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PubMed1994

Characterization of a family of related cellular transcription factors which can modulate human immunodeficiency virus type 1 transcription in vitro.

LBP-1 is a cellular protein which binds strongly to sequences around the human immunodeficiency virus type 1 (HIV-1) initiation site and weakly over the TATA box. We have previously shown that LBP-1 represses HIV-1 transcription by inhibiting the binding of TFIID to the TATA box. Four similar but distinct cDNAs encoding LBP-1 (LBP-1a, -b, -c, and -d) have been isolated. These are products of two related genes, and each gene encodes two alternatively spliced products. Comparison of the amino acid sequence of LBP-1 with entries in the available protein data bases revealed the identity of LBP-1c to alpha-CP2, an alpha-globin transcription factor. These proteins are also homologous to Drosophila melanogaster Elf-1/NTF-1, an essential transcriptional activator that functions during Drosophila embryogenesis. Three of the recombinant LBP-1 isoforms show DNA binding specificity identical to that of native LBP-1 and bind DNA as a multimer. In addition, antisera raised against recombinant LBP-1 recognize native LBP-1 from HeLa nuclear extract. Functional analyses in a cell-free transcription system demonstrate that recombinant LBP-1 specifically represses transcription from a wild-type HIV-1 template but not from an LBP-1 mutant template. Moreover, LBP-1 can function as an activator both in vivo and in vitro, depending on the promoter context. Interestingly, one isoform of LBP-1 which is missing the region of the Elf-1/NTF-1 homology is unable to bind DNA itself and, presumably through heteromer formation, inhibits binding of the other forms of LBP-1, suggesting that it may function as a dominant negative regulator.

Amino Acid Sequence↗
PubMed1994

One exon of the human LSF gene includes conserved regions involved in novel DNA-binding and dimerization motifs.

The transcription factor LSF, identified as a HeLa protein that binds the simian virus 40 late promoter, recognizes direct repeats with a center-to-center spacing of 10 bp. The characterization of two human cDNAs, representing alternatively spliced mRNAs, provides insight into the unusual DNA-binding and oligomerization properties of LSF. The sequence of the full-length LSF is identical to that of the transcription factors alpha CP2 and LBP-1c and has similarity to the Drosophila transcription factor Elf-1/NTF-1. Using an epitope-counting method, we show that LSF binds DNA as a homodimer. LSF-ID, which is identical to LBP-1d, contains an in-frame internal deletion of 51 amino acids resulting from alternative mRNA splicing. Unlike LSF, LSF-ID did not bind LSF DNA-binding sites. Furthermore, LSF-ID did not affect the binding of LSF to DNA, suggesting that the two proteins do not interact. Of three short regions with a high degree of homology between LSF and Elf-1/NTF-1, LSF-ID lacks two, which are predicted to form beta-strands. Double amino acid substitutions in each of these regions eliminated specific DNA-binding activity, similarly to the LSF-ID deletion. The dimerization potential of these mutants was measured both by the ability to inhibit the binding of LSF to DNA and by direct protein-protein interaction studies. Mutations in one homology region, but not the other, functionally eliminated dimerization.

Alternative Splicing↗
PubMed1996

The myeloid-cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor.

The protein product of the c-fps/fes (c-fes) proto-oncogene has been implicated in the normal development of myeloid cells (macrophages and neutrophils). mRNA for c-fes has been detected exclusively in myeloid cells and vascular endothelial cells in adult mammals. Although a 13-kilobase-pair (kb) human c-fes transgene exhibits high levels of expression in mice, the sequences that confer myeloid-cell-specific expression of the human c-fes gene have not been defined. Transient-transfection experiments demonstrated that plasmids containing 446 bp of c-fes 5'-flanking sequences linked to a luciferase reporter gene were active exclusively in myeloid cells. No other DNA element within the 13-kb human c-fes locus contained positive cis-acting elements, with the exception of a weakly active region within the 3'-flanking sequences. DNase I footprinting assays revealed four distinct sites that bind myeloid nuclear proteins (-408 to -386, -293 to -254, -76 to -65, and -34 to +3). However, the first two footprints resided in sequences that were largely dispensable for transient activity. Plasmids containing 151 bp of 5'-flanking sequences confer myeloid-cell-specific gene expression. Electrophoretic mobility shift analyses demonstrated that the 151-bp region contains nuclear protein binding sites for Sp1, PU.1, and/or Elf-1, and a novel factor. This unidentified factor binds immediately 3' of the PU.1/Elf-1 sites and appears to be myeloid cell specific. Mutation of the PU.1/Elf-1 site or the 3' site (FP4-3') within the context of the c-fes promoter resulted in substantially reduced activity in transient transfections. Furthermore, transient-cotransfection assay demonstrated that PU.1 (and not Elf-1) can transactivate the c-fes promoter in nonmyeloid cell lines. We conclude that the human c-fes gene contains a strong myeloid-cell-specific promoter that is regulated by Sp1, PU.1, and a novel transcription factor.

Animals↗
PubMed2005

Potential autoregulation of transcription factor PU.1 by an upstream regulatory element.

Regulation of the hematopoietic transcription factor PU.1 (Spi-1) plays a critical role in the development of white cells, and abnormal expression of PU.1 can lead to leukemia. We previously reported that the PU.1 promoter cannot induce expression of a reporter gene in vivo, and cell-type-specific expression of PU.1 in stable lines was conferred by a 3.4-kb DNA fragment including a DNase I hypersensitive site located 14 kb upstream of the transcription start site. Here we demonstrate that this kb -14 site confers lineage-specific reporter gene expression in vivo. This kb -14 upstream regulatory element contains two 300-bp regions which are highly conserved in five mammalian species. In Friend virus-induced erythroleukemia, the spleen focus-forming virus integrates into the PU.1 locus between these two conserved regions. DNA binding experiments demonstrated that PU.1 itself and Elf-1 bind to a highly conserved site within the proximal homologous region in vivo. A mutation of this site abolishing binding of PU.1 and Elf-1 led to a marked decrease in the ability of this upstream element to direct activity of reporter gene in myelomonocytic cell lines. These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.

Animals↗
PubMed2002

Airways in cystic fibrosis are acidified: detection by exhaled breath condensate.

BACKGROUND: The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO(3)(-)) secretion is also impaired in CFTR expressing tissues and CFTR is thought to regulate HCO(3)(-) secretion at the apical membrane of epithelial cells. We hypothesised that the epithelial lining fluid (ELF) of patients with CF would be acidified and that this may be worsened during an infective exacerbation due to the increased inflammatory burden. METHODS: pH and nitrite levels in exhaled breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with CF (11 of whom were in an infective exacerbation) were measured. A further nine patients were studied before and after intravenous antibiotic treatment for an exacerbation of CF. RESULTS: The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) micro m v 1.6 (1.6) micro m p=0.047). No correlation was found between EBC pH and nitrite levels. CONCLUSIONS: These findings support the hypothesis that airway acidification occurs in CF. This acidity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.

Adult↗
PubMed2005

Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury.

BACKGROUND: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. METHODS: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. RESULTS: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4-54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9-3192) pg/ml v 4761 (1349-7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor alpha. CONCLUSION: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS.

Adolescent↗
PubMed1998

Acute inhalation of cigarette smoke increases lower respiratory tract nitric oxide concentrations.

BACKGROUND: Cigarette smoking is associated with a number of common pulmonary diseases including chronic airflow limitation and bronchial carcinoma. Lower respiratory tract (LRT) nitric oxide (NO) concentrations are reduced in habitual cigarette smokers between cigarettes, and although this finding has been implicated in the pathogenesis of smoking related disease, the underlying mechanisms are unclear. A study was undertaken to determine the nature and time course for changes in LRT NO concentrations following acute inhalation of cigarette smoke. METHODS: Twenty four healthy habitual smokers were studied. The concentration of LRT NO in exhaled breath before, one and ten minutes after smoking a single cigarette was measured using chemiluminescence. RESULTS: LRT NO concentrations increased in all subjects from a mean (SE) of 2.6 (0.27) to 4.8 (0.26) ppb (p < 0.0001) at one minute, and at 10 minutes remained significantly raised above the baseline level at 3.2 (0.25) ppb (p = 0.003). The mean (95% CI) increases in NO concentrations were 2.2 (1.7 to 2.7) and 0.6 (0.2 to 1.0) ppb, respectively. CONCLUSIONS: These findings were unexpected in both their direction and time course. They suggest a novel mechanism for the handling of NO in the human lung. We hypothesise that NO is trapped in the epithelial lining fluid (ELF) of the normal human respiratory tract in bioequivalent forms such as S-nitrosothiols or peroxynitrite and that this trapping mechanism is sensitive to the redox state of the ELF. LRT NO concentrations will thus increase with oxidant exposure and decline as pulmonary antioxidant defence mechanisms take effect. These findings may have implications for the pathogenesis and diagnosis of oxidant mediated pulmonary disease.

Adult↗
PubMed2004

Interfacial phospholipids inhibit ozone-reactive absorption-mediated cytotoxicity in vitro.

The intrapulmonary distribution of inhaled ozone (O(3)) and induction of site-specific cell injury are related to complex interactions among airflow patterns, local gas-phase concentrations, and the rates of O(3) flux into, and reaction and diffusion within, the epithelial lining fluid (ELF). Recent studies demonstrated that interfacial phospholipid films appreciably inhibited NO(2) absorption. Because surface-active phospholipids are present on alveolar and airway interfaces, we investigated the effects of interfacial films on O(3)-reactive absorption and acute cell injury. Compressed films of dipalmitoyl-glycero-3-phosphocholine (DPPC) and rat lung lavage lipids significantly reduced O(3)-reactive absorption by ascorbic acid, reduced glutathione, and uric acid. Conversely, unsaturated phosphatidylcholine films did not inhibit O(3) absorption. We evaluated O(3)-mediated cell injury using a human lung fibroblast cell culture system, an intermittent tilting exposure regimen to produce a thin covering layer, and nuclear fluorochrome permeability. Exposure produced negligible injury in cells covered with MEM. However, addition of AH(2) produced appreciable (<50%) cell injury. Film spreading of DPPC monolayers necessitated the use of untilted regimens. Induction of acute cell injury in untilted cultures required both AH(2) plus very high O(3) concentrations. Addition of DPPC films significantly reduced cell injury. We conclude that acute cell injury likely results from O(3) reaction with ELF substrates. Furthermore, interfacial films of surface-active, saturated phospholipids reduce the local dose of O(3)-derived reaction products. Finally, because O(3) local dose and tissue damage likely correlate, we propose that interfacial phospholipids may modulate intrapulmonary distribution of inhaled O(3) and the extent of site-specific cell injury.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Downmodulation of IL-8 receptors, type A and type B, on human lung neutrophils in vivo.

We examined the expression of interleukin (IL)-8 receptors (Rs), type A (IL-8-RA) and type B (IL-8-RB), on peripheral blood and bronchoalveolar lavage (BAL) fluid neutrophils; we also examined IL-8 and other chemoattractants in the epithelial lining fluid (ELF) of patients with chronic lower respiratory tract infection (CLI) to elucidate the in vivo regulation of IL-8Rs. Neutrophils were stained with monoclonal antibodies specific for IL-8-RA and IL-8-RB. We detected higher levels of IL-8 (81.6 +/- 25.4 ng/ml, mean +/- SE), leukotriene (LT) B4, and IL-1 beta in the ELF of the CLI patients than in their serum (P < 0.05). The expression of IL-8Rs on BAL neutrophils was significantly lower than that on peripheral blood neutrophils (P < 0.01 for both). In vitro analysis showed that low-level IL-8 (50 ng/ml) alone did not affect IL-8R expression but that it was downregulated by high-level IL-8 (500 ng/ml) alone and by low-level IL-8 in combination with LTB4 or IL-1 beta. Staurosporine reduced the downmodulation by low-level IL-8 plus LTB4 or IL-1 beta but not by high-level IL-8 alone. We speculate that pulmonary IL-8-RA and IL-8-RB may have been downmodulated by the combined effect of local chemoattractants through, in part, a protein kinase C-dependent mechanism.

Adult↗
PubMed2001

Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice.

Recent studies suggest that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein modulates epithelial reduced glutathione (GSH) transport and when defective creates an antioxidant imbalance. To test whether the CFTR protein modulates lung antioxidant defenses in vivo, epithelial lining fluid (ELF) and lung tissue from CFTR knockout (CFTR-KO) and wild-type (WT) mice were compared for GSH content and the activities of glutathione reductase, glutathione peroxidase, and gamma-glutamyltransferase. In the CFTR-KO mice, the ELF concentration of GSH was decreased (51%) compared with that in WT mice. The concentration of GSH in the lung tissue of CFTR-KO mice, however, was not significantly different from that in WT mice. The activities of glutathione reductase and glutathione peroxidase in the lung tissue of CFTR-KO mice were significantly increased compared with those in WT mice (48 and 28%, respectively). Tissue lipid and DNA oxidation were evaluated by measurement of thiobarbituric acid-reactive substances and 8-hydroxy-2'-deoxyguanosine, respectively. The levels of thiobarbituric acid-reactive substances and 8-hydroxy-2'-deoxyguanosine in the lung tissue of CFTR-KO mice were significantly increased compared with those in WT mice. These data support our hypothesis that a mutation in the CFTR gene can affect the antioxidant defenses in the lung and may contribute to the exaggerated inflammatory response observed in CF.

Animals↗
PubMed1983

Effects of hypotonic, isotonic, and hypertonic fluids on thoracic duct lymph flow.

To test whether whole-body lymph flow responses to vascular volume loading depend on osmolality, we measured left thoracic duct lymph flow rate and protein concentration, plasma protein concentration, plasma osmolality, hematocrit, and arterial and venous pressures in pentobarbital-anesthetized, acutely nephrectomized dogs. Hypo- (100 mosmol), iso- (309 mosmol), and hypertonic (600 mosmol) saline, isotonic lactated Ringer solution, and 5% glucose in lactated Ringer solution (580 mosmol) were infused into the jugular vein (20 ml/kg per infusion over 5 min at 30-min intervals). Changes in blood, interstitial, and cellular volumes were calculated from the infused volume and from the hematocrit and plasma osmolality. The hypotonic fluid increased lymph flow about half as much as the isotonic fluid, whereas the hypertonic fluids increased lymph flow about twice as much as the isotonic infusions. Responses appeared independent of the osmotic agent, because hypertonic NaCl was as effective as hypertonic glucose in increasing lymph flow. Responses were not altered appreciably after lowering arterial pressure by 25 mmHg. The major finding of this study is that for every condition we explored, the excess lymph flow over 30 min (ELF in ml X kg-1 X 30 min-1) correlated with the change in interstitial fluid volume (delta ISFV in ml/kg); ELF = 0.076 delta ISFV (r = 0.909). These data suggest that cellular fluid that enters the interstitium is equally effective in increasing thoracic duct lymph flow as is vascular fluid that filters into the interstitium.

Animals↗
PubMed2001

Proteomics as the tool to search for lung disease markers in bronchoalveolar lavage.

Most lung disorders are known to be associated to considerable modifications of surfactant composition. Numerous of these abnormalities have been exploited in the past to diagnose lung diseases, allowing proper treatment and follow-up. Diagnosis was then based on phospholipid content, surface tension and cytological features of the epithelial lining fluid (ELF), sampled by bronchoalveolar lavage (BAL) during fiberoscopic bronchoscopy. Today, it appears that the protein content of ELF displays a remarkably high complexity, not only due to the wide variety of the proteins it contains but also because of the great diversity of their cellular origins. The significance of the use of proteome analysis of BAL fluid for the search for new lung disease marker proteins and for their simultaneous display and analysis in patients suffering from lung disorders has been examined.

Animals↗
PubMedDate not supplied

Quantitative assessment and repeatability of chlorine in exhaled breath condensate.

BACKGROUND: Airway condition is presumably reflected in epithelial lining fluid (ELF). Exhaled breath condensate (EBC) has been used as a surrogate marker of the composition of ELF. OBJECTIVES: This study aimed at assessing the technical repeatability of chlorine measurements in EBC and comparing two separate condensators (Ecoscreen and R Tube regarding recovery and repeatability. Furthermore, the association between condensate recoveries and variations in the airway status were scrutinized. METHODS: EBC was collected using two condensators from 10 healthy volunteers. In addition, 13 asthmatic patients produced EBC with or without an added resistance of 5 cm H2O (Res5), applied to the outflow tract of Ecoscreen. All tests were done in random order. Chlorine levels (analyzed by a coulometric technique) in EBC served as a tool for investigation. RESULTS: Chlorine was measurable in all samples. The coefficient of repeatability of chlorine measurements was <10%. Chlorine levels were higher in EBC obtained from R Tube (p < 0.001), and differences in recoveries and variability in chlorine levels were presumably related to technical differences in the condensators and not to the repeatability of chlorine measurements per se. Air-flow-dependent chlorine levels were obtained from healthy volunteers. Application of Res5, recruiting additional alveoli, resulted in increased recovery of the EBC volume, but not of chlorine, from those that had the most pronounced airway obstruction (p = 0.05). CONCLUSION: We conclude that by employing a sensitive analysis technique, chlorine is repeatedly measurable in EBC. We suggest that the bulk of chlorine in EBC originates from large airways and not from the alveolar area. Both condensators were comparable regarding repeatability but differed regarding chlorine recovery.

Adult↗
PubMed1999

Changes in collagen turnover in early acute respiratory distress syndrome.

Pulmonary fibrosis is a well-recognized feature of acute respiratory distress syndrome (ARDS). Using immunoassays of bronchoalveolar lavage (BAL), fluid we investigated the synthesis of type I procollagen (PICP) and type I/II collagen degradation products (COL2-3/4C(short) neoepitope) in patients with ARDS, acute lung injury (ALI), subjects with risk factors for ARDS (At Risk), and healthy/ventilated control subjects. PICP was measured by ELISA as a marker of type I procollagen synthesis. COL2-3/4C(short) neoepitope was measured by an inhibition ELISA as a marker of collagenase degradation of type I/II collagen. BAL was performed initially within 48 h of ventilation (Day 1) and then subsequently on Day 4. Dilution of epithelial lining fluid (ELF) was corrected for by plasma urea comparison. Increased PICP levels were observed in the ELF from ARDS and ALI subjects on Day 1 compared with subjects At Risk (median values, 124.9 and 95.0 ng/ml versus 38.0 ng/ml, respectively, p < 0.0005). By contrast, the levels of COL2-3/4C(short) neoepitope were significantly reduced in the subjects with ARDS versus the At Risk subjects (13.22 ng/ml versus 32.33 ng/ml, p < 0.0005). This translated into a greatly increased PICP:COL2-3/4C(short) ratio in the subjects with ARDS (p < 0.0001). There was a significant decline in the PICP level in the subjects with ARDS between Days 1 and 4 (n = 15, p < 0.05). Linear regression analysis showed a significant association between PICP and lung injury score in the subjects with ARDS (p = 0.01). Our data suggests an early shift in balance between type I collagen synthesis and degradation by collagenase. The resultant increase in type I collagen would favor matrix deposition and the development of pulmonary fibrosis in the lungs of subjects with ARDS.

Adolescent↗
PubMed2000

The effects of chronic alcohol abuse on pulmonary glutathione homeostasis.

The incidence and severity of the acute respiratory distress syndrome (ARDS) is increased in critically ill patients with a prior history of chronic alcohol abuse; however, the specific mechanisms responsible for this association are unknown. Recently, we determined that chronic ethanol ingestion in rats decreased the alveolar epithelial lining fluid (ELF) concentration of the antioxidant glutathione (GSH), which is a characteristic finding in patients with ARDS. However, the effects of chronic alcohol abuse on the human alveolar epithelium are essentially unknown. Therefore, as a first step we asked if chronic alcohol abuse, independent of other comorbid conditions, decreases the concentration of GSH in the human lung. We determined that otherwise healthy chronic alcoholics had significantly decreased ELF concentrations of GSH compared with nonalcoholic control subjects (79 micromol [48 to 118 micromol] versus 576 micromol [493 to 728 mmol], p < 0.001). Furthermore, the percentage of GSH in the oxidized form was higher in the chronic alcoholics (9.8% [2.2 to 14.8%] versus 2.8% [0.4 to 4.0%] p = 0.05), indicative of increased utilization of GSH. This is the first report that chronic alcohol abuse alters GSH homeostasis in the human lung, and suggests a potential mechanism by which chronic alcohol abuse predisposes susceptible patients to develop ARDS.

Alcoholism↗
PubMed1989

Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis.

Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine, GSH), a sulfhydryl-containing tripeptide produced by most mammalian cells, is an efficient scavenger of toxic oxidants, including hydrogen peroxide, an oxidant that plays a major role in the oxidant burden placed on the epithelial surface of the lower respiratory tract in chronic inflammatory states. GSH is present in the epithelial lining fluid of the normal lower respiratory tract, where it is thought to play a major role in providing antioxidant protection to the epithelial cells. In this regard, we hypothesized that the lower respiratory tract of patients with IPF may be chronically depleted of this antioxidant, thus leading to an increased susceptibility of lung epithelial cells to oxidant injury. To evaluate this concept, the concentration of glutathione was determined in the epithelial lining fluid of the lower respiratory tract of 15 patients with IPF and compared to that of 19 normal subjects. Strikingly, whereas ELF glutathione concentrations were high in normal subjects (429 +/- 34 microM), a fourfold decrease was found in patients with IPF (97 +/- 18 microM, p less than 0.001). In the context of the known oxidant burden present in the lower respiratory tract of patients with IPF, these observations of a "GSH deficiency" in IPF ELF suggest that there is a marked oxidant-antioxidant imbalance at the alveolar surface of these persons, thus increasing the susceptibility to the severe epithelial cell damage characteristic of this disease.

Adult↗
PubMed1992

Increased levels of bronchoalveolar lavage fluid interleukin-6 in preterm ventilated infants after prolonged rupture of membranes.

This study investigated the effect of prolonged rupture of the amniotic membranes (PROM) and probable maternal or fetal sepsis without PROM on the newborn preterm airway. Bronchoalveolar lavage fluid (BALF) was obtained from 38 infants in the first day of life and analyzed for number of white cells and concentration of interleukin-6 (IL-6). The volume of lung epithelial lining fluid (ELF) was estimated using the urea dilution technique. Infants with PROM (n = 13) and those with sepsis (n = 8) had higher total numbers of white cells in BALF compared with infants without PROM or sepsis (n = 17) (55 and 44 versus 7 x 10(4) white cells, p less than 0.01). Uncorrected and urea-corrected IL-6 concentrations were also higher in the two groups (18.5 and 30.8 versus 5.0 fmol/ml BALF, p less than 0.01; 157.7 and 444 versus 88.5 fmol/ml ELF, p less than 0.05). There was a significant correlation between BALF white cells and uncorrected IL-6 concentrations (rs = 0.78, p less than 0.0001). Detectable serum C-reactive protein in newborn infants was associated with increased levels of IL-6 in BALF (42.2 versus 11.8 fmol/ml BALF, p less than 0.05). We conclude that PROM is associated with airway inflammation and raised levels of IL-6 in neonatal lung fluid within the first 24 h of life and that this may initiate a systemic stress response.

Bacterial Infections↗
PubMed1993

Soluble and cellular markers of T cell activation in patients with pulmonary sarcoidosis.

We have characterized the activation state of T cells in the bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) from patients with sarcoidosis, to obtain more information about their mechanisms of activation. We analyzed the expression of activation markers (CD25, HLA-DR, Leu-8, and two recently defined markers, CD69 and CD27) on T cells by two-color flow cytometry. We also measured the levels of soluble CD27 and soluble CD25 in nonconcentrated BALF and in serum by ELISA. We found that most T cells in BALF from patients, but not in the peripheral blood, expressed CD69, whereas they did not express CD27. The phenotype (CD69+CD27-) of most BALF T cells and the coexpression of CD69 with HLA-DR and/or VLA-1 indicates that they are in a state of recent and persistent activation. We confirmed previous findings of expression of CD25, HLA-DR, and Leu-8 by T lymphocytes in BALF from patients. We also confirmed increased levels of soluble CD25 in the serum from these patients. The levels of sCD27 and sCD25 in the epithelial lining fluid (ELF) were calculated on the basis of urea in BALF and serum. They were increased in the patients compared with control subjects. In both patients and control subjects, levels in ELF were higher than in the peripheral blood. This indicates shedding of sCD27 (and sCD25) in the lung compartment, which likely contributes to levels in the serum. It is known that in vitro CD27+ cells become CD27- after repeated stimulation and that CD27- cells, after restimulation, do not shed sCD27.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗