Effects of respiratory viruses on pulmonary alveolar macrophages.
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Antigen-Presenting Cells↗
Biomedical subjects
R Grad
Publications and source records attributed to R Grad.
Bronchoalveolar lavage fluid cytology reflects airway inflammation in beagle puppies with acute bronchiolitis.
Beagle puppies infected with both canine parainfluenza virus type 2 (CPI2) and Bordetella bronchiseptica (Bb) develop more severe acute bronchiolitis and airways hyperresponsiveness than do those infected with CPI2 or Bb alone. The aim of our study was to characterize the inflammatory response associated with airway hyperresponsiveness, and to determine whether the inflammatory cell response of bronchoalveolar lavage fluid (BALF) reflected changes in the bronchioles in this model. We investigated 25 beagle puppies (ages 76 +/- 5 days, mean +/- SEM) in four groups: controls (n = 6), or puppies inoculated with both CPI2 and Bb (CPI2-Bb) (n = 11), with only CPI2 (n = 4), or only Bb (n = 4). The puppies were killed 3-4 days after inoculation, the lungs excised, the intermediate lobe lavaged, and BALF and the bronchiolar wall tissue examined for neutrophils and other inflammatory cells. Control puppies had no evidence of inflammation. However, the CPI2-Bb puppies had developed cough and rhinitis, positive cultures for CPI2 and Bb, and a neutrophilic cellular response in both the bronchioles and the BALF. Puppies inoculated with only CPI2 or Bb had milder illnesses and no significant bronchiolar and BALF neutrophilic response. For all groups, the severity of bronchiolar wall inflammation correlated with the total number of BALF inflammatory cells, and bronchiolar wall neutrophil counts correlated with the percentage of neutrophils in the BALF. The illness and the airway hyperresponsiveness observed in the CPI2-Bb group were associated with airway neutrophilia. Our studies support the hypothesis that neutrophils are associated with airway dysfunction in this model, and the use of BALF to study the process.
Acute Disease↗
Changes in lung mechanics and histamine responsiveness after sequential canine adenovirus 2 and canine parainfluenza 2 virus infection in beagle puppies.
We determined the effects of an immediately antecedent viral lower respiratory tract infection (LRI) on the severity of clinical illness, changes in lung function and airway histamine responsiveness produced by a subsequent LRI in 9-12 week old beagle puppies inoculated with canine adenovirus 2, followed in 2 weeks by inoculation with canine parainfluenza 2 virus (CAV2-CP12, n = 7). We compared their acute responses to puppies infected with CP12 alone (n = 5), CAV2 alone (n = 7), and no infection (control, n = 6). Puppies inoculated with either virus alone developed a LRI 3 to 6 days after inoculation which resolved by 12-14 days after inoculation. However, the illness was more severe in the CAV2 group. In the CAV2-CP12 group, CP12 infection following CAV2 infection resulted in a clinical illness nearly comparable to that observed with CAV2 alone. Whereas in control and CP12 puppies, lung resistance (RL) decreased and dynamic lung compliance (Cdyn) increased during the study due to normal growth, RL increased and Cdyn remained unchanged in the CAV2 group. In contrast, RL did not change and Cdyn increased in the CAV2-CP12 group. Airway histamine responsiveness in the CAV2-CP12 group increased during infection with CP12 and was similar to that observed with CAV2 alone. In contrast, infection with CP12 alone produced a small, but non-significant increase in histamine responsiveness. The duration of the increase in histamine responsiveness was not prolonged in the CAV2-CP12 group in comparison to CP12 or CAV2 alone. However, the length of clinical illness was extended in the CAV2-CP12 group in comparison to the other infected groups. These data suggest that an immediately antecedent viral LRI can potentiate the clinical and physiologic effects of a subsequent viral LRI.
Adenoviridae Infections↗
Effect of smoke inhalation on immediate changes in lung chemical mediators.
We studied the effects of acute smoke exposure on lung and alveolar macrophage (AM) function in New Zealand white rabbits. Six rabbits were exposed to smoke (SE, N = 6) and a control group of rabbits (SS, N = 6) were exposed to sham smoke. The smoke exposure consisted of 60 tidal volume breaths of air and smoke which were aspirated by syringe from a sampling port of a smoke chamber. The smoke was generated by the combustion of 20 ml diesel fuel and 0.2 g polycarbonate plastic shavings. The smoke was administered in 8-9 min. The rabbits were then killed and the lungs were removed for lavage. Acute smoke exposure caused a significant (p = 0.037) increase in bronchoalveolar lavage fluid levels of leukotriene B4 in the SE rabbits; 643 (+/- 30, SEM) pg/ml compared to 539 (+/- 43, SEM) pg/ml for SS rabbits at 3-4 min post-exposure. Lung surfactant, measured as mumoles/kg phosphatidylcholine, was decreased (p = 0.039) in SE rabbits' bronchoalveolar lavage fluid, 1.07 (+/- 0.12, SEM) -vs- 1.45 (+/- 0.15, SEM) for SS. Furthermore, cultured SE alveolar macrophage superoxide secretion after stimulation with phorbol myristate acetate was significantly decreased versus SS alveolar macrophage superoxide values at 40 min in culture. We conclude that acute smoke exposure causes immediate increases in bronchoalveolar lavage fluid levels of LTB4, and decreases in alveolar macrophage superoxide production and lung surfactant. These changes in chemical mediators may contribute to the lung injury caused by the smoke insult.
Animals↗
Changes in lung mechanics and reactivity with age after viral bronchiolitis in beagle puppies.
We measured changes with growth in lung function and airway reactivity after acute canine parainfluenza virus type 2 (CPI2, n = 5), canine adenovirus type 2 (CAV2, n = 7), and sequential CAV2-CPI2 (n = 6) infections or no infection (controls, n = 6) in beagle puppies (age approximately 79 days). In the CPI2 and CAV2 groups, a lower respiratory illness developed by day 3 postinfection with clinical recovery by day 14. In the CAV2-CPI2 group, puppies were inoculated initially with CAV2 and 12 days later with CPI2. In this group, illness persisted until day 14 after infection with CPI2. Lung resistance (RL), dynamic (Cdyn) and static (Cst) lung compliance, functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured before infection and at periodic intervals until 239 +/- 43 days of age. Lung function data were analyzed using a longitudinal random effects model. In all groups, FRC, Cst, and Cdyn increased with age. In all infected groups, the regression slopes for Cdyn were steeper than in controls. RL decreased linearly with age without group slope differences. Histamine reactivity increased with age, but there were no differences in slope among groups. Lung pathological studies showed areas of obliterative bronchiolitis and chronic small airways inflammation particularly in the CAV2 and CAV2-CPI2 groups. Thus, viral bronchiolitis produces chronic small airways inflammation in beagle puppies and alters the changes in lung function occurring with growth. Histamine reactivity increases with age and is not modified by viral infection.
Adenoviridae Infections↗
Canine parainfluenza type 2 bronchiolitis increases histamine responsiveness in beagle puppies.
Histamine hyperresponsiveness with viral bronchiolitis may depend on previous exposures to viruses or to other pathogens. We studied 32 outbred beagle puppies 80 to 155 days of age who were raised in isolation and who were specific pathogen-free. Puppies were inoculated with canine parainfluenza type 2 (CPI2, n = 8), Bordetella bronchiseptica (Bb, n = 7), or both CPI2 and Bb (CPI2-Bb, n = 9). Control puppies (C, n = 8) were not inoculated. The puppies were anesthetized with sodium thiopental (5 mg/kg) and chloralose (80 mg/kg) and were ventilated mechanically. Lung resistance (RL), dynamic lung compliance (Cdyn), functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured 3 days prior to inoculation (Day -3), on the day of inoculation (Day 0), and on Days 3-4, 6, 8-10, and 12-14 after inoculation. Histamine responsiveness was measured as: (1) the concentration of histamine base that increased RL to 150% (PC 150% RL) or decreased Cdyn to 75% (PC 75% Cdyn) of the response to saline (RL sal and Cdyn sal, respectively), and (2) the change in RL or Cdyn after inhalation of 11 mg/ml of histamine when compared with RL sal and Cdyn sal. On Day 0 there were no significant (p greater than 0.05) differences among groups with regard to age-corrected weights, FRC, RL, Cdyn, or histamine responsiveness. Control puppies remained healthy, and their pulmonary function and histamine responsiveness did not change. CPI2-Bb puppies increased RL and decreased FRC on Day 3-4, and were moderately ill and histamine-hyperresponsive on Day 3-4 and on Day 6.(ABSTRACT TRUNCATED AT 250 WORDS)
Airway Resistance↗
Acute canine adenovirus 2 infection increases histamine airway reactivity in beagle puppies.
Acute infection with canine adenovirus was studied in 23 specific pathogen-free outbred beagle puppies (median age = 78 days, range = 67 to 86 days) to determine its effects on pulmonary function and airway responsiveness to aerosolized histamine. The following groups were studied: uninoculated (n = 6, Control); inoculated with canine adenovirus type 2 (CAV2) (n = 11, Infected); and subclinical spontaneous infection with CAV2 (n = 6, Subclinical). While anesthetized with chloralose and mechanically ventilated, lung function and responsiveness to aerosolized histamine were measured 3 days before inoculation (Day -3), the day of inoculation (Day 0), and 3 to 4 (Day 3-4), 6 (Day 6), 8 to 10 (Day 8-10), and 12 to 14 (Day 12-14) days after inoculation. Histamine responsiveness was assessed by calculating the provocation concentration of histamine diphosphate to increase lung resistance (RL) to 150% (PC 150% RL), or decrease dynamic lung compliance (Cdyn) to 75% (PC 75% Cdyn) of the response to saline [RL(sal) and Cdyn(sal), respectively]. Arterial blood gases, functional residual capacity (FRC), specific static lung compliance (spCst), RL, Cdyn, and histamine responsiveness were not significantly different on Day 0 among the groups (p greater than 0.05). Control and Subclinical puppies remained healthy, had a mean weight gain of 0.7 kg, and did not change their histamine responsiveness during the study period. Infected puppies developed moderate to severe clinical illnesses, had poor weight gain, and were histamine hyperresponsive on Days 3-4 and 6. One infected puppy died on Day 3-4, and two died on Day 6 of their illness.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Localization of inflammation and virions in canine adenovirus type 2 bronchiolitis.
Beagle puppies develop bronchiolar inflammation and histamine hyperresponsiveness with canine adenovirus type 2 (CAV2) infections. We determined the distribution of bronchiolar lesions and correlated inflammation with virions and bronchoalveolar lavage fluid (BALF) cytology. Nineteen beagle puppies were inoculated with tissue culture fluid (control puppies, n = 8), or CAV2 (CAV2, n = 11). The puppies had clinical assessments and measurements of lung resistance (RL), and dynamic compliance (Cdyn) immediately before inoculation (Day zero) and 3 days later (Day 3). The puppies were killed on Day 3, the lungs were removed, and the right intermediate lobe was lavaged. The BALF was assessed for total and differential cell counts. Bronchiolar inflammation was quantitated by bronchiolar inflammation scores (BIS). CAV2 was localized by immunofluorescent antibody staining and electron microscopy. The control puppies remained healthy. The CAV2 puppies had positive cultures for CAV2, respiratory symptoms, and generalized necrotizing bronchiolitis. Alveolar inflammation was quantitatively less prominent than bronchiolar inflammation, and RL and Cdyn were unchanged. The BALF neutrophilia correlated with the BIS. CAV2 was present within bronchiolar epithelium, alveolar epithelial type 2 cells, neutrophils, and macrophages. CAV2 was not found in airways smooth muscles or nerves, nor in any noninflamed tissues of CAV2 puppies or in control animals. Our data suggest that acute CAV2 in beagle puppies produces an inflammation of most bronchioles. Intracellular CAV2 was found in bronchiolar epithelium, macrophages, neutrophils, and alveolar epithelial type 2 cells. Bronchiolar inflammation was reflected in BALF cytology. We conclude that bronchiolar inflammation as indicated by BIS and BALF cytology is related temporarily to histamine hyperresponsiveness in our beagle puppies.
Adenoviridae↗
Airway responses to inhaled Ascaris suum antigen in naturally sensitized beagle dogs.
To characterize the airway responses to inhaled Ascaris suum antigen in a group of adult Beagle dogs with cutaneous Ascaris sensitivity, 9 dogs were challenged with aerosolized Ascaris antigen and 6 were subsequently challenged 1 to 2 weeks later with aerosolized saline. Changes in lung resistance, dynamic lung compliance, and responsiveness to aerosolized histamine were measured during the ensuing 6 hours. Inhalation of Ascaris antigen produced immediate bronchoconstriction, but no spontaneous late bronchoconstrictive responses were noted. Two dogs demonstrated increased histamine responsiveness 6 hours after Ascaris challenge, and 4 dogs were histamine hyperresponsive 1 to 2 weeks later. We conclude that exposure to Ascaris antigen in naturally sensitized Beagle dogs produces an immediate asthmatic response and may result in airway hyperresponsiveness for several weeks. However, spontaneous late responses do not occur.
Airway Resistance↗
Intravenous chloralose is a safe anesthetic for longitudinal use in beagle puppies.
Chloralose is an intravenous anesthetic which preserves vagal and central baroreceptor reflexes, thus rendering it useful for physiologic research. However, chloralose is recommended for terminal experiments only, due to concerns relating to long-term toxicity. We investigated the safety of chloralose in longitudinal pulmonary function studies in beagle puppies. Twelve puppies received chloralose anesthesia repeatedly (8-12 times per dog) between the ages of 80 and 300 days. Constant anesthetic depth was maintained reliably throughout the course of the experiments. Recovery lasted approximately 4 hours in each experiment and occurred in four definable stages. Following recovery, the puppies exhibited normal health and growth as compared with other colony animals. There was no biochemical evidence of acute renal, hepatic, pancreatic or cardiac toxicity prior to and immediately after anesthesia, and no evidence of chronic toxicity following completion of the study protocol, after a total cumulative dose of 1.18 g/kg chloralose. These studies demonstrate that intravenous chloralose is a safe anesthetic for longitudinal use.
Anesthesia, Intravenous↗
Member heads Infant Mortality Task Force.
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Humans↗
Addiction to benzodiazepines--how common?
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Anti-Anxiety Agents↗
Adverse events associated with prescription drug cost-sharing among poor and elderly persons.
CONTEXT: Rising costs of medications and inequities in access have sparked calls for drug policy reform in the United States and Canada. Control of drug expenditures by prescription cost-sharing for elderly persons and poor persons is a contentious issue because little is known about the health impact in these subgroups. OBJECTIVES: To determine (1) the impact of introducing prescription drug cost-sharing on use of essential and less essential drugs among elderly persons and welfare recipients and (2) rates of emergency department (ED) visits and serious adverse events associated with reductions in drug use before and after policy implementation. DESIGN AND SETTING: Interrupted time-series analysis of data from 32 months before and 17 months after introduction of a prescription coinsurance and deductible cost-sharing policy in Quebec in 1996. Separate 10-month prepolicy control and postpolicy cohort studies were conducted to estimate the impact of the drug reform on adverse events. PARTICIPANTS: A random sample of 93 950 elderly persons and 55 333 adult welfare medication recipients. MAIN OUTCOME MEASURES: Mean daily number of essential and less essential drugs used per month, ED visits, and serious adverse events (hospitalization, nursing home admission, and mortality) before and after policy introduction. RESULTS: After cost-sharing was introduced, use of essential drugs decreased by 9.12% (95% confidence interval [CI], 8.7%-9.6%) in elderly persons and by 14.42% (95% CI, 13.3%-15.6%) in welfare recipients; use of less essential drugs decreased by 15.14% (95% CI, 14.4%-15.9%) and 22.39% (95% CI, 20.9%-23.9%), respectively. The rate (per 10 000 person-months) of serious adverse events associated with reductions in use of essential drugs increased from 5.8 in the prepolicy control cohort to 12.6 in the postpolicy cohort in elderly persons (a net increase of 6.8 [95% CI, 5.6-8.0]) and from 14.7 to 27.6 in welfare recipients (a net increase of 12.9 [95% CI, 10.2-15.5]). Emergency department visit rates related to reductions in the use of essential drugs also increased by 14.2 (95% CI, 8.5-19.9) per 10 000 person-months in elderly persons (prepolicy control cohort, 32.9; postpolicy cohort, 47.1) and by 54.2 (95% CI, 33.5-74.8) among welfare recipients (prepolicy control cohort, 69.6; postpolicy cohort, 123.8). These increases were primarily due to an increase in the proportion of recipients who reduced their use of essential drugs. Reductions in the use of less essential drugs were not associated with an increase in risk of adverse events or ED visits. CONCLUSIONS: In our study, increased cost-sharing for prescription drugs in elderly persons and welfare recipients was followed by reductions in use of essential drugs and a higher rate of serious adverse events and ED visits associated with these reductions.
Adult↗
Bronchoscopic evaluation of airway obstruction in campomelic dysplasia.
Campomelic dysplasia is a generalized disorder of cartilaginous growth and development, leading to early death from pulmonary insufficiency. We describe the airway dynamics as observed bronchoscopically in two affected infants. Both infants demonstrated anatomic compromise of the upper airway and diffuse laryngotracheobronchomalacia. Additionally, both had a characteristically small, bell-shaped thoracic cage. The abnormal airway dynamics produced serious inspiratory and expiratory obstruction in these infants and, in combination with the restrictive chest wall defect, led rapidly to the development of respiratory failure. While palliative procedures such as tracheostomy may temporarily improve airway dynamics, future respiratory tract insults may prove fatal.
Airway Obstruction↗
Piriprost pretreatment attenuates the smoke-induced increase in 99mTcDTPA lung clearance.
We studied the effects of acute smoke exposure on lung permeability, eicosanoids, and inflammatory cell activity. Thirty-five New Zealand white rabbits were anesthetized, paralyzed, and exposed to 60 tidal volume breaths of diesel fuel-polycarbonate plastic smoke or sham smoke within 10 min. At 1 h postexposure the rabbits were killed and their lungs were removed for bronchoalveolar lavage (BAL) or pathologic procedures. Smoke exposure caused decreases in technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, mol. wt. 492 Da) biological half-life (t1/2), BAL plasminogen activator, and BAL leukotriene B4 (LTB4). In addition, alveolar macrophage acid phosphatase enzyme activity increased in smoke-exposed rabbits. The leukotriene synthesis inhibitor, piriprost (U-60,257), given before smoke exposure, caused attenuation of the changes in 99mTcDTPA uptake and plasminogen activator, swelling of type I alveolar cell epithelium, a large increase in lung inflammatory cells, and decreases in BAL LTB4, prostaglandin E2 (PGE2), and TxB2 (stable metabolite of thromboxane, TxA2). We conclude that changes in alveolar-capillary barrier permeability and plasminogen activator activity occur within 1 h after exposure to smoke and may play an early role in the inflammatory process associated with smoke inhalation injury. Furthermore, piriprost attenuates the smoke-induced increase in alveolar-capillary barrier permeability and decrease in plasminogen activator activity and causes a swelling of type I alveolar epithelium. However, our data suggest that neither lung eicosanoids or the alveolar macrophage lysis process plays a major role in the smoke-induced increase in alveolar-capillary barrier permeability.
Animals↗
Search for a policy direction: infant mortality and teenage pregnancy--an interview with Rae Grad, PhD, RN. Interview by Lorna Hines Harris.
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Adolescent↗
Retention of neonatal resuscitation skills and knowledge: a randomized controlled trial.
BACKGROUND AND OBJECTIVES: This study compared the effectiveness of two booster strategies designed to improve retention of skills and knowledge in neonatal resuscitation by family practice residents. METHODS: Residents were randomly allocated to one of three groups: video, hands on, or control. Residents in the two experimental groups received a "booster" 3-5 months after the Neonatal Resuscitation Program (NRP) course. All participants completed the follow-up test 6-8 months after taking the course. The main outcome measures consisted of the NRP written examination and the performance checklists. RESULTS: A total of 44 residents completed the study (video, n = 13; hands-on, n = 14; control, n = 17). Overall, participants had significantly lower scores at follow-up than at baseline, indicating deterioration in both neonatal skills and knowledge. Residents in the hands-on booster group made significantly fewer errors across all five checklists in life-supporting but not in lifesaving scores than those allocated to the control and video groups. CONCLUSIONS: The beneficial effect of mannequin practice or video boosters on skills and knowledge retention was less than what had been anticipated, and no benefit could be demonstrated in comparison to the control group. Deteriorating knowledge and skills remain a major concern, since boostering by hands-on or video at 3-5 months do not seem to have an impact on the retention of knowledge or lifesaving skills.
Adult↗