-modification. Of the four markers, TXA2 production exhibits the most significant and widespread penicillamine sparing. TXA2 is a potent vasoconstrictor, promoter of platelet aggregation, and mediator of inflammation, and partial prevention of the radiation-induced hyperproduction of this eicosanoid may account in part for penicillamine's therapeutic action in this model.

Animals↗

PubMed1987

Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats.

Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.

Animals↗

PubMed1986

Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817.

Pulmonary injury induced by the plant alkaloid monocrotaline is partially prevented by the angiotensin-converting enzyme (ACE) inhibitor captopril. CL242817 [(S-[R*,S*])-1-([3-acetylthio]-3-benzoyl-2-methyl-propionyl)- L-proline] is a new orally active ACE inhibitor under evaluation as an antihypertensive agent. To determine whether CL242817 also can modify monocrotaline-induced pulmonary injury, male rats were divided into four groups: control; CL242817 (60 mg/kg/day, po); monocrotaline (2.4 mg/kg/day, po); or monocrotaline plus CL242817, and were sacrificed after 6 weeks of continuous treatment. Rats receiving monocrotaline alone exhibited occlusive medial thickening of the pulmonary arteries, cardiomegaly, and right ventricular hypertrophy. Electron micrographs of monocrotaline-treated lung revealed degeneration of both endothelial and Type I epithelial cells, as well as marked interstitial hypercellularity and fibrosis. Hydroxyproline (collagen) content of monocrotaline-treated lung also increased significantly, confirming the fibrosis observed in the electron micrographs. These structural changes were accompanied by decreased lung ACE and plasminogen activator (PLA) activities, indicative of pulmonary endothelial dysfunction. Concomitant CL242817 treatment ameliorated all anatomic manifestations of monocrotaline injury, particularly the right ventricular hypertrophy, pulmonary arterial occlusion, epithelial degeneration, and interstitial fibrosis. CL242817 also significantly prevented the monocrotaline-induced increase in lung hydroxyproline content. In contrast, concomitant CL242817 did not significantly influence the suppressed lung ACE and PLA activities in monocrotaline-treated rats. CL242817 alone produced retarded weight gain, decreased heart weight relative to body weight, decreased lung hydroxyproline content and ACE activity, and increased serum ACE activity and plasma AII concentration. Thus CL242817 resembles captopril, both in its ability to ameliorate monocrotaline-induced pulmonary injury in rats, and in many of its side effects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1985

The relationship between endothelial dysfunction and collagen accumulation in irradiated rat lung.

Male rats were killed 2 months (early fibrosis) or 6 months (peak fibrosis) after a range of single doses of 60Co gamma rays to the right hemithorax. Pulmonary arterial perfusion scans were performed at 2 months on animals scheduled for autopsy at 6 months. Lung angiotensin converting enzyme (ACE) activity was used to monitor endothelial function, and hydroxyproline (HP) concentration served as an index of interstitial collagen accumulation (fibrosis). ACE activity also was measured in right lung bronchoalveolar lavage (BAL) fluid and blood serum, to determine whether information obtained from a minimally invasive procedure might serve as an index or predictor of the severity of lung damage. Linear dose-response curves (r = 0.92-0.99) were obtained for right lung arterial perfusion, ACE activity and HP concentration. At 2 months, perfusion decreased 2.7% per Gy, ACE activity (per lung, per mg wet weight, or per mg protein) decreased 3.0-4.2% per Gy, and HP concentration (per g dry weight) increased 1.7% per Gy. At 6 months, the slopes of the response curves were virtually identical to those at 2 months; the Y intercept of the response curve for ACE activity was unchanged, whereas that for HP concentration was 50% higher at 6 than at 2 months. ACE activity and protein concentration in the BAL increased with increasing dose, but the variation within groups was too large, and the sensitivity was too low to serve as a reliable index of lung status. Serum ACE activity was independent of radiation dose at both autopsy times. Thus in rat lung, arterial perfusion, endothelial dysfunction and interstitial fibrosis exhibit similar but not identical radiosensitivities. The dose-effect curves for these three responses of the lung in situ change less than 5% per Gy over the dose range of 10-30 Gy, a smaller variation than would be predicted from endothelial cell survival data based on clonogenic assays in vitro or in vivo.

Animals↗

PubMed1985

Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine.

The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.

Animals↗

PubMed1984

Monocrotaline-induced pulmonary endothelial dysfunction in rats.

To study the role of endothelial damage in the pathogenesis of lung injury induced by the pyrrolizidine alkaloid monocrotaline, three functions (angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) production) associated with the pulmonary endothelium were examined, and were correlated with pulmonary arterial perfusion and ultrastructure in rats receiving monocrotaline in their drinking water (20 mg/liter) for 1-12 weeks. Lung ACE activity increased after 1 week of monocrotaline, then decreased steadily from 1 to 6 weeks, before plateauing at approximately 55% of normal. PLA activity in monocrotaline-treated lungs did not change significantly for the first 2 weeks, then decreased to 59 and 79% of the control value after 6 and 12 weeks, respectively. In contrast, PGI2 production increased progressively, reaching 140 and 270% of the control level after 6 and 12 weeks of monocrotaline treatment, respectively. These endothelial functional changes were not accompanied by significant changes in pulmonary arterial perfusion as visualized by 99mTc lung scans. Electron microscopy of monocrotaline-treated lungs revealed endothelial damage (perivascular and subendothelial edema, degeneration) starting at 1 week, and inflammatory and hemorrhagic reactions starting at 2 weeks. At 6 and 12 weeks, monocrotaline-treated rats also exhibited increased pulmonary arterial wall thickness, right heart enlargement, and cardio- and hepatomegaly. Thus, monocrotaline-induced pulmonary injury is accompanied, and in some cases preceded, by structural and functional abnormalities in the pulmonary endothelium.

Animals↗

PubMed1984

Radiation injury in rat lung. IV. Modification by D-penicillamine.

To determine whether D-penicillamine, known to reduce fibrosis in irradiated rat lung (W. F. Ward, A. Shih - Hoellwarth , and R. D. Tuttle , Radiology 146, 533-537, 1983), also ameliorates radiation injury in the pulmonary endothelium, we measured angiotensin-converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) production in the lungs of penicillamine-treated (10 mg/day, po, continuous after irradiation) and untreated rats from 2 weeks to 6 months after a single dose of 25 Gy of 60Co gamma rays to the right hemithorax. Both ACE and PLA activity in the irradiated right lung of untreated rats decreased dramatically between the 1st and 2nd months after exposure, then reached a plateau through 6 months at approximately 25 and 50% of the normal level, respectively. For the first 2 months after irradiation, penicillamine-treated animals exhibited significantly (P less than 0.05) higher activities of both ACE and PLA than did untreated rats. From 3 to 6 months after irradiation, however, the only significant drug effect on these enzymes was a 25% increase in PLA activity at 6 months. PGI2 production by the irradiated lung of untreated rats increased continuously, and at 6 months was approximately 10 times higher than normal. Penicillamine significantly (P less than 0.05) reduced this hypersecretion, and at 6 months after irradiation, PGI2 production by the lungs of drug-treated rats was only half that of untreated animals. In contrast, the drug had no significant effect on enzyme activities in the lungs of sham-irradiated rats. Thus the antifibrotic agent D-penicillamine delays the onset of radiation-induced enzyme dysfunction in the pulmonary endothelium. In addition at 6 months after irradiation, the lungs of penicillamine-treated rats exhibit 25% more PLA activity and only half as severe a hypersecretion of PGI2 as do the lungs of untreated animals. The drug is most effective in ameliorating endothelial damage during the first 2 months after irradiation, preceding the development of interstitial fibrosis. However, the effect of this penicillamine regimen on pulmonary endothelial function is not as large as its effect on collagen accumulation in irradiated rat lung.

Animals↗

PubMed1983

Radiation injury in rat lung. II. Angiotensin-converting enzyme activity.

To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of 60Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90-150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.

Animals↗

PubMed1981

Variability of the volume of isoflow.

Twenty healthy hospital workers produced maximal expiratory flow-volume curves before and after three vital capacity inhalations of an 80 percent helium and 20 percent oxygen mixture (HE+O2) in the morning and afternoon for four days during one week. Ten healthy trade union apprentices underwent the same tests, twice on one day and again one month later. Measurements made from curves (and their mean coefficients of variation) were: VisoV (105 percent) FVC (3 percent), FEF50% (6 percent), FEF75% (8 percent), the ratio of FEF50% breathing He+O2 to FEF50% breathing air (6 percent), and the ratio of FEF75% breathing He+O2 to FEF75% breathing air (9 percent). Differences among separate observers contributed significantly to the high variability of the VisoV. Diurnal changes and training effects over the week of study were not significant. In conclusion, VisoV is poorly reproducible compared with the FVC and expiratory flow rates at low lung volumes breathing air and He+O2. This should be considered when interpreting results in a given individual.

Adult↗

PubMed1981

Serial observations of angiotensin-converting enzyme and pulmonary function in sarcoidosis.

Fifty-six measurements of angiotensin-converting enzyme (ACE) level, diffusing capacity (DLCO), and total lung capacity (TLC) were made in 18 sarcoid patients with a maximum of 25 months of follow-up observation. During spontaneous or corticosteroid-induced changes in disease activity, there was a significant inverse correlation between changes in ACE level and changes in DLCO and between changes in ACE level and changes in TLC. These observations suggest that ACE measurement may be a useful adjunct to pulmonary function tests to follow the course of sarcoidosis and to monitor the effects of corticosteroid therapy on the lung.

Adrenal Cortex Hormones↗

PubMed1977

Living histamine-containing cells from the bronchial lumens of humans. Description and comparison of histamine content with cells of rhesus monkeys.

Cell populations obtained by bronchial lavage from human subjects were examined for the presence of cells related to the mast cell-basophil series. Such bronchial lumen histamine-containing cells (BLHCC) were identified. The BLHCC stained with toluidine blue may be identified by bright field or dark field microscopy. The BLHCC are alive as evidenced by ability to release histamine (H) after exposure to anti-IgE or calcium ionophore. Although H release from peripheral blood leukocytes by these two agents is potentiated by the presence of D2O, H release from BLHCC of the same subjects by anti-IgE or calcium ionophore was not potentiated by D2O. In studies comparing bronchial cell populations of humans and rhesus monkeys with peripheral blood leukocyte populations of the same subjects, the histamine content of the bronchial cell population was much higher in rhesus monkeys. IgE/Alb ratios of respiratory secretions and serum of the same human subjects were of the same order of magnitude in contrast to previous comparisons done on these fluids in rhesus monkeys.

Animals↗

PubMed1976