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Biomedical subjects

M Aubier

Publications and source records attributed to M Aubier.

At least 37 records · Page 2Linked to original sources
PubMed2001

Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.

BACKGROUND: Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity, but the risks and benefits of using them in patients with milder asthma are less clear. We have compared the change in bone mineral density over 2 years in adults with mild asthma randomised to receive an inhaled corticosteroid or non-corticosteroid treatment. METHODS: Subjects with mild asthma (mean forced expiratory volume in one second (FEV(1)) 86% predicted, mean age 35 years, taking beta agonists only) were randomised to receive inhaled budesonide, inhaled beclomethasone dipropionate, or non-corticosteroid treatment for 2 years in a prospective randomised open study in 19 centres in France, New Zealand, Spain, and the UK. The corticosteroid dose was adjusted according to a written self-management plan. The main outcome measure-change in bone mineral density after 6, 12, and 24 months-was measured "blind". Secondary outcomes included lung function, the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism. RESULTS: Of 374 subjects randomised, 239 (64%) completed the study and were included in the analysis. The median daily doses of inhaled budesonide (n=87) and beclomethasone (n=74) were 389 microg and 499 microg, respectively. Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group (n=78). Change in bone mineral density did not differ between the three groups over the 2 years, nor did it correlate with changes in markers of bone metabolism. The mean change in bone mineral density over 2 years in the budesonide, beclomethasone dipropionate, and reference groups was 0.1%, -0.4%, and 0.4% for the lumbar spine and -0.9%, -0.9%, and -0.4% for neck of the femur. Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck. CONCLUSION: In subjects with mild asthma an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years. The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone. Since inhaled steroid dose is also related inversely to lung function, an effect of asthma severity on bone density was also possible.

Administration, Inhalation↗
PubMed2001

Protective role of heme oxygenases against endotoxin-induced diaphragmatic dysfunction in rats.

Reactive oxygen species are strongly implicated in diaphragmatic dysfunction during sepsis. We investigated whether the heme oxygenase (HO) pathway, which is a powerful protective cellular system, protects the diaphragm against oxidative stress and contractile failure during sepsis. A basal expression of both the inducible and constitutive HO protein isoforms (HO-1 and HO-2, respectively) was found in the diaphragm. Enhanced HO-1 expression in diaphragmatic myocytes was observed 24 h after Escherichia coli endotoxin (lipopolysaccharide, LPS) inoculation and remained elevated for at least 96 h. Enhanced HO-1 expression was also observed in the rectus abdominis and soleus muscles and in the left ventricular myocardium of endotoxemic animals. Diaphragmatic HO-2 expression was not modified by endotoxin. Diaphragmatic HO activity exhibited a biphasic time course characterized by a transient decrease during the first 12 h followed by a significant increase at 24 h, corresponding to HO-1 induction. Diaphragmatic force was significantly reduced 24 h after LPS, concomitantly with muscular oxidative stress. Administation of an inhibitor of heme oxygenase activity, zinc protoporphyrin IX (ZnPP-IX), further impaired muscular oxidative stress and contractile failure. By contrast, increased levels of HO-1 expression obtained by pretreatment of rats with hemin, a powerful inducer of HO-1, completely prevented LPS-mediated diaphragmatic oxidative stress and contractile failure. This protective effect was reversed by ZnPP-IX. These results show an important protective role for the HO pathway against sepsis-induced diaphragmatic dysfunction, which could be related to its antioxidant properties.

Animals↗
PubMed2001

Neural substrates for the perception of acutely induced dyspnea.

Little is currently known about the brain regions involved in central processing of dyspnea. We performed a functional imaging study with positron emission tomography (PET) to assess brain activation associated with an important component of dyspnea, respiratory discomfort during loaded breathing. We induced respiratory discomfort in eight healthy volunteers by adding external resistive loads during inspiration and expiration. Brain activation was characterized by a significant increase in regional cerebral blood flow (rCBF) (Z score of peak activation > 3.09). As compared with the unloaded control condition, high loaded breathing was associated with neural activation in three distinct brain regions, the right anterior insula, the cerebellar vermis, and the medial pons (respective Z scores = 4.75, 4.44, 4.41). For these brain regions, we further identified a positive correlation between rCBF and the perceived intensity of respiratory discomfort (respective Z scores = 4.45, 4.75, 4.74) as well as between rCBF and the mean amplitude of mouth pressure swings (DeltaPm), the index of the main generating mechanism of the sensation (respective Z scores = 4.67, 4.36, 4.31), suggesting a common activation by these two parameters. Furthermore, we identified an area in the right posterior cingulate cortex where neural activation was specifically associated with perceived intensity of respiratory discomfort that is not related to DeltaPm (Z score = 4.25). Our results suggest that respiratory discomfort related to loaded breathing may be subserved by two distinct neural networks, the first being involved in the concomitant processing of the genesis and perception of respiratory discomfort and the second in the modulation of perceived intensity of the sensation by various factors other than its main generating mechanism, which may include emotional processing.

Acute Disease↗
PubMed2001

Somatostatin receptor scintigraphy and gallium scintigraphy in patients with sarcoidosis.

UNLABELLED: Somatostatin receptor scintigraphy (SRS) has been shown to reveal sarcoidosis sites. The aim of this study was to prospectively compare SRS and gallium scintigraphy in the evaluation of pulmonary and extrapulmonary involvement in patients with proven sarcoidosis. METHODS: Eighteen patients with biopsy-proven sarcoidosis were included. Nine were or recently had been receiving steroid therapy at the time of the examination. Planar gallium scintigraphy (head, chest, abdomen, and pelvis) and thoracic SPECT were performed at 48-72 h after injection of a mean dose of 138 +/- 21 MBq 67Ga. Planar SRS and thoracic SPECT were performed at 4 and 24 h after injection of a mean dose of 148 +/- 17 MBq 111n-pentetreotide. RESULTS: Gallium scintigraphy found abnormalities in 16 of 18 patients (89%) and detected 64 of 99 clinically involved sites (65%). SRS found abnormalities in 18 of 18 patients and detected 82 of 99 clinically involved sites (83%). Of the 9 treated patients, gallium scintigraphy found abnormalities in 7 (78%), detecting 23 of 39 clinically involved sites (59%), whereas SRS found abnormalities in 9, detecting 32 of 39 clinically involved sites (82%). CONCLUSION: This study suggests that, compared with gallium scintigraphy, SRS appears to be accurate and contributes to a better evaluation of organ involvement in sarcoidosis patients, especially those treated with corticosteroids.

Adrenal Cortex Hormones↗
PubMed2001

Involvement of caspases and of mitochondria in Fas ligation-induced eosinophil apoptosis: modulation by interleukin-5 and interferon-gamma.

In this study, we examined the relative importance of caspases and mitochondria in Fas-mediated eosinophil apoptosis. Stimulation of human peripheral blood eosinophils with an agonistic anti-human Fas monoclonal antibody, but not with control IgM, induced a time-dependent increase in their apoptosis, which was associated with a loss in mitochondrial transmembrane potential (DeltaPsi(m)) and with caspase-8 and caspase-3 activation. Interleukin (IL)-5 and interferon (IFN)-gamma, two cytokines known to prolong eosinophil survival, inhibited Fas-mediated apoptosis and caspase activation but poorly affected the decrease in DeltaPsi(m). Eosinophil incubation with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore (MPTP) opening, failed to modify Fas-mediated loss in DeltaPsi(m), caspase activation, and apoptosis. In contrast, caspase inhibitors markedly reduced eosinophil apoptosis without significantly affecting DeltaPsi(m) dissipation. We conclude that caspase-8 and caspase-3 activation, but not MPTP opening, mediate Fas-induced eosinophil apoptosis and are the main targets for the protective effect of IL-5 and IFN-gamma.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Differential effects of halothane and thiopental on surfactant protein C messenger RNA in vivo and in vitro in rats.

BACKGROUND: Pulmonary surfactant is a complex mixture of proteins and phospholipids synthetized by alveolar type II cells. Volatile anesthetics have been shown to reduce surfactant phospholipid biosynthesis by rat alveolar type II cells. Surfactant-associated protein C (SP-C) is critical for the alveolar surfactant functions. Our goal was to evaluate the effects of halothane and thiopental on SP-C messenger RNA (mRNA) expression in vitro in rat alveolar type II cells and in vivo in mechanically ventilated rats. METHODS: In vitro, freshly isolated alveolar type II cells were exposed to halothane during 4 h (1, 2, 4%) and 8 h (1%), and to thiopental during 4 h (10, 100 micrometer) and 8 h (100 micrometer). In vivo, rats were anesthetized with intraperitoneal thiopental or inhaled 1% halothane and mechanically ventilated for 4 or 8 h. SP-C mRNA expression was evaluated by ribonuclease protection assay. RESULTS: In vitro, 4-h exposure of alveolar type II cells to thiopental 10 and 100 micrometer increased their SP-C mRNA content to 145 and 197%, respectively, of the control values. In alveolar type II cells exposed for 4 h to halothane 1, 2, and 4%, the SP-C mRNA content increased dose-dependently to 160, 235, and 275%, respectively, of the control values. In vivo, in mechanically ventilated rats, 4 h of halothane anesthesia decreased the lung SP-C mRNA content to 53% of the value obtained in control (nonanesthetized, nonventilated) animals; thiopental anesthesia increased to 150% the lung SP-C mRNA content. CONCLUSIONS: These findings indicate that halothane and thiopental used at clinically relevant concentrations modulate the pulmonary SP-C mRNA content in rats. In vivo, the additive role of mechanical ventilation is suggested.

Actins↗
PubMed2000

Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients.

OBJECTIVES: To determine bronchoalveolar lavage (BAL) fluid concentrations of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), two potent growth factors for alveolar type II epithelial cells, in patients with acute respiratory distress syndrome (ARDS). DESIGN: Prospective study. SETTING: An adult trauma/surgical intensive care unit in an urban teaching hospital. PATIENTS: A total of 32 ventilated patients with pulmonary infiltrates prospectively identified with ARDS (n = 17) or without ARDS (n = 15), including eight patients with hydrostatic edema (HE), and ten nonventilated patients serving as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: BAL was performed 2.88 days +/- 2.4, 3.5 days +/- 2.4, and 2.3 days +/- 2.2 after the lung insult in ARDS, HE, and other non-ARDS patients respectively (p = .32). KGF was detected in BAL fluid in 13 of the 17 ARDS patients (median, 31.6 pg/mL), in one patient with HE, and in none of other non-ARDS patients. In ARDS patients, detection of KGF in BAL was associated in BAL fluid with the detection of type III procollagen peptide (PIIIP), a biological marker of fibroproliferation. In ARDS patients, detection of KGF in BAL was associated with death (p = .02). HGF was detected in 15 ARDS patients (median, 855 pg/mL), in seven patients with HE (median, 294 pg/mL; p = .05 for the comparison with ARDS group), in six of other non-ARDS patients (median, 849 pg/mL; p = .32 with ARDS group). HGF concentrations were higher in nonsurvivors than in survivors (p = .01). None of the ten BAL of controls contained either KGF or HGF. CONCLUSION: KGF was detected almost exclusively in BAL fluid from ARDS patients and correlated with a poor prognosis in this group. In contrast, HGF was detected in the BAL fluid from a majority of patients with or without ARDS. Elevated HGF concentrations were associated with a poor prognosis in the overall group.

Adult↗
PubMed2000

Mechanisms of GM-CSF increase by diesel exhaust particles in human airway epithelial cells.

We have previously shown that exposure to diesel exhaust particles (DEPs) stimulates human airway epithelial cells to secrete the inflammatory cytokines interleukin-8, interleukin-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) involved in allergic diseases. In the present paper, we studied the mechanisms underlying the increase in GM-CSF release elicited by DEPs using the human bronchial epithelial cell line 16HBE14o-. RT-PCR analysis has shown an increase in GM-CSF mRNA levels after DEP treatments. Comparison of the effects of DEPs, extracted DEPs, or extracts of DEPs has shown that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and not to the metals present on the DEP surface because the metal chelator desferrioxamine had no inhibitory effect. Furthermore, radical scavengers inhibited the DEP-induced GM-CSF release, showing involvement of reactive oxygen species in this response. Moreover genistein, a tyrosine kinase inhibitor, abrogated the effects of DEPs on GM-CSF release, whereas protein kinase (PK) C, PKA, cyclooxygenase, or lipoxygenase inhibitors had no effect. PD-98059, an inhibitor of mitogen-activated protein kinase, diminished the effects of DEPs, whereas SB-203580, an inhibitor of p38 mitogen-activated protein kinase, had a lower effect, and DEPs did actually increase the active, phosphorylated form of the extracellular signal-regulated kinase as shown by Western blotting. In addition, cytochalasin D, which inhibits the phagocytosis of DEPs, reduced the increase in GM-CSF release after DEP treatment. Together, these data suggest that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and that the effect of native DEPs requires endocytosis of the particles. Reactive oxygen species and tyrosine kinase(s) may be involved in the DEP-triggered signaling of the GM-CSF response.

Bronchi↗
PubMed2000

Muscular contractile failure in septic patients: role of the inducible nitric oxide synthase pathway.

Skeletal muscle failure is a frequent manifestation of sepsis that affects prognosis and rehabilitation by impairing respiration and ambulation. Animal studies have shown that the inducible NO synthase (NOS2) is expressed in skeletal muscles during sepsis, likely affecting muscular function, by promoting the formation of the strong oxidant peroxynitrite. In contrast, whether human skeletal muscle expresses a functional NOS2 in similar conditions is unknown. We studied NOS2 expression (mRNA and protein) and activity and its role in contractile function in samples from rectus abdominis muscle obtained during surgical procedure in 16 septic patients and in 21 controls. Peroxynitrite formation was detected by immunohistochemical detection of nitrotyrosine residues. The main results of this study are as follows: (1) A significant increase in NOS2 mRNA, protein, and activity was found in muscles from septic patients, the expression of NOS2 protein positively correlating with sepsis severity. (2) Contractile force was significantly lower in septic than in control muscles. This phenomenon was not reverted by muscle incubation ex vivo with the NOS inhibitor L-NMMA, indicating that NO was not involved in force reduction at the time of biopsy. (3) NOS2 expression in skeletal myocytes was strongly co-localized with nitrotyrosine, revealing muscular peroxynitrite generation during the septic process, before the muscle was biopsied. Exposure of control muscles to an amount of peroxynitrite similar to that generated in septic muscles during the septic process resulted in a nonreversible reduction in force generation. These results suggest that NOS2 could be involved in the decreased muscular force of septic patients via the local generation of peroxynitrite.

Adult↗
PubMed2000

Halothane reduces the early lipopolysaccharide-induced lung inflammation in mechanically ventilated rats.

Several studies suggest that anesthetics modulate the immune response. The aim of this study was to investigate the effect of halothane and thiopental on the lung inflammatory response. Rats submitted or not to intratracheal (IT) instillation of lipopolysaccharides (LPS) were anesthetized with either halothane (0. 5, 1, or 1.5%) or thiopental (60 mg. kg(-1)) and mechanically ventilated for 4 h. Control rats were treated or not by LPS without anesthesia. Lung inflammation was assessed by total and differential cell counts in bronchoalveolar lavage fluids (BALF) and by cytokine measurements (tumor necrosis factor-alpha [TNF-alpha], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and monocyte chemoattractant protein-1 [MCP-1]) in BALF and lung homogenates. In the absence of LPS treatment, neither halothane nor thiopental modified the moderate inflammatory response induced by tracheotomy or mechanical ventilation. Cell recruitment and cytokine concentrations were increased in all groups receiving IT LPS. However, in halothane-anesthetized rats (halothane > or = 1%), but not in thiopental-anesthetized rats, the LPS-induced lung inflammation was altered in a dose-dependent manner. Indeed, when using 1% halothane, polymorphonuclear leukocyte (PMN) recruitment was decreased by 55% (p < 0.001) and TNF-alpha, IL-6, and MIP-2 concentrations in BALF and lung homogenates were decreased by more than 60% (p < 0.001) whereas total protein and MCP-1 concentrations remained unchanged. The decrease of MIP-2 (observed at the protein and messenger RNA [mRNA] level) was strongly correlated to the decrease of PMN recruitment (r = 0.73, p < 0.05). This halothane-reduced lung inflammatory response was transient and was reversed 20 h after the end of the anesthesia. Our study shows that halothane > or = 1%, delivered during 4 h by mechanical ventilation, but not mechanical ventilation per se, alters the early LPS-induced lung inflammation in the rat, suggesting a specific effect of halothane on this response.

Anesthetics, Inhalation↗
PubMed2000

[Diesel particles and allergy: cellular mechanisms].

Urbain air pollutants, particularly diesel exhaust particles are now known to contribute to the increased prevalence of asthma and allergic rhinitis. Diesel exhaust particles act as adjuvants in the immune response and may lead to the enhancement of allergic inflammation. This was first suggested by epidemiological studies and now largely confirmed by numerous experimental studies in animals and humans. We review the different mechanisms involved, including effects on cytokine and chemokine production, as well as activation of different immune cells. We also discuss the metabolic and cellular activation pathways used by polycyclic aromatic hydrocarbons, allergens and their interaction with diesel particles which act in synergy in this immune response toward IgE production and induction of allergic inflammation.

Allergens↗
PubMed2000

[Air pollution and allergic asthma].

The prevalence of asthma and allergic diseases is increasing in all industrialized countries. Genetic and environmental factors, and their interactions, are responsible for this increasing prevalence. A certain number of genes are currently screened to determine their suspected role in the immunogenesis of asthma, but in themselves, they cannot explain the increasing prevalence of asthma observed over the last 20 years. Environmental factors appear to be the most plausible explanation. Among these factors, air pollution and changing lifestyle as well as lower resistance due to fewer infectious diseases during childhood may be the most important factors. Experimental studies have shown that some pollutants such as ozone or diesel exhaust particles can interact with allergens, amplifying allergic reactions. Epidemiological studies have provided contradictory results. Acutely high concentrations of different pollutants can induce transient respiratory symptoms in asthmatic subjects but the long-term effects of air pollution on the genesis of asthma are still quite unclear.

Air Pollution↗
PubMed2000

[Special characteristics of the diaphragm muscle cell].

The diaphragm is the main inspiratory muscle, accounting for more than 50% of the tidal volume during quiet breathing. It works continuously, contracting rhythmically and generally at a low intensity. In this respect, it is close to the myocardium, being the only vital skeletal muscle. From a general point of view, functional and biochemical characteristics of the diaphragm are similar to those of other skeletal muscles with a similar fiber type composition. However, the diaphragm presents some specificities allowing a high supply of metabolic substrates. This could serve to preserve contractile function in different physiological and physiopathological situations. Such specificities concern muscular vascularization, the microvascular network and the content of mitochondria and myoglobin. These characteristics are detailed and compared to those of other striated muscles.

Diaphragm↗
PubMed2000

111In-pentetreotide scintigraphy in patients with Langerhans' cell histiocytosis.

UNLABELLED: Langerhans' cell histiocytosis is a granulomatous disease that may involve multiple organs and the prognosis of which is highly variable. Because the prognosis depends particularly on the number of tissues involved, the accurate identification of the organs involved by granulomatous lesions is of critical importance. We hypothesized that 111In-pentetreotide scintigraphy would be useful for evaluation of patients with Langerhans' cells histiocytosis. METHODS: Thirteen patients (38.3+/-10.4 y) with Langerhans' cell histiocytosis (8 patients with unifocal lung disease, 5 with multifocal disease) received intravenous 111In-pentetreotide (111-222 MBq), and planar images were obtained at 24 h after injection. Pulmonary uptake was quantified using a lung-to-background ratio (L/B) and compared with a population of 10 normal scintigrams. For the other sites, uptake of radioactivity in disease-related areas was visually assessed. RESULTS: Ten of 12 patients with lung involvement had increased lung uptake (UB, 2.23+/-0.49 versus 1.34+/-0.07; P < 0.001). In the patients with multifocal disease, increased 111In-pentetreotide uptake was found in disease-related areas such as the salivary glands, the skin, the soft tissues, and the bones. However, somatostatin receptor imaging was insensitive for detecting central nervous system and liver involvement and most skin lesions. CONCLUSION: 111In-pentetreotide imaging may be useful in Langerhans' cell histiocytosis. Further study will indicate whether 111In-pentetreotide is a relevant tracer in the management of histiocytosis.

Adult↗
PubMed2000

[Role of nitric oxide in diaphragmatic dysfunction genesis during sepsis in rats].

Nitric oxide (NO) is a vasodilator agent that is cytotoxic and negatively inotropic in the heart. More recently, it has been shown that during sepsis there is a high amount of NO production by a NO synthase (NOS) that is inducible by cytokines. The aim of this study was to investigate the role of NO in the genesis of diaphragmatic dysfunction during sepsis. Rats were inoculated i.p. injection with 10 mg/kg of Escherichia coil endotoxin (E animals) or saline (C animals). Six hours after endotoxin or saline inoculation, diaphragmatic force and muscularc GMP (Cyclic guanosine monophosphate) were assessed by in vitro force frequency curves and ELISA method, respectively. As compared to C animals, E animals showed a significant decrease in diaphragmatic force for all the frequencies of stimulation (p < 0.01). This reduction was associated with a significant increase in muscular cGMP. Inhibition of NO synthesis in E animals with either dexamethasone (4 mg/kg IV, 45 min before endotoxin or saline) or NG-monomethyl-L-arginine (L-NMMA, 8 mg/kg IV, 90 min after endotoxin or saline) prevented the effects of endotoxin. However, no modification was seen with NG-monomethyl-D-arginine (D-NMMA), a molecule which does not inhibit NO synthesis. Administration of dexamethasone or L-NMMA in C animals did not induce any significant change in diaphragmatic force, and cGMP ratio. We conclude that NO has a contributive role in diaphragmatic dysfunction during Escherichia coli induced sepsis in rats.

Animals↗
PubMed1999

Myocardial cell death in fibrillating and dilated human right atria.

OBJECTIVES: The aim of the present study was to determine if myocytes can die by apoptosis in fibrillating and dilated human atria. BACKGROUND: The cellular remodeling that occurs during atrial fibrillation (AF) may reflect a degree of dedifferentiation of the atrial myocardium, a process that may be reversible. METHODS: We examined human right atrial myocardium specimens (n = 50) for the presence of apoptotic myocytes. We used immunohistochemical and Western blotting analysis to examine the expression of a final effector of programmed cell death, caspase-3 (CASP-3) and of regulatory proteins from the BCL-2 family. RESULTS: Sections from atria in AF contained a high percentage of large myocytes with a disrupted sarcomeric apparatus replaced by glycogen granules (64.4 +/- 6.3% vs. 12.2 +/- 5.8%). These abnormal myocytes, which also predominated in atria from hearts with decreased left ventricular ejection fraction (42.3 +/- 10.1%), contained large nuclei, most of which were TUNEL positive, indicating a degree of DNA breakage. None of these abnormal myocytes expressed the proliferative antigen Ki-67. A small percentage of the enlarged nuclei (4.2 +/- 0.8%) contained condensed chromatin and were strongly TUNEL positive. Both the pro- and activated forms of CASP-3 were detected in diseased myocardial samples, which also showed stronger CASP-3 expression than controls. Expression of the antiapoptotic BCL-2 protein was decreased in diseased atria, whereas that of the proapoptotic BAX protein remained unchanged. CONCLUSIONS: In fibrillating and dilated atria, apoptotic death of myocytes with myolysis contributes to cellular remodeling, which may not be entirely reversible.

Adult↗
PubMed1999

Inducible expression and regulation of the alpha 1-acid glycoprotein gene by alveolar macrophages: prostaglandin E2 and cyclic AMP act as new positive stimuli.

We have reported that alpha 1-acid glycoprotein (AGP) gene expression was induced in lung tissue and in alveolar type II cells during pulmonary inflammatory processes, suggesting that local production of this immunomodulatory protein might contribute to the modulation of inflammation within the alveolar space. Because AGP may also be secreted by other cell types in the alveolus, we have investigated the expression and the regulation of the AGP gene in human and rat alveolar macrophages. Spontaneous AGP secretion by alveolar macrophages was increased 4-fold in patients with interstitial lung involvement compared with that in controls. In the rat, immunoprecipitation of [35S]methionine-labeled cell lysates showed that alveolar macrophages synthesize and secrete AGP. IL-1 beta had no effect by itself, but potentiated the dexamethasone-induced increase in AGP production. RNase protection assay demonstrated that AGP mRNA, undetectable in unstimulated cells, was induced by dexamethasone. Conditioned medium from LPS-stimulated macrophages as well as IL-1 beta had no effect by themselves, but potentiated the dexamethasone-induced increase in AGP mRNA levels. In addition to cytokines, PGE2 as well as dibutyryl cAMP increased AGP mRNA levels in the presence of dexamethasone. When AGP expression in other cells of the monocyte/macrophage lineage was examined, weak and no AGP production by human blood monocytes and by rat peritoneal macrophages, respectively, were observed. Our data showed that 1) AGP expression is inducible specifically in alveolar macrophages in vivo and in vitro; and 2) PGE2 and cAMP act as new positive stimuli for AGP gene expression.

Adult↗