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Biomedical subjects

J A Kern

Publications and source records attributed to J A Kern.

At least 91 records · Page 5Linked to original sources
PubMed1992

Effects of in vivo cyclosporine administration on endothelium-dependent responses in isolated vascular rings.

BACKGROUND: Although in vitro studies suggest that cyclosporine (CSA) reduces endothelium-dependent relaxation (EDR), controversy still remains regarding the effects of in vivo CSA treatment. The lack of correlation between CSA dosages and therapeutic efficacy has led to an increased emphasis on the monitoring of CSA blood levels in clinical immunosuppression. We therefore studied the effects of in vivo administration to rats of a therapeutic level of CSA on endothelium-dependent vascular reactivity using isolated vascular rings obtained from these animals. METHODS AND RESULTS: Thoracic aorta vascular rings from adult Sprague-Dawley rats treated with subcutaneous injections of CSA (5 mg/kg/day) for 7 and 21 days were suspended in Krebs buffer containing indomethacin and tested for EDR to methacholine (1 x 10(-7) to 5 x 10(-5) M) and for endothelium-independent relaxation (EIR) to nitroprusside (5 x 10(-6) M). Mean whole blood CSA trough levels were 978 +/- 287 and 2,865 +/- 379 ng/ml for the 7- and 21-day groups, respectively. No differences were noted in both EDR and EIR between untreated control rats and the treated groups. Maximal EDR (mean +/- SEM) was 83 +/- 3%, 79 +/- 2%, and 81 +/- 3% for control rats and 7- and 21-day treatment groups, respectively. Relative developed tension (grams) to 5 x 10(-6) M phenylephrine was significantly (p < 0.05) increased in the CSA-treated groups (1.03 +/- 0.01 and 1.08 +/- 0.01 g at 7 and 21 days, respectively, versus 0.73 +/- 0.01 g (p = NS) for untreated controls). Minimal endothelial disruption was evident on scanning electron microscopy in the CSA-treated animals. CONCLUSIONS: We conclude that CSA-induced vascular dysfunction may be in part a result of an increased sensitivity to direct vasoconstriction rather than of an attenuation of endothelium-dependent relaxation.

Animals↗
PubMed1992

Growth potential of porcine reduced-size mature pulmonary lobar transplants.

The use of mature pulmonary lobes for pediatric lung transplantation has recently been described. Successful application of this technique could help alleviate the pediatric donor lung shortage. Whether an already mature lobe can grow by forming new alveolar units after transplantation into a developing recipient is not known. We therefore measured functional residual capacity, fixed lung volume and weight, alveolar size and air space volume percent, and total number of alveoli in mature left lower lobe porcine lung transplants 12 weeks after transplantation into growing piglets. Comparisons were made with nontransplanted mature left lower lobes to determine if functional or morphologic growth had occurred after transplantation. The transplanted and control lobes were all taken from 6-month-old animals (mean body weight 105 +/- 4 kg). Recipients of the transplanted lobes were 9 weeks old and weighed 22 +/- 2 kg. By the end of the 12-week holding period, the recipient animals increased their body weight approximately fourfold (85 +/- 4 kg). No significant differences were seen in functional residual capacity or morphologic analysis of total alveolar number and alveolar size between the transplanted and nontransplanted lobes (p = not significant). Although the reduced-size mature porcine lobar transplants did not display a significant increase in either functional residual capacity or total alveolar number, there was significant growth of the transplanted mature lobes as determined by fixed volume and total lobar weight (p < or = 0.05 versus control animals).

Animals↗
PubMed1991

Weight is not an accurate criterion for adult cardiac transplant size matching.

Owing to the limited availability of donor hearts, standard donor criteria for heart size matching need to be reexamined. The current practice at most centers is to match the donor's body weight to within +/- 20% of the recipient's. Our hypothesis was that minimal differences exist in heart sizes of the adult donor population, and therefore, the donor pool could be expanded for any given patient. M-mode echocardiographic measurements of left and right ventricular internal dimensions, left ventricular mass, and percent fractional shortening were reviewed in 235 normal adult subjects (101 men, 134 women). Low correlation coefficients and a high degree of variance were consistently observed between cardiac parameters and body size. There were no significant differences in left ventricular internal dimension when women weighing 40 to 109 kg were compared with men statistically different among men weighing 50 to 99 kg. No difference was noted in right ventricular size among men and women. Echocardiography is a simple and accurate technique to assess cardiac dimensions. Body weight does not correlate well with adult cardiac size and should not be used as an exclusion criterion for a donor heart.

Body Height↗
PubMed1991

First single lung transplant in Virginia.

Lung transplantation is now established as a clinical reality for patients with irreversible, lethal pulmonary conditions. We report the first successful application of this treatment modality in Virginia.

Humans↗
PubMed1990

p185neu expression in human lung adenocarcinomas predicts shortened survival.

p185neu is the protein product of the HER2/neu protooncogene. This protein has characteristics of a tyrosine kinase growth factor receptor and is postulated to be important in human carcinogenesis. To define the significance of the expression of this protein in human non-small cell lung cancer, 55 tumors from patients with squamous cell carcinoma (16), adenocarcinoma (29), or large cell carcinoma (10) of the lung were examined for p185neu using immunohistological methods. Five of 16 squamous cell carcinomas and 10 of 29 adenocarcinomas were found to overexpress p185neu relative to levels of expression seen in uninvolved bronchiolar epithelium. For the adenocarcinomas, p185neu expression was associated with older age (66.6 +/- 10.1 versus 57.5 +/- 10.8 years) (P = 0.04) and shortened survival (83.7 +/- 94.1 versus 188.5 +/- 120 weeks) (P = 0.01). In this group, using Cox's multivariate survival analysis, p185neu expression was found to be a significant determinant of survival (P = 0.04) even after accounting for the effect of tumor stage. For the squamous cell carcinomas, p185neu expression was not correlated with any of our clinicopathological parameters. Our findings indicate that non-small cell lung cancers which express p185neu do so at levels higher than that found in normal bronchiolar epithelium, and expression in adenocarcinomas of the lung is independently associated with diminished survival intervals.

Adenocarcinoma↗
PubMed1990

Expression of the neu gene-encoded protein (P185neu) in human non-small cell carcinomas of the lung.

The neu protooncogene is a recently described transforming gene originally isolated from ethylnitrosourea-induced rat neuroblastomas. We have examined the expression of the neu gene in human non-small cell lung carcinomas using immunoprecipitation and immunohistochemistry. The neu protein product (p185neu) was present in eight of 22 non-small cell carcinoma cell lines derived from human lung tumors. Expression of p185neu was found in all histological subtypes of non-small cell carcinomas including large cell carcinomas, squamous cell carcinomas, and adenocarcinomas. Extension of these data to biopsy specimens of human lung tumors demonstrated that normal ciliated bronchial epithelium of the peripheral airways expressed p185neu at low levels. Neoplastic cells in four of 12 adenocarcinomas and three of five squamous cell carcinomas also expressed p185neu at levels higher than the normal ciliated bronchial epithelium. Together these studies indicate that p185neu expression is a common feature of human lung tumors.

Biopsy↗
PubMed1990

Cytokine networks in the regulation of inflammation and fibrosis in the lung.

To understand the processes regulating inflammation and fibrosis in the human lung, we characterized the effects of recombinant interleukin-1, tumor necrosis factor, and gamma interferon on fibroblast proliferation, collagen production, interleukin-1-alpha production, interleukin-1-beta production, and interleukin-6-production. These studies demonstrated the existence of complex cytokine networks by which inflammatory cells regulate fibroblast function and fibroblasts, in turn, feed back to regulate inflammatory cell function. They also demonstrated that, in this complex network, the effect of an individual cytokine varies with the state of activation of the target cell, the presence of other cytokines in the local microenvironment, and the ability of the target cell to produce bioactive autocoids such as prostaglandins. Aspects of this cytokine network are discussed and a testable hypothesis for granuloma and abscess formation is detailed.

Cell Division↗
PubMed1989

A synergistic interaction of IL-6 and IL-1 mediates the thymocyte-stimulating activity produced by recombinant IL-1-stimulated fibroblasts.

We characterized the ability of normal human lung fibroblasts to elaborate thymocyte-stimulating activity, spontaneously, and in response to rIL-1. Supernatants from unstimulated fibroblasts did not contain thymocyte-stimulating activity, whereas supernatants from fibroblasts incubated with rIL-1 alpha or rIL-1 beta contained more thymocyte-stimulating activity than could be accounted for by passively transferred rIL-1 alone. This heightened thymocyte-stimulating activity was mediated by fibroblast-derived IL-6 inasmuch as it was neutralized by anti-serum against human rIL-6, and rIL-1-stimulated fibroblasts to accumulate messenger RNA for IL-6 and produce soluble IL-6 protein. However, IL-6 alone could not account for the intensity of this effect because rIL-6 only weakly stimulated thymocyte proliferation. In addition, antisera against the rIL-1 moiety that was used to prepare the supernatant had different effects on supernatants that contained and did not contain active IL-6. In the presence of IL-6 these antisera caused a greater decrease in thymocyte-stimulating activity than could be accounted for by passively transferred rIL-1 alone. When the IL-6 was neutralized the remaining thymocyte-stimulating activity could be quantitatively accounted for and neutralized by antisera against the rIL-1 that was passively transferred. Furthermore, rIL-6 and rIL-1 (alpha or beta) synergized in stimulating thymocyte proliferation. Thus, rIL-1 stimulates fibroblasts to produce a thymocyte-stimulating activity that is largely mediated by a synergistic interaction of fibroblast-derived IL-6 and IL-1. These findings suggest that fibroblast production of IL-6 may mediate or amplify some of the tissue effects of IL-1. In addition they suggest that biologic effects previously attributed to IL-1 may be due to IL-6 alone or the concerted action of IL-1 and IL-6.

Adult↗
PubMed1989

Histamine H1 receptors mediate increased blood-retinal barrier permeability in experimental diabetes.

To test the hypothesis that histamine receptors mediate increased blood-retinal barrier permeability in experimental diabetes, 51 rats were made diabetic by streptozocin injection (65 mg/kg; jugular vein) and were held for four weeks. The seven animal groups were as follows: untreated controls; untreated diabetic rats; diabetic rats receiving diphenhydramine hydrochloride (Benadryl); diabetic rats receiving cimetidine hydrochloride (Tagamet); diabetic rats receiving diphenhydramine and cimetidine; diabetic rats receiving purified pork insulin (Iletin II); and diabetic rats receiving insulin and diphenhydramine. All treatments were given during the last week. Blood-retinal barrier permeability was assessed through measurement of the vitreous content of fluorescein isothiocyanate conjugated to bovine serum albumin (FITCBSA) after 20 minutes of FITCBSA circulation. Vitreous FITCBSA content of the diabetic group was 64% greater than control content. Diabetic rats treated with either diphenhydramine or diphenhydramine and insulin had respective decreases of 43% and 40% in vitreous FITCBSA content. The vitreous content of the diabetic group receiving insulin was lowered 37% below untreated diabetic values, while the vitreous FITCBSA content of the diabetic group receiving both insulin and diphenhydramine was reduced 63%. These data indicate that retinal histamine H1-receptor activation may be partially responsible for initial blood-retinal barrier leakage of macromolecules into the vitreous and that this abnormal leakage can be prevented both by diphenhydramine and by insulin. Histamine H1 receptors may play an important role in mediating increased blood-retinal barrier permeability in experimental diabetes.

Animals↗
PubMed1989

Fibroblast interleukin 1 beta: synergistic stimulation by recombinant interleukin 1 and tumor necrosis factor and posttranscriptional regulation.

To understand the role fibroblasts play in mediating and amplifying the effects of inflammatory cytokines, we determined whether recombinant interleukin 1 (IL-1) and recombinant tumor necrosis factor (TNF), alone and in combination, stimulated fibroblasts to produce IL-1 beta. Recombinant IL-1 (alpha and beta) stimulated fibroblast IL-1 beta mRNA accumulation, whereas recombinant TNF did not. In addition, simultaneous stimulation with recombinant IL-1 (alpha or beta) and recombinant TNF resulted in a synergistic increase in IL-1 beta mRNA levels. However, in all cases, IL-1 beta mRNA accumulation was not associated with fibroblast production of soluble IL-1 beta protein. Lysates of unstimulated, recombinant IL-1-stimulated, and recombinant TNF-stimulated fibroblasts did not contain IL-1 beta prohormone. In contrast, IL-1 beta prohormone was detected in lysates of fibroblasts incubated simultaneously with recombinant IL-1 and recombinant TNF. These studies demonstrate that recombinant IL-1 stimulates fibroblast IL-1 beta mRNA accumulation and that recombinant IL-1 and recombinant TNF synergize to further up-regulate IL-1 beta mRNA levels. In addition, they show that IL-1 beta production by human lung fibroblasts is inhibited at a posttranscriptional level. Translational control appears to be important in recombinant IL-1-stimulated fibroblasts and posttranslational control is important in fibroblasts stimulated simultaneously with recombinant IL-1 and recombinant TNF.

Antibodies↗
PubMed1989

Endotoxin stimulates platelet-derived growth factor production from cultured human pulmonary endothelial cells.

The interaction of Gram-negative bacterial cell wall products (endotoxins) with endothelial cells is thought to be responsible for many of the damaging manifestations of Gram-negative sepsis. Because cultured human endothelial cells are relatively resistant to the direct cytotoxic actions of endotoxin, it is possible that many of the systemic effects of endotoxin may be caused by stimulation of endothelial cells to produce biologically active mediators which could then act on targets such as smooth muscle cells, fibroblasts, and leukocytes. We hypothesized that one such endothelial cell-derived mediator could be platelet-derived growth factor (PDGF), a protein that causes proliferation of mesenchymal cells, chemotaxis of leukocytes, fibroblasts and smooth muscle cells, and vasoconstriction. We therefore examined the effect of endotoxin on PDGF-like protein production by cultured adult human pulmonary artery endothelial cells. Twenty-four hours of endotoxin exposure resulted in a threefold increase in the steady-state levels of mRNA coding for PDGF B-chain (c-sis) and a two- to threefold increase in the amount of newly synthesized PDGF released into the media, as measured by immunoprecipitation of [35S]methionine-labeled protein with anti-PDGF antiserum. We conclude that human pulmonary artery endothelial cells in culture are stimulated both to produce increased amounts of PDGF mRNA and to release PDGF-like protein after exposure to endotoxin. This increased release of PDGF-like protein by human endothelial cells may play a role in the inflammatory infiltrate, vasospasm, and fibroblast proliferation that characterize the host response to endotoxin.

Adult↗
PubMed1988

Requirement for extracellular calcium or magnesium in mitogen-induced activation of human peripheral blood lymphocytes.

The importance of calcium in lymphocyte activation is well recognized, but the levels of extracellular ionized free calcium (Ca++) necessary for lymphocyte proliferation via various pathways have not been investigated in detail. We studied the ability of a lectin mitogen (PHA) and a calcium ionophore (ionomycin) to induce interleukin 2 receptors, interleukin 2 (IL2) production, and proliferation over various concentrations of extracellular Ca++. Reducing the Ca++ levels from the normal 200 microM to 10 microM in PHA-stimulated cultures partially inhibited IL2 receptor expression, IL2 production, and subsequent proliferation. At 1 microM Ca++, both IL2 activity and proliferation were eliminated, but partial IL2 receptor expression was still observed. Ionomycin did not induce any of these events in cultures where the extracellular Ca++ concentration was below 100 microM. Restoring calcium in the medium resulted in normal levels of IL2 receptor expression, IL2 activity, and proliferation when PBL were stimulated with either mitogen. Exogenous magnesium partially restored these events in PHA-stimulated cultures, but had no effect when ionomycin was used as the mitogen. These data indicate that stimulation by ionomycin is much more dependent upon the levels of extracellular Ca++ than is PHA. Extracellular calcium also appears to be necessary subsequent to IL2 receptor acquisition, since the latter was seen without IL2 activity or proliferation at very low extracellular Ca++, and IL2 failed to restore the proliferative response under these conditions. The data also suggest that PHA, but not ionomycin, can activate lymphocytes via a magnesium-dependent pathway, or that PHA has a lower specificity for divalent cation cofactors.

Calcium↗
PubMed1988

Interleukin-1-beta gene expression in human monocytes and alveolar macrophages from normal subjects and patients with sarcoidosis.

To assess the ability of human alveolar macrophages to produce interleukin-1-beta (IL1-beta), we examined IL1-beta mRNA accumulation in autologous monocytes and alveolar macrophages from normal volunteers. Escherichia coli lipopolysaccharide stimulation of monocytes induced rapid IL1-beta mRNA accumulation, reaching a maximum at 2 to 4 h and declining thereafter. Alveolar macrophages, however, accumulated much less mRNA than did monocytes. This difference could not be explained by differences in kinetics of IL1-beta gene expression between the 2 cell types, isolation techniques, or alveolar macrophage lidocaine exposure. This suggests that differences in transcription of the IL1-beta gene exist between these 2 cell types. Aging is a possible factor important in some functional differences between these 2 cell types. To determine if this difference in the capacity to express the IL1-beta gene might be a function of cell maturity, monocytes were aged in vitro for 7 days. After this culture period, monocytes had a marked decrease in the ability to accumulate IL1-beta mRNA, suggesting that cell aging may be one mechanism involved in producing these transcriptional differences. Because IL1-beta has also been implicated in the inflammatory and fibrotic responses in pulmonary sarcoidosis, 4 patients with newly diagnosed sarcoidosis underwent bronchoalveolar lavage, and IL1-beta mRNA accumulation was compared in their alveolar macrophages and blood monocytes. Comparing normal alveolar macrophages to those from patients with sarcoidosis showed no differences in the kinetics of IL1-beta mRNA expression or in the LPS-induced levels of IL1-beta mRNA accumulation. In addition, augmented levels of IL1-beta transcript were not noted in unstimulated sarcoid alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1988

Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms.

Dexamethasone is known to have an inhibitory effect on IL-1 production. To determine the mechanism(s) of this inhibition, adherent human blood monocytes were stimulated with Escherichia coli lipopolysaccharide (LPS) (10 micrograms/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1 beta gene transcription two- to fourfold and that this induction was unaffected by dexamethasone exposure (10(-5) M). The lack of dexamethasone's transcriptional effects was further supported by the absence of any significant change in IL-1 beta mRNA accumulation between LPS-stimulated monocytes exposed or unexposed to dexamethasone, as determined by Northern blot analysis. Posttranscriptionally, dexamethasone was found to have multiple effects: slight prolongation of IL-1 beta mRNA half-life, moderate inhibition of translation of the IL-1 beta precursor, and profound inhibition of the release of IL-1 beta into the extracellular fluid. The data indicate that IL-1 beta is first translated as the 33,000-D pro-IL-1 beta protein, the predominant intracellular form, and the processed to a 17,500-D IL-1 beta protein before or during extracellular transport. The major inhibitory effects of dexamethasone appear to be directed at the translational and posttranslational steps involved in these events.

Dexamethasone↗
PubMed1988

Proliferative response of bronchoalveolar lymphocytes to beryllium. A test for chronic beryllium disease.

STUDY OBJECTIVE: to ascertain whether measuring the proliferative response of bronchoalveolar lymphocytes to beryllium salts is useful for diagnosing chronic beryllium disease. DESIGN: prospective case series compared to normal volunteers and patients with sarcoidosis. SETTING: university referral center. PATIENTS: twenty-three consecutive beryllium workers were evaluated. Fourteen had chronic beryllium disease diagnosed on the basis of histologic evidence of a progressive pulmonary granulomatosis. Four had biopsy evidence of non-beryllium disease. Three had probable chronic beryllium disease but did not have lung biopsies. Two did not have biopsies and had basilar fibrosis on chest roentgenogram suggestive of non-beryllium lung disease. These patients were compared with 6 normal volunteers and 16 patients with sarcoidosis. MEASUREMENTS AND MAIN RESULTS: bronchoalveolar lavage was done and the proliferative response of the lung cells to two beryllium salts was tested. A positive proliferative test was defined as a stimulation index of more than five on two determinations. The sensitivity of this test was 100% in the 14 patients with definite chronic beryllium disease. The specificity of the test was also 100% among the normal volunteers and the 16 patients with sarcoidosis. The test was positive in none of the four patients with biopsy evidence of non-beryllium disease, none out of two patients with lower lobe fibrosis suggestive of non-beryllium disease, and all of three patients with probable chronic beryllium lung disease. CONCLUSIONS: the proliferative response of bronchoalveolar lymphocytes to beryllium appears to be a useful test for chronic beryllium disease.

Berylliosis↗
PubMed1987

Chronic beryllium disease in a precious metal refinery. Clinical epidemiologic and immunologic evidence for continuing risk from exposure to low level beryllium fume.

Five workers at a precious metal refinery developed granulomatous lung disease between 1972 and 1985. The original diagnosis was sarcoidosis, but 4 of the workers were subsequently proved to have hypersensitivity to beryllium by in vitro proliferative responses of lymphocytes obtained by bronchoalveolar lavage. Review of medical records of coworkers and extensive industrial hygiene surveillance of the plant demonstrated that 4 cases occurred in the furnace area where air concentrations of beryllium fume were consistently below the permissible exposure limit of 2 micrograms/M3. A single case has been recognized from parts of the refinery where exposures to cold beryllium dust often exceeded the standard by as much as 20-fold. These data demonstrate that chronic beryllium disease still occurs and confirm the importance of specific immunologic testing in patients suspected of having sarcoidosis but with potential exposure to beryllium. The data raise concern about the adequacy of modern industrial controls, especially in the setting of exposure to highly respirable beryllium fume.

Adult↗
PubMed1987

Alveolar macrophages, blood monocytes, and density-fractionated alveolar macrophages differ in their ability to promote lymphocyte proliferation to mitogen and antigen.

We compared the relative abilities of alveolar macrophages (AM), blood monocytes (BM), and density-fractionated AM to support antigen- and mitogen-induced proliferation of autologous T cells in normal volunteers. The AM were able to promote the T-cell proliferative response to antigen, but they did so less effectively than did the BM. Density-fractionated AM were heterogeneous in their ability to support T-cell responses. More proliferation occurred with the densest AM than with the least dense AM. In contrast to antigen-induced responses, mitogen-induced responses were supported more effectively by AM and density-fractionated AM than by BM. The ability of AM, density-fractionated AM, and BM to support T-cell responses did not correlate with surface expression of class II major histocompatibility determinants. Addition of purified IL-1 resulted in a partial restoration of T-cell proliferation when low-density AM were used but no augmentation when unfractionated AM were used. This suggests that reduced IL-1 activity may partially explain the decreased ability of low density AM to promote T-cell responses, but that other processes may also contribute to differences in accessory cell function among AM, BM, and density-fractionated AM.

Antigens↗