Animals in medical research. Official statement of the American Thoracic Society.
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Animal Experimentation↗
Biomedical subjects
J G Clark
Publications and source records attributed to J G Clark.
The challenge of bone marrow transplantation.
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Bone Marrow Transplantation↗
Collagen synthesis during lung development and during hyaline membrane disease in the nonhuman primate.
To assess maturational changes in collagen synthesis, lung tissue was obtained from healthy Macaca nemestrina monkeys at different ages, ranging from 68% of term gestation to adulthood. We hypothesized that infants delivered prematurely have a greater rate of collagen synthesis than do older animals because of their greater rate of lung growth during gestation. Secondly, we hypothesized that lung repair in infants with hyaline membrane disease (HMD) is associated with an additional increase in lung collagen synthesis rate. Therefore, lung tissue was obtained during the first week of life from monkeys delivered at 82% of term gestation, a stage at which half of them developed HMD. The rate of total protein synthesis in lung samples was determined by measuring the incorporation of [3H]proline; the rate of collagen synthesis was determined by measuring the conversion of proline into hydroxyproline. Premature monkeys had a higher rate of collagen synthesis (9.9 +/- 2.7 nmol/mg DNA/h) than did term infants (5.3 +/- 1.1) or older animals (2.1 +/- 0.4, p less than 0.05). There was no additional increase in rate of collagen synthesis in animals with HMD from 3 h (14.3 +/- 6.9) to 7 days of age (15.1 +/- 6.1); control premature animals also had no significant change during the first week of life (10.9 +/- 3.0 at 3 h; 11.6 +/- 4.6 at 7 days). The early stage of recovery from HMD in premature monkeys does not appear to be associated with an increase in collagen production beyond the already increased synthesis rate associated with lung growth.
Analysis of Variance↗
Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course.
To describe the clinical presentation and progression of obstructive lung disease after marrow transplantation, we examined a sequential sample of 35 patients who had allogeneic marrow transplantation between January 1980 and January 1987, were 16 years or older, had normal pulmonary function tests before transplantation, and developed airflow obstruction defined as FEV1/FVC less than 70% and FEV1 less than 80% predicted 50 days or more after transplantation. Cases were selected from 1029 adult (older than 16 years) patients who underwent allogeneic marrow transplantation during the same period. Patients with airflow obstruction presented with symptoms of cough, dyspnea, or wheezing, or a combination. In 80% the chest radiograph was normal. Airflow obstruction was diagnosed within 1.5 years after transplantation in 33 of 35 patients. Clinical, extensive, chronic graft-versus-host disease was present in 24 patients. Only 4 patients had a complete response to primary therapy of chronic graft-versus-host disease. Serum IgG and IgA levels were decreased in 15 and 25 patients, respectively. The FEV1 declined rapidly (decrease in FEV1 greater than 30% between tests) in 21 patients, but 14 patients with slowly progressive or reversible disease were identified. Mortality was 65% at 3 years after transplant, a significantly higher value (P = 0.016) than the 3-year mortality rate of 44% in a comparison group of 412 concurrent patients with chronic graft-versus-host disease who were 16 years or older, survived more than 80 days after transplantation, and had normal pulmonary function. We concluded that obstructive lung disease after marrow transplantation may be variable with respect to time of onset and rate of progression. Obstructive lung disease was frequently associated with serum immunoglobulin deficiency and clinical, extensive, chronic graft-versus-host disease that was not readily responsive to treatment. Mortality was high but long-term survivors were identified.
Adolescent↗
Monocyte-derived growth factors in asbestos-induced interstitial fibrosis.
Asbestos-induced pulmonary fibrosis is thought to result from a series of cellular interactions involving the alveolar macrophage and the lung fibroblast. Although a dose-response relation has been established between asbestos exposure and the development of interstitial fibrosis, the majority of workers exposed even to high concentrations of asbestos do not develop radiographically evident interstitial fibrosis. As a means of understanding the pathogenesis of asbestos-induced fibrosis and the differential host response to the asbestos fiber, we studied the production of monocyte-derived growth factors in subjects with asbestosis (N = 5) and normal exposure-matched controls (N = 5). Under unstimulated culture conditions, the conditioned medium (CM) from monocytes from control subjects had a greater proliferative effect on fibroblasts than monocyte CM from patients with asbestosis. With CM from concanavalin A-stimulated monocytes, the proliferative response of the fibroblast was similar in those with asbestosis and control subjects. Freshly isolated monocytes from both normal subjects and patients with asbestosis did not express the gene for the B chain of platelet-derived growth factor (PDGF) as evaluated by hybridization with a PDGF-specific human cDNA probe. After 20 hr of culture in concanavalin A, monocytes from normal subjects expressed the gene for the B chain of PDGF while, under the same culture conditions, none of the monocyte preparations from patients with asbestosis produced mRNA for this growth factor. These data indicate that peripheral blood monocytes from patients with asbestosis compared to exposure-matched controls have a reduced capacity to produce growth factor activity as measured by mitogenic activity and mRNA levels for the B chain of PDGF. These results suggest that peripheral blood monocytes from patients with asbestosis may comprise a less mature population of cells compared to exposure-matched controls.
Animals↗
Pulmonary venoocclusive disease following bone marrow transplantation.
We report two cases of pulmonary venoocclusive disease (PVOD) in children with acute lymphoblastic leukemia treated by marrow allograft transplantation following conditioning with high-dose 1-3 bis chloroethyl-1 nitrosourea (BCNU), etoposide (VP-16), and cyclophosphamide (Cy). Both patients developed symptomatic pulmonary hypertension documented by right heart catheterization. Open-lung biopsy of one patient demonstrated PVOD evident even on frozen sections stained with hematoxylin and eosin. High-dose methylprednisolone was associated with significant clinical improvement in both patients. Pulmonary symptoms resolved in one patient who subsequently died in leukemic relapse. PVOD resolved in the other patient, only to recur when steroids were discontinued and then again respond to reinstitution of therapy. More aggressive therapy for malignant diseases may increase the incidence of PVOD. Prompt recognition of its subtle clinical and histological manifestations allows early institution of steroid therapy, which may be beneficial.
Bone Marrow Transplantation↗
Biopsy diagnosis and clinical outcome of persistent focal pulmonary lesions after marrow transplantation.
We reviewed the results of all percutaneous fine needle aspirations (FNA) and open lung biopsies (OLB) after bone marrow transplantation at our center (1984-1987) for the evaluation of focal lung lesions that developed or persisted despite antibiotic administration. We sought to determine the prevalence and types of infections, the yield of diagnostic procedures, and the clinical outcome of these focal lesions. Infection was documented in 78% (18/23) of all lesions and was fungal in each case. FNA detected fungal lung infection with a sensitivity of 67% (10/15) but had a negative predictive value of only 50% (5/10). Complications occurred in 15% of FNA. OLB without prior FNA was performed in 6 cases and demonstrated fungal infections in 5. Overall, seven of the 18 patients with localized invasive fungal lung disease recovered after antifungal therapy. This study demonstrates that focal lung lesions that develop or persist despite antibiotics after BMT are most often fungal. FNA may safely identify these localized infections in selected patients and with appropriate treatment recovery may be achieved.
Biopsy, Needle↗
Effects of interferon-gamma on expression of cell surface receptors for collagen and deposition of newly synthesized collagen by cultured human lung fibroblasts.
We used cultured human diploid lung fibroblasts as a model system to examine the effects of recombinant IFN-gamma on synthesis of collagen, matrix deposition of newly synthesized collagen, and the expression of cell surface receptors for collagen. Using [3H]proline-labeled cells we found that IFN-gamma resulted in dose-dependent inhibition of fibroblast collagen synthesis. Pulse-chase experiments to analyze compartmentalization of newly synthesized collagen showed that the decrease in collagen synthesis was confined to the soluble pool of procollagen in the medium, while extracellular matrix associated collagen was not changed, indicating that a larger proportion of newly synthesized collagen was deposited into the matrix in IFN-gamma exposed fibroblasts (34.2 vs. 25.3%). This increase in the efficiency of collagen matrix deposition was associated with enhanced expression of a cell surface receptor for collagen as detected by indirect immunofluorescence labeling and analysis by flow cytometry. Fibroblasts (IMR-90) cultured in the presence of IFN-gamma (1,000 U/ml) exhibited a twofold increase in mean linear fluorescence intensity compared with cells cultured under control conditions. The distribution of log fluorescence intensity in both control and IFN-gamma exposed cells was normally distributed about the mean, indicating that discrete subpopulations with respect to receptor expression were not present. Increased fluorescence intensity and log normal distribution of fluorescence intensity also were identified in IFN-gamma-treated lung fibroblasts from a normal adult individual and two strains obtained from patients with pulmonary fibrosis. These results indicate that IFN-gamma modulates fibroblast collagen matrix deposition as well as collagen synthesis. The associated increase in collagen receptors suggests that cytokine-mediated modulation of the cell surface maybe a contributing factor in regulation of fibroblast collagen accumulation in the extracellular matrix or in cellular interaction with collagen-containing matrix. Such an effect could modulate the interaction of fibroblasts with extracellular matrix at sites of inflammation and play an important role in the remodeling of matrix during repair from tissue injury.
Adult↗
Mechanical ventilation after marrow transplantation. Risk factors and clinical outcome.
The risk factors for and the outcome of mechanical ventilatory support after marrow transplantation were analyzed in 1,089 consecutive marrow recipients. Of 232 patients receiving ventilatory support at this center, 63 (27%) survived an initial episode of ventilatory support. In contrast, 74% of nonventilated patients survived at least 6 months after transplantation. Among patients with malignant disease (n = 992), a multivariate regression model revealed 3 pretransplant factors that were associated with ventilatory support: age greater than or equal to 21 yr (RR = 1.6, 95% confidence intervals [Cl] = 1.3, 2.0), hematologic malignancy in relapse (RR = 2.1, 95% Cl = 1.7, 2.4), and HLA nonidentical donor-recipient pair (nonidentical graft) (RR = 1.7, 95% Cl = 1.4, 2.1). Survival after ventilatory support was not found to be associated with any pretransplant or post-transplant factors examined. We conclude that although the risk factors for mechanical ventilatory support after marrow transplantation can be defined, we are unable to identify characteristics predictive of survival after such support. The implications of these findings in relation to patient selection and future research activities are discussed.
Adult↗
Open lung biopsy diagnosis of diffuse pulmonary infiltrates after marrow transplantation.
The results were reviewed of 111 open lung biopsies (OLB) performed on 109 marrow transplantation recipients with diffuse pulmonary infiltrates between January 1983 and July 1987. We determined the frequency and types of infections identified, and the relationship to time after transplantation. Infection was found in 70 of the 111 cases (63 percent) and cytomegalovirus (CMV) was present in 90 percent of all cases with infection. Infection was identified in only five of 26 (19 percent) cases within the first 30 days after transplant, and when present, was viral. The prevalence of infection after 30 days (over 75 percent of 85 cases) was significantly higher (chi 2 = 26.2, p = 0.00001). Bacterial or yeast infections were found in only four cases (4 percent) (two cases each), and Pneumocystis carinii in six cases (6 percent). Simultaneous infection with two or more organisms was found in four cases (4 percent). Four of 25 autopsies performed within ten days after OLB revealed fungal infections with Aspergillus not detected at OLB. Thus, the prevalence of infection detected by OLB is low within the first 30 days after marrow transplantation among patients receiving broad spectrum antibiotics. CMV infection is found in most transplantation recipients who undergo OLB with diffuse infiltrates between days 30 and 180.
Anti-Bacterial Agents↗
Rapid detection of cytomegalovirus pulmonary infection by bronchoalveolar lavage and centrifugation culture.
Cytomegalovirus infection remains a major cause of morbidity and mortality in marrow transplant recipients. Results of a rapid centrifugation viral culture of bronchoalveolar lavage specimens from 33 marrow transplant recipients with pneumonia were compared with those for conventional viral culture of concurrently or subsequently obtained lung tissue. The centrifugation culture results were also compared to results of cytologic and immunochemical examination of these specimens. Centrifugation culture was positive within 16 hours of inoculation in 22 of 23 (96%) specimens from patients with positive conventional culture of lung tissue. Detection of cells positive for cytomegalovirus by immunofluorescent antibody staining or cytologic identification was less sensitive (59% and 29%, respectively). There was no evidence of cytomegalovirus in specimens from patients without evidence of cytomegalovirus pulmonary infection by any technique. The sensitivity (96%) and specificity (100%) of centrifugation culture of specimens from marrow transplant recipients approach that of viral culture of lung tissue.
Adolescent↗
Modulation of the effects of alveolar macrophages on lung fibroblast collagen production rate.
Alveolar macrophages (AM) may function as effector cells that can either stimulate or inhibit lung fibroblast collagen production. However, conditions that determine the predominant effect of AM on fibroblasts are not well understood. To delineate factors that modulate the effects of AM on lung fibroblasts, we studied the interaction of AM products and fibroblasts in vitro. The AM were obtained by bronchoalveolar lavage of hamsters with bleomycin-induced pulmonary fibrosis. Conditioned medium (CM) from the AM cultures was incubated in varying amounts with lung fibroblast (IMR-90) cultures. After metabolic labeling with [3H]proline, fibroblast collagen production based on procollagen-specific radioactivity was determined (Anal Biochem 1984; 140:478). Macrophage CM in concentrations greater than 5% suppressed collagen production, an event attributed to the macrophage-derived suppressive factor that we have previously characterized (J Clin Invest 1983; 72:2082). Macrophages were also determined to produce PGE2 in culture (500 pg/10(6) cells). Authentic PGE2 at concentrations found in CM was found to suppress fibroblast collagen production, indicating that AM-derived PGE2 contributes to the suppressive activity in CM. To examine possible stimulatory factors in CM, the fibroblasts were preincubated with indomethacin. This approach was based on our previous observation that AM-derived suppressive factor increases endogenous fibroblast PGE2 and that its activity can be blocked by indomethacin. Macrophage CM in a concentration of 20% did not suppress the collagen production of indomethacin-treated fibroblasts. However, CM concentrations of 5 and 10% increased collagen production (173 and 143% of control values, respectively), indicating the presence of stimulatory factor(s) in macrophage-conditioned medium.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Diagnostic approaches to pulmonary complications of marrow transplantation.
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Bone Marrow Transplantation↗
Risk factors for airflow obstruction in recipients of bone marrow transplants.
Obstructive lung disease is a complication of bone marrow transplantation. To identify risk factors we analyzed pulmonary function tests of 281 adult patients 1 year after marrow transplantation. The forced expiratory volume at 1 second divided by the forced vital capacity (FEV1/FVC) was used to measure airflow rates. Factors associated with a lower year-1 FEV1/FVC (%) included increased age (p less than 0.0001), male gender (p = 0.02), cigarette smoking (p = 0.01), lower FEV1/FVC before transplantation (p less than 0.0001), HLA-nonidentical grafts (p = 0.001), chronic graft-versus-host disease (p = 0.0002), and immunosuppressive therapy with methotrexate (p = 0.01). There was no significant association between the year-1 FEV1/FVC and underlying disease, dose of conditioning irradiation, or development of acute graft-versus-host disease. Linear multivariate regression analysis, after controlling for the FEV1/FVC before transplantation, shows both chronic graft-versus-host disease and administration of methotrexate independently associated with decrements in the year-1 FEV1/FVC. The combined occurrence of chronic graft-versus-host disease and methotrexate also was strongly associated with decreases in the year-1 FEV1/FVC, indicating an interaction of these risk factors.
Adult↗
Alaryngeal speech intelligibility and the older listener.
Past investigations of alaryngeal speech intelligibility have focused on comparative intelligibility as perceived by young normally hearing adults. However, the spouses and social companions of laryngectomees may have significantly different auditory capabilities compared to young listeners. This report presents a comparison of alaryngeal and laryngeal speech identification performance for a group of young normally hearing listeners and a group of older adult listeners representative of the age of the laryngectomee's social companions. The speech signals investigated included normal laryngeal speech, artificial larynx speech, traditional esophageal speech, and tracheoesophageal speech. The results obtained reveal not only differences in speech signals but also a difference in the proficiency of speech perception for the two groups, favoring the younger listeners. The results of the speech identification measures in the presence of auditory competition revealed greatest intelligibility for the artificial larynx speech signal and poorest for the tracheoesophageal speech signal.
Adult↗
Whorled milkweed poisoning.
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Administration, Oral↗