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Biomedical subjects

A H Limper

Publications and source records attributed to A H Limper.

At least 73 records · Page 4Linked to original sources
PubMed1993

Pneumocystis carinii stimulates tumor necrosis factor-alpha release from alveolar macrophages through a beta-glucan-mediated mechanism.

Recent studies suggest that TNF-alpha plays a central role in host defenses during Pneumocystis carinii pneumonia. To determine whether P. carinii directly stimulates TNF-alpha secretion, rat alveolar macrophages were cultured in the presence of purified P. carinii. Whereas unstimulated alveolar macrophages released only 13.0 +/- 2.7 pg/ml of TNF-alpha into the medium, macrophages stimulated with P. carinii released 108.2 +/- 20.4 pg/ml of TNF-alpha after overnight culture (p = 0.0001). Maximal TNF-alpha release was observed after 8 h of incubation and required a P. carinii: macrophage ratio of at least 2.5:1. Autoclaved P. carinii were also able to trigger TNF-alpha release from macrophages albeit at a reduced level. In view of recent evidence that P. carinii is phylogenetically related to the fungi and contains a beta-glucan-rich cell wall, we hypothesized that TNF-alpha release might in part be mediated by this cell wall component. Preincubation of macrophages with particulate beta-glucan derived from Baker's yeast resulted in complete inhibition of TNF-alpha release in response to P. carinii. In addition, digestion of P. carinii with zymolyase, a preparation containing predominantly beta-glucanase activity, substantially reduced the ability of P. carinii to cause TNF-alpha release from macrophages. In a similar manner, macrophages incubated with P. carinii in the presence of laminariheptaose, an oligosaccharide that binds to macrophage beta-glucan receptors, also displayed decreased TNF-alpha release. Interestingly, TNF-alpha release may not be completely linked to the adherence of the organism to macrophages. Particulate beta-glucan significantly reduced P. carinii adherence to macrophages and also impaired TNF-alpha release. However, yeast mannan also significantly reduced P. carinii adherence to macrophages and also impaired TNF-alpha release. However, yeast mannan also significantly reduced P. carinii adherence but had no effect on TNF-alpha release. These data demonstrate that P. carinii can directly stimulate the secretion of TNF-alpha from alveolar macrophages and that this effect is largely mediated by beta-glucan components of the P. carinii cell wall.

Animals↗
PubMed1993

Fungal beta-glucans modulate macrophage release of tumor necrosis factor-alpha in response to bacterial lipopolysaccharide.

Tumor necrosis factor-alpha (TNF alpha) is a potent cytokine believed to participate in the development of endotoxin-induced shock and the adult respiratory distress syndrome. Treatment of animals with beta-glucan prior to bacterial challenge reduces TNF alpha release and prevents death. We therefore hypothesized that beta-glucan might regulate TNF alpha secretion from macrophages in response to lipopolysaccharide (LPS). Rat alveolar macrophages were cultured in the presence of beta-glucan alone and the TNF alpha secretion quantified using an L929 cytotoxicity assay. Concentrations of beta-glucan less than 500 micrograms/ml were found to stimulate TNF alpha release from macrophages. However, concentrations of beta-glucan greater than 500 micrograms/ml resulted in suppression of the TNF alpha activity released. This reduction in TNF alpha release was not mediated by a toxic effect of beta-glucan, as large concentrations of beta-glucan had no effect on macrophage viability. We further observed that the incubation of macrophages with large concentrations of beta-glucan (500 micrograms/ml) also inhibited the secretion of TNF alpha induced by bacterial LPS. Furthermore, interferon-gamma (IFN gamma), a potent activator of TNF alpha expression, failed to overcome the inhibition of TNF alpha caused by beta-glucan. These data suggest an immunomodulatory role for beta-glucan which may explain both the TNF alpha-stimulating and -inhibiting effects of fungal beta-glucans during infection.

Animals↗
PubMed1993

Vitronectin binds to Pneumocystis carinii and mediates organism attachment to cultured lung epithelial cells.

Pneumocystis carinii attaches to alveolar epithelial cells during the development of pneumonia. Adhesive proteins found within the alveolar space have been proposed to mediate P. carinii adherence to lung cells. Vitronectin (Vn), a 75-kDa glycoprotein present in the lower respiratory tract, has substantial cell-adhesive properties and might participate in the host-parasite interaction during P. carinii pneumonia. To address whether Vn binds to P. carinii, we studied the interaction of radiolabeled Vn with purified P. carinii organisms. Vn bound to P. carinii, occupying an estimated 5.47 x 10(5) binding sites per organism, with an affinity constant, Kd, of 4.24 x 10(-7) M. Interestingly, the interaction of Vn with P. carinii was not mediated through the Arg-Gly-Asp cell-adhesive domain of Vn. Addition of Arg-Gly-Asp-Ser (RGDS) peptides did not inhibit binding. In contrast, Vn binding to P. carinii was substantially inhibited by the addition of heparin or by digesting the organisms with heparitinase, suggesting that P. carinii may interact with the glycosaminoglycan-binding domain of Vn. To determine whether Vn might enhance P. carinii attachment to lung epithelial cells, we studied the binding of 51Cr-labeled P. carinii to cultured A549 lung cells. Addition of Vn resulted in significantly increased binding of P. carinii to A549 cells, whereas a neutralizing anti-Vn serum substantially reduced the binding of P. carinii to A549 cells. These data suggest that Vn binds to P. carinii and that Vn might provide an additional means by which P. carinii attaches to respiratory epithelial cells.

Amino Acid Sequence↗
PubMed1993

Pneumocystis carinii induces the release of arachidonic acid and its metabolites from alveolar macrophages.

Pneumocystis carinii is an opportunistic organism that causes severe lung injury in immunocompromised hosts. Macrophage responses to P. carinii are poorly defined. Arachidonic acid (AA) and its metabolites are potent mediators of inflammation and have been implicated in host response to microorganisms. We therefore examined the production of eicosanoids from rat and rabbit alveolar macrophages stimulated with purified P. carinii. [14C]AA-labeled rabbit macrophages released 8.50 +/- 1.33% of the incorporated [14C]AA after 90 min in response to P. carinii (P = 0.0001 compared with unstimulated controls). In contrast, a similar number of rat alveolar macrophages exhibited a smaller but significant response to P. carinii, releasing 3.84 +/- 1.54% of their [14C]AA after 90 min (P = 0.001 compared with control). We further determined that P. carinii stimulated substantial production of prostaglandin E2 and concurrently a small amount of leukotriene B4 release from alveolar macrophages. To further investigate whether serum opsonization of P. carinii enhances these alterations in AA metabolism, we assessed the effect of P. carinii immune serum on P. carinii-induced AA release. P. carinii opsonized with this antiserum caused significantly greater AA release from rat alveolar macrophages than either unopsonized P. carinii or organisms opsonized with nonimmune serum. Previous studies suggest that P. carinii interacts with macrophage beta-glucan and mannose receptors. However, incubation of macrophages with P. carinii in the presence of either soluble beta-glucan or alpha-mannan failed to alter the release of AA from macrophages in response to P. carinii. Macrophage release of eicosanoids represents a potentially important host inflammatory response to P. carinii infection.

Animals↗
PubMed1993

Interlobar variation in the recovery of bronchoalveolar lavage fluid, cell populations, and angiotensin-converting enzyme in normal volunteers.

Although bronchoalveolar lavage (BAL) is useful in studying a variety of lung diseases, it results in substantial dilution of cells and soluble proteins recovered from the lower respiratory tract. Surprisingly little is known about regional differences in BAL recovery in normals and patients with lung disorders. In order to assess regional differences in BAL in normals, we performed a prospective study of BAL in twenty non-smoking volunteers. With the subjects supine, BAL was performed in the right middle lobe (RML), right lower lobe (RLL) and Lingula (LING). The volumes recovered, cell numbers, and angiotensin converting enzyme (ACE) activities were determined separately for each BAL site. ACE was chosen as a representative soluble protein found in the lower respiratory tract which was easily measured in the BAL of normals. BAL volumes recovered from the RLL were significantly smaller than from the RML or LING, perhaps related to the dependent location of the RLL (P = 0.0002). The concentration of ACE and cells recovered per ml of BAL were significantly greater in the RLL than either the RML or LING (P = 0.05). In contrast, the total numbers of cells and total ACE recovered were similar from all sites sampled. This suggests that the differences in measured concentrations were due to different fluid recovery from these sites, resulting in variable dilution of proteins and cells. Urea measurement has been proposed as a means to quantify the epithelial lining fluid (ELF) volume sampled by BAL and estimate the actual concentrations of proteins present in the lower respiratory tract (J Appl Physiol 1986; 60:532-538).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The Cushing syndrome induced by bronchial carcinoid tumors.

OBJECTIVES: To define the clinical spectrum of bronchial carcinoid tumors in patients presenting with the Cushing syndrome, to evaluate the role of chest radiographs and computed tomography in their diagnosis, to review the characteristic histologic features, and to determine patient outcome. DESIGN: Retrospective analysis of consecutive patients. SETTING: A referral-based medical center. PATIENTS: Fifteen consecutive patients with the Cushing syndrome evaluated at the Mayo Clinic with histologically proven bronchial carcinoid tumors. MEASUREMENTS: Clinical, radiographic, and histologic features. RESULTS: The Cushing syndrome was the initial clinical presentation, and bronchial carcinoid tumors were found later in all 15 patients. The diagnosis of carcinoid tumor was proved histologically in all cases. Ten biopsies showed typical carcinoid tumors, three were histologically atypical, and three were metastatic. Corticotropin was detected by immunostaining in seven of these tumors. Biochemical analysis showed marked elevations of circulating corticotropin with a mean serum value of 156 +/- 58 pmol/L (normal, 4 to 22 pmol/L). Additional clinical features included hypokalemia in six patients and glucocorticoid response to either high-dose dexamethasone or metyrapone in 6 of 13. These hormonally active carcinoid tumors were frequently radiographically occult, with 10 of 15 patients initially having normal chest radiographs. Computed tomography was successful in locating carcinoid tumors in five patients with negative chest radiographs evaluated after 1980. All five remaining patients with normal chest radiographs evaluated before 1980 eventually developed nodular lesions on standard chest radiography from 1 to 10 years later. Ten patients achieved complete remission and two patients, partial remission of the Cushing syndrome after surgical resection. Three patients continued to have symptomatic glucocorticoid excess due to metastatic disease. CONCLUSIONS: Although uncommon, the Cushing syndrome may be the initial clinical manifestation of an otherwise indolent bronchial carcinoid tumor. Radiographic imaging of occult lesions can be successfully accomplished with computed tomography. Surgical resection is curative in most patients with this disorder.

ACTH Syndrome, Ectopic↗
PubMed1992

Fibronectin. A versatile matrix protein with roles in thoracic development, repair and infection.

Fibronectin, a dimeric cell-adhesive extracellular matrix glycoprotein, is secreted by mesenchymal cells and assembled into insoluble matrices which have important biological functions in embryologic development as well as in tissue response to injury. Fibronectin interacts with numerous cell types including mesenchymal cells and inflammatory cells which bear appropriate fibronectin receptors. In vitro, fibronectin serves as an adhesive substrate and promotes cell proliferation and cytodifferentiation. During development, fibronectin-rich matrices are deposited in specific location and regulate the directional migration of embryonic cells. In particular, fibronectin matrices appear to be of critical importance to normal cardiopulmonary development. Following embryologic development, the tissue expression of fibronectin is greatly reduced, but increases markedly following tissue injury, where newly expressed fibronectin matrices appear critical to tissue repair. Recent evidence has documented increased expression of fibronectin in numerous pulmonary conditions including the adult respiratory distress syndrome (ARDS), bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pulmonary fibrosis (IPF). Additionally, fibronectin also interacts with a large number of microorganisms and therefore also is potentially important in microbial adherence to airway epithelium and subsequent infections of the respiratory system.

Fibronectins↗
PubMed1991

Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis.

Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, we demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, we now demonstrate the presence of transforming growth factor beta 1 (TGF-beta 1), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-beta 1 may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-beta 1 is the alveolar macrophage, and we demonstrate the expression of abundant TGF-beta 1 mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

Fibronectins↗
PubMed1991

Cell surface molecules that bind fibronectin's matrix assembly domain.

The assembly of fibronectin into disulfide cross-linked extracellular matrices requires the interaction of mesenchymal cells with two distinct sites on fibronectin, the Arg-Gly-Asp cell adhesive site and an amino-terminal site contained within the first five type I homologous repeats (Quade, B. J., and McDonald, J. A. (1988) J. Biol. Chem. 263, 19602-19609). Proteolytically derived 29-kDa fragments of fibronectin (29kDa) containing these repeats bind to monolayers of cultured fibroblasts and inhibit fibronectin matrix assembly. The cell surface molecules interacting with fibronectin's 29-kDa matrix assembly domain have resisted purification using conventional methods such as affinity chromatography. Accordingly, in order to identify molecules which bind this fragment, 125I-labeled 29kDa was allowed to bind to fibroblast monolayers and chemically cross-linked to the cell surface with bis(sulfosuccinimidyl) suberate. Extraction of the cross-linked cell layer yielded radiolabeled complexes of 56, 150, and 280 kDa. Formation of these cross-linked complexes was specifically inhibited by the addition of excess unlabeled 29kDa but was unaffected by the presence of fibronectin fragments containing other type I repeats outside of the 29kDa matrix assembly domain. The cross-linked complexes were insoluble in nondenaturing detergents but soluble when denatured and reduced, suggesting that 29kDa may be cross-linked to components of the pericellular matrix. Immunoprecipitation of cross-linked cell extracts with a polyclonal antibody to fibronectin that does not recognize the amino terminus demonstrate that the 280-kDa band contains 29kDa cross-linked to fibronectin present on the cell surface. Formation of the 150-kDa complex was inhibited by EDTA, suggesting that divalent cations are required for its formation. Although the molecular mass and divalent cation requirement suggest that the 150-kDa complex may be related to an integrin, this complex was not immunoprecipitated by polyclonal antibodies generated to the alpha 5 beta 1 integrin fibronectin receptor.

Animals↗
PubMed1991

Modulation of Pneumocystis carinii adherence to cultured lung cells by a mannose-dependent mechanism.

Pneumocystis carinii is an opportunistic parasite that attaches to the alveolar epithelium during the initiation of pneumonia. It is unknown whether P. carinii recognizes specific receptors on the surface of lung cells. Our study indicates that concanavalin A (Con A), a lectin that recognizes mannose-containing glycoproteins, binds to P. carinii organisms in a saturable manner with a binding affinity of Kd = 11 x 10(-6) mol/L and with 18.5 x 10(6) Con A binding sites per P. carinii organism. Con A binds predominantly to glycoprotein 120, a mannose-rich glycoprotein on the surface of P. carinii. Treatment of cultured target lung cells (A549 cells) with Con A resulted in dramatic reduction of P. carinii attachment, from 34.9% +/- 4.1% to 8.1% +/- 1.3% (p less than 0.001), suggesting that mannose-containing cell surface molecules may be important in P. carinii adherence to target lung cells. In contrast, treatment of P. carinii with Con A resulted in slightly increased adherence of P. carinii when compared with controls. The effects of Con A on P. carinii adherence were reversed when Con A treatments were conducted in the presence of excess mannose, the sugar ligand for Con A. Further, pretreatment of A549 cell monolayers with excess mannose (5000 micrograms/ml) resulted in significant reduction of P. carinii adherence to A549 cells, from 39.4% +/- 2.5% to 28.4% +/- 1.3% (p = 0.003). These studies, for the first time, implicate mannose-containing cell surface molecules as important mediators of attachment between P. carinii and target lung cells.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1991

Parasitic adherence and host responses in the development of Pneumocystis carinii pneumonia.

Pneumocystis carinii pneumonia is a common cause of morbidity and mortality in patients with acquired immunodeficiency syndrome. In this article, the parasitic and host factors contributing to the pathophysiology of P carinii pneumonia will be reviewed. In particular, P carinii adherence to alveolar epithelial cells plays a central role in the development of pneumonia. Potential mechanisms mediating this attachment include cell surface glycoproteins, exogenous fibronectin and components of the parasitic cytoskeleton. Host factors contributing to respiratory impairment also have been recently evaluated. Inflammatory responses, aimed at ridding the lung of P carinii, may result in further deterioration of respiratory function. A better understanding of the host-parasite relationship in P carinii pneumonia eventually will lead to the development of novel therapies for this increasingly common respiratory disorder.

Adhesiveness↗
PubMed1990

Lung extracellular matrix: physiology and pathophysiology.

In addition to providing structural support and defining tissue compartments, the lung's extracellular matrix plays an important role in regulating cell behavior. Normal and pathologic interactions between the matrix, or its components, and cells of the lung are examined. Such interactions assume major importance in lung injury and repair.

Basement Membrane↗
PubMed1990

Tracheobronchial foreign bodies in adults.

STUDY OBJECTIVE: To define the clinical spectrum of tracheobronchial foreign body aspiration in adults, assess predisposing conditions, evaluate the efficacy of bronchoscopy, and determine outcome and complications. DESIGN: Retrospective analysis of a consecutive clinical series. SETTING: A tertiary care, referral-based medical center. PATIENTS: Sixty consecutive adult patients (over 16 years of age) evaluated for tracheobronchial foreign body aspiration. INTERVENTIONS: All 60 patients had bronchoscopic evaluation; 59 of them had foreign bodies identified and removal was attempted using either rigid or flexible fiberoptic bronchoscopy. MAIN RESULTS: Of 60 consecutive patients, 25 had underlying impairment of protective airway mechanisms (primary neurologic disorders, trauma with loss of consciousness, or sedative or alcohol use). Fifty-seven were successfully managed with bronchoscopy. Fiberoptic bronchoscopy was successful in 14 of 23 patients, and rigid bronchoscopy was successful in 43 of 44 patients, including 6 of 7 patients in whom previous fiberoptic bronchoscopy had failed. Thoracotomy was required in 3 patients. Complications of bronchoscopy were rare and not serious. Chronic complications of prolonged foreign body impaction included bronchiectasis in 3 patients. CONCLUSIONS: Although rare, tracheobronchial foreign body aspiration in adults can occur in various clinical settings. High clinical suspicion is necessary for diagnosis. Removal of foreign bodies can usually be accomplished with bronchoscopy.

Adolescent↗
PubMed1990

Pneumocystis carinii: inhibition of lung cell growth mediated by parasite attachment.

Pneumocystis carinii pneumonia is a significant cause of mortality in immunocompromised patients. Current concepts suggest that attachment of P. carinii to alveolar epithelium is required for development of pneumonia. We examined the mechanism of P. carinii adherence to cultured A549 cells, a permanent cell line derived from human alveolar epithelium. P. carinii adherence was quantified by measuring attachment of 51Cr-labeled P. carinii to cultured A549 cells. After 8 h of incubation, 37.4 +/- 4.2% of P. carinii were adherent to A549 cells. In the presence of agents known to impair cytoskeletal function, including 10(-5) M cytochalasin B, 10(-5) M colchicine, and 10(-5) M trimethylcolchicinic acid (TMCA), adherence was decreased from 57.4 +/- 4.2% to 9.3 +/- 3.4%, 12.5 +/- 3.6%, and 21.5 +/- 3.6%, respectively (P less than 0.01, all comparisons). Secondly, we examined the effect of P. carinii on the function of A549 cells. P. carinii resulted in significant impairment of A549 cell growth, indicating P. carinii adversely affected the function of target lung cells. A P. carinii:A549 cell ratio of 50:1 resulted in 43.5 +/- 2.9% inhibition of A549 cell growth (P less than 0.001). Additionally, TMCA, which significantly prevented attachment of P. carinii, reversed the impairment of A549 cell growth. These data demonstrate that P. carinii attachment to cultured lung cells can be quantified, is dependent on intact cytoskeletal function and is necessary for impairment of lung cell replication.

Adhesiveness↗
PubMed1989

Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS.

Pneumocystis carinii pneumonia has emerged as a significant cause of morbidity and mortality in immunocompromised patients with and without AIDS. To determine differences in P. carinii pneumonia in patients with and without AIDS, the P. carinii parasite numbers, lung inflammatory cell populations, gas exchange, and survival were assessed in a series of 75 consecutive patients with P. carinii pneumonia. Bronchoalveolar lavage was used to quantify the parasite and inflammatory cell numbers in these patients. The data from this study indicate: (1) patients with P. carinii pneumonia and AIDS have significantly greater numbers of P. carinii per ml of lavage compared to other immunocompromised patients with P. carinii pneumonia (p less than 0.0001); (2) patients with P. carinii pneumonia and AIDS also have significantly fewer neutrophils recovered in the lavage compared to other immunocompromised patients with P. carinii pneumonia (p = 0.0001); (3) patients with AIDS and P. carinii pneumonia have higher arterial oxygen tensions than those patients with P. carinii pneumonia in conditions other than AIDS (p = 0.008); and (4) increased lavage neutrophils (rather than parasite number) correlate with poorer oxygenation and poorer patient survival (p = 0.01). This investigation demonstrates substantial differences in lung inflammation and parasite number during P. carinii pneumonia in patients with and without AIDS. The data further suggest that lung inflammation contributes substantially to respiratory impairment in patients with P. carinii pneumonia.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Cardiopulmonary metastatic lesions of osteosarcoma and associated cerebral infarction.

Osteogenic sarcoma frequently disseminates by hematogenous routes. A 32-year-old patient underwent evaluation for an acute cerebral infarction. Cardiac auscultation disclosed an abnormal diastolic sound. Echocardiographic examination revealed a large left atrial mass, which was found at thoracotomy to be metastatic osteogenic sarcoma. Cerebral computed tomographic scans at the time of initial examination and 3 months later demonstrated new cerebral lesions consistent with metastatic growths. The abrupt cerebral infarction, other clinical findings, and results of diagnostic studies strongly suggested that the acute cerebrovascular event was the result of metastatic cerebral embolization from the tumor material found in the thorax. Cerebral infarction is an unusual and catastrophic complication of thoracic metastatic lesions of osteogenic sarcoma.

Adult↗