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PubMed2002

Pharmacodynamic modeling of clarithromycin against macrolide-resistant [PCR-positive mef(A) or erm(B)] Streptococcus pneumoniae simulating clinically achievable serum and epithelial lining fluid free-drug concentrations.

The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug C(p) maximum of 2 micro g/ml, t(1/2) of 6 h; in ELF, C(ELF(total)) maximum of 35 micro g/ml, t(1/2) of 6 h; C(ELF(free)) maximum of 14 micro g/ml, t(1/2) of 6 h). Starting inocula were 10(6) CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of > or =90% (AUC(0-24)/MIC ratio, > or =61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC(0-24)/MIC ratios of > or =30.5 to 38) resulted in a 1.2 to 2.0 log(10) CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of < or =8% (AUC(0-24)/MIC ratio, < or =17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 micro g/ml. However, mef(A) isolates for which MICs are > or =16 micro g/ml along with erm(B) may result in bacteriological failures.

Anti-Bacterial Agents↗
PubMed2004

Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state.

We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.

Adult↗
PubMed2005

Increased microvascular blood content is an early event in colon carcinogenesis.

BACKGROUND: Increased premalignant epithelial microvascular blood content is a common theme in neoplastic transformation; however, demonstration of this phenomenon in colon carcinogenesis has been stymied by methodological limitations. Our group has recently developed a novel optics technology, four dimensional elastic light scattering fingerprinting (4D-ELF), which allows examination of the colonic mucosal architecture with unprecedented accuracy. In this study, we utilised 4D-ELF to probe the preneoplastic colonic microvasculature. METHODS: Colonic mucosal blood content was assessed by 4D-ELF at serial preneoplastic time points from azoxymethane (AOM) treated Fisher 344 rats and age matched control animals. We also examined the pretumorigenic intestinal mucosa of the MIN mouse, and compared with wild-type mice. Finally, in a pilot study, we examined superficial blood content from the endoscopically normal mid transverse colon in 37 patients undergoing screening colonoscopy. RESULTS: In the AOM treated rat model, augmentation of superficial mucosal and total mucosal/superficial submucosal blood supply preceded the appearance of aberrant crypt foci (ACF) and temporally and spatially correlated with future ACF occurrence. These findings were replicated in MIN mice. The 4D-ELF based results were corroborated with immunoblot analysis for haemoglobin on mucosal scrapings from AOM treated rats. Moreover, 4D-ELF analysis of normal human colonic mucosa indicated that there was a threefold increase in superficial blood in patients who harboured advanced adenomas. CONCLUSION: We report, for the first time, that blood content is increased in the colonic microvasculature at the earliest stages of colon carcinogenesis. These findings may provide novel insights into early biological events in colorectal carcinogenesis and have potential applicability for screening.

Adenoma↗
PubMed1994

Concentration of amoxycillin and clavulanate in lung compartments in adults without pulmonary infection.

BACKGROUND: The efficacy of an antibiotic is usually predicted from serum levels and MIC90 values for likely pathogens, but in the lung tissue concentrations may be more informative. This study compares concentrations of amoxycillin and clavulanate in serum, epithelial lining fluid (ELF), alveolar macrophages, and bronchial mucosa in 15 adults. METHODS: Amoxycillin 500 mg and clavulanic acid 250 mg were given 1-2 hours before diagnostic bronchoscopy for haemoptysis or radiological abnormality. Mucosal biopsy samples were taken from macroscopically normal sites, alveolar macrophages harvested by lavage, and ELF volume derived from urea concentrations in bronchial lavage fluid and blood. Amoxycillin was assayed by inhibition of growth of Micrococcus lutea, and clavulanate (in serum, ELF, and bronchial mucosa) by inhibition of growth of Klebsiella pneumoniae; in macrophages clavulanate was measured by high performance liquid chromatography. RESULTS: The median concentrations in serum were 6.90 mg/l for amoxycillin and 5.25 mg/l for clavulanate. The median bronchial mucosal concentration of amoxycillin was 2.99 mg/l and of clavulanate was 1.65 mg/l; the median concentrations in ELF were 0.89 and 0.96 mg/l, and in macrophages 0 and 0.76 mg/l, respectively. In macrophages amoxycillin levels were undetectable in 10 of 14 subjects (71%); by contrast, only 6 of 14 subjects (43%) had no detectable clavulanate. CONCLUSIONS: Clavulanate levels exceeded quoted MIC90 values (around 0.25 mg/l) for Legionella pneumophila both in ELF and in macrophages. Amoxycillin-clavulanate may therefore have a clinical role in infections with Legionella pneumophila.

Adult↗
PubMed1992

Biological interactions and potential health effects of extremely-low-frequency magnetic fields from power lines and other common sources.

Various different effects of ELF magnetic fields have been reported to occur at the cellular, tissue, and animal levels. Certain effects, such as the induction of magnetophosphenes in the visual system, have been established through replication in several laboratories. Many other effects, however, have not been independently verified or, in some cases, replication efforts have led to conflicting results. A substantial amount of experimental evidence indicates that the effects of ELF magnetic fields on cellular biochemistry, structure, and function can be related to the induced current density, with a majority of the reported effects occurring at current density levels in excess of 10 mA/m2. These effects, therefore, occur at induced current-density levels that exceed the endogenous currents normally present in living tissues. From this perspective, it is extremely difficult to interpret the results of recent epidemiological studies that have reported a correlation between cancer incidence and exposure to 50-Hz or 60-Hz magnetic fields with very low flux densities. The levels of current density induced in tissue by occupational or residential exposure to these fields are, in nearly all circumstances, significantly lower than the levels found in laboratory studies to produce measurable perturbations in biological functions. There is a clear need for additional epidemiological research to clarify whether exposure to ELF magnetic fields is, in fact, causally linked to cancer risk. Laboratory animal studies conducted under controlled conditions are also needed to determine whether ELF magnetic fields can initiate or promote tumors. In addition, more studies of both a theoretical and experimental nature are needed to elucidate the molecular and cellular mechanisms through which low-intensity magnetic fields can influence living systems. A growing body of evidence indicates that cell membranes play a key role in the transduction and amplification of ELF field signals. Elucidation of the physical and biochemical pathways that mediate these transmembrane signaling events will represent a major advance in our understanding of the molecular basis of magnetic field effects of biological systems.

Bedding and Linens↗
PubMed1997

NO2-induced generation of extracellular reactive oxygen is mediated by epithelial lining layer antioxidants.

Nitrogen dioxide (NO2) is an environmental oxidant that causes acute lung injury. Absorption of this aqueous insoluble gas into the epithelial lining fluid (ELF) that covers air space surfaces is, in part, governed by reactions with ELF constituents. Consequently, NO2 absorption is coupled to its chemical elimination and the formation of ELF-derived products. To investigate mechanisms of acute epithelial injury, we developed a model encompassing the spatial arrangements of the lung surface wherein oxidation of cell membranes immobilized below a chemically defined aqueous compartment was assessed after NO2 exposures. Because aqueous-phase unsaturated fatty acids displayed minimal NO2 absorptive activity, these studies focused on glutathione (GSH) and ascorbic acid (AH2) as the primary NO2 absorption substrates. Results demonstrated that membrane oxidation required both gasphase NO2 and aqueous-phase GSH and/or AH2. Membrane oxidation was antioxidant concentration and exposure duration dependent. Furthermore, studies indicated that GSH- and AH2-mediated NO2 absorption lead to the production of the reactive oxygen species (ROS) O-2. and H2O2 but not to .OH and that Fe-O2 complexes likely served as the initiating oxidant. Similar results were also observed in combined systems (GSH + AH2) and in isolated rat ELF. These results suggest that the exposure-induced prooxidant activities of ELF antioxidants generate extracellular ROS that likely contribute to NO2-induced cellular injury.

Animals↗
PubMed1987

Normal alveolar epithelial lining fluid contains high levels of glutathione.

The epithelial cells on the alveolar surface of the human lower respiratory tract are vulnerable to toxic oxidants derived from inhaled pollutants or inflammatory cells. Although these lung cells have intracellular antioxidants, these defenses may be insufficient to protect the epithelial surface against oxidants present at the alveolar surface. This study demonstrates that the epithelial lining fluid (ELF) of the lower respiratory tract contains large amounts of the sulfhydryl-containing antioxidant glutathione (GSH). The total glutathione (the reduced form GSH and the disulfide GSSG) concentration of normal ELF was 140-fold higher than that in plasma of the same individuals, and 96% of the glutathione in ELF was in the reduced form. Compared with nonsmokers, cigarette smokers had 80% higher levels of ELF total glutathione, 98% of which was in the reduced form. Studies of cultured lung epithelial cells and fibroblasts demonstrated that these concentrations of reduced glutathione were sufficient to protect these cells against the burden of H2O2 in the range released by alveolar macrophages removed from the lower respiratory tract of nonsmokers and smokers, respectively, suggesting that the glutathione present in the alveolar ELF of normal individuals likely contributes to the protective screen against oxidants in the extracellular milieu of the lower respiratory tract.

Adult↗
PubMed1992

Solute exchange between the plasma and epithelial lining fluid of rat lungs.

Although the transport of solutes from air spaces to plasma has been extensively studied, comparatively little information is available concerning solute equilibration between the plasma and the epithelial lining fluid (ELF) of air-filled lungs. In the present study, 11 lipophobic indicators varying in molecular mass between 22 and 80,000 Da were injected intravenously and/or intramuscularly into anesthetized rats in a manner designed to keep blood concentrations constant. The animals were killed by rapid lavage of their lungs at various intervals up to 120 min after the injections had been made. Indicator concentrations in the bronchoalveolar lavage (BAL) fluid and plasma were determined, and BAL-to-plasma concentration ratios were calculated for indicators that were injected (exogenous: [14C]urea, 22Na+, [3H]mannitol, 99mTc-diethylenetriaminepentaacetate (a chelate), 51Cr-(ethylene dinitrilo)tetraacetate (a chelate), 113mIn-transferrin, human albumin, and Evans blue-labeled rat albumin) and those that were already present from the plasma and ELF (unlabeled urea, rat albumin, and rat transferrin). Leakage of exogenous indicators in the blood into the BAL fluid was observed during the lavage procedure. Leakage of [14C]urea, 22Na+, and [3H]mannitol exceeded that of the heavier solute molecules. Diffusion of proteins and the labeled chelates into the ELF before lavage occurred at similar rates, suggesting vesicular transport. Use of rapidly diffusible solutes such as urea for determining dilution of ELF by BAL should be accompanied by intravascular injections of labeled solutes to correct for diffusion from the blood during lavage. Alternatively, labeled chelates or serum proteins can be used to estimate dilution of ELF by BAL. Interstitial sampling may be inevitable if the epithelium has been injured before lavage.

Animals↗
PubMed1992

Intravenous recombinant secretory leukoprotease inhibitor augments antineutrophil elastase defense.

Secretory leukoprotease inhibitor (SLPI), a 12-kDa serine antiprotease, normally protects the upper airway epithelial surface from attack by neutrophil elastase (NE). In the context that a variety of inflammatory lung diseases are characterized by large neutrophil burdens with resultant high levels of NE in the lung, recombinant SLPI (rSLPI), a molecule identical to natural SLPI, may be an effective means to augment the anti-NE protective screen of the lung. To determine whether intravenous rSLPI will augment respiratory tract and epithelial surface levels of SLPI and anti-NE capacity, rSLPI was administered intravenously to sheep and SLPI levels were quantified in plasma, lung lymph (as a measure of lung interstitial levels), lung epithelial lining fluid (ELF), and urine. rSLPI (1 g) was administered over 10 min, and after 30 min plasma levels of SLPI were 8 microM and decreased with a half-life of 1.8 h. Lymph SLPI levels paralleled the plasma levels: 4 h after infusion the lymph-to-plasma ratio was 0.8. ELF SLPI levels paralleled the lymph levels: 4 h after infusion the ELF-to-lymph ratio was 0.3. Western analysis demonstrated intact SLPI in lymph and ELF, and functional analysis showed increases in lymph and ELF anti-NE capacity that paralleled the levels of SLPI. As might be expected from a protein with a molecular mass of 12 kDa, urine excretion was high, with 20% of the SLPI excreted over 5 h. However, if the rate of infusion was slowed, SLPI excretion decreased significantly, with a 3-h infusion associated with 9% excretion and a 12-h infusion associated with less than 0.2% excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Antioxidant activity in bronchoalveolar lavage fluid from patients with lung cancer.

Glutathione (GSH) is one of the key components of the lung antioxidant defenses. Chronic smokers have higher GSH concentrations in their epithelial lining fluid than do nonsmokers. The aim of this study was to compare antioxidant concentrations in epithelial lining fluid (ELF) from nonsmokers, smokers with, and smokers without non-small-cell lung cancer. The study found that GSH in ELF from patients with lung cancer was significantly greater than in ELF from smokers and nonsmokers, at 1,485.5 +/- 208, 544 +/- 97.6 microM, and 339.3 +/- 112 microM, respectively (p < 0.05). In contrast, superoxide dismutase (SOD) was lower in ELF from patients with lung cancer than in that from smokers and nonsmokers, at 3.52 +/- 0.99, 30.82 +/- 8.2, and 43.91 +/- 10.1 U/ml, respectively (p < 0.05). Spontaneous superoxide anion release by adherent alveolar macrophages (AM) showed no difference between smokers with and without lung cancer. These data indicate that patients with lung cancer have marked modifications in their ELF antioxidant defenses by comparison with those of smokers. It is difficult to distinguish whether changed antioxidant status is a primary disturbance involved in the cancer process or whether it is a consequence of the neoplastic changes in malignancy.

Adult↗
PubMed1999

Comparison of two methods of diagnostic lung lavage in ventilated infants with lung disease.

The methods of nonbronchoscopic lung lavage used for collection of samples of epithelial lining fluid (ELF) in intubated patients are poorly standardized and incompletely validated. In infants with lung disease requiring ventilatory support, we evaluated two techniques of small volume saline lavage for the collection of a specimen suitable for pulmonary surfactant analysis. We aimed to compare apparent origin of the return fluid obtained by each method, equivalence and agreement of the estimates of measured pulmonary surfactant concentration, and the relative strength of association between surfactant indices and lung dysfunction. Fifty-three contemporaneous paired samples of lung lavage fluid suitable for surfactant analysis were collected from 31 infants using tracheal aspirate (TA, 4 x 0.5 ml saline), and then nonbronchoscopic bronchoalveolar lavage (NB-BAL, 3 x 1 ml/kg). Return fluid from TA had higher mean ELF concentration of total protein and IgA secretory component (SC), and a lower surfactant protein A (SP-A) concentration than NB-BAL, indicating that the TA lavage was sampling ELF more proximally in the tracheobronchial tree (protein: TA 7.7 versus NB-BAL 4.7 mg/ml; SC: 21 versus 1.8 microgram/ml; SP-A: 9.8 versus 19 microgram/ml; all p < 0.01). Mean concentration of surfactant indices in ELF differed only for SP-A, but for all indices, paired values showed poor agreement on Bland-Altman analysis, highlighting the potential imprecision associated with small volume lung lavage. TA return fluid yielded estimates of surfactant indices which were at least equivalent to NB-BAL in prediction of the severity of lung dysfunction. We conclude that NB-BAL return fluid has more distal origin, but analysis of TA fluid may have equal validity in the estimation of indices of pulmonary surfactant. The results of individual estimates of ELF constituents in a single sample of lavage fluid should be interpreted with caution, even when standardized sampling techniques are employed.

Bronchoalveolar Lavage↗
PubMed1999

Validity of markers of dilution in small volume lung lavage.

Definitive analysis of solute concentrations in lung lavage fluid involves the use of a marker of dilution to correct for variable recovery of epithelial lining fluid (ELF), but the question of the most appropriate dilutional marker remains unresolved. In lavage fluid collected from infants with lung disease and healthy control subjects, we examined ELF concentration of protein, albumin, sphingomyelin (SM), and IgA secretory component (SC), and critically appraised the relative validity of SC and urea as dilutional markers in the context of lung infection and lung injury. Protein, albumin, and SM were found not to be valid dilutional markers, as their ELF concentration varied significantly between the diseased, recovering, and normal lung. Differences in concentration were noted in both tracheal aspirate samples (TA, 4 x 0.5 ml) and nonbronchoscopic bronchoalveolar lavage fluid (NB-BAL, 3 x 1 ml/kg), but were not uniform (e.g., TA-disease versus control: albumin 2.8 versus 0.68 mg/ml, SM 45 versus 16 microgram/ml, both p < 0.05; NB-BAL-disease versus recovery: protein 8.1 versus 4.8 mg/ml, albumin 2.9 versus 1. 4 mg/ml, both p < 0.05). Overall, SC concentrations in ELF were not different between the diseased and normal lung, but in the NB-BAL samples, significantly higher SC concentration was noted in viral bronchiolitis and pneumonia than in noninfective lung diseases. No clear evidence of additional influx of urea into lavage fluid in association with epithelial disruption was found in the diseased lung. Comparative analysis of SC and urea revealed no difference in TA samples, but in NB-BAL specimens, urea best standardized the lavage concentration of surfactant indices to correspond to the degree of lung dysfunction as indicated by oxygenation index. We conclude that SC and urea, but not protein, albumin, or SM, are valid dilutional markers with which to estimate ELF recovery during small volume lung lavage. Urea appears a more appropriate choice in return fluid derived from the distal tracheobronchial tree, and SC should not be used in the context of lung infection.

Albumins↗
PubMed1988

High levels of transforming growth factor-beta are present in the epithelial lining fluid of the normal human lower respiratory tract.

Transforming growth factor-beta (TGF-beta), a mediator capable of modulating a broad range of effects on the behavior of many normal cells, was found in high concentrations in the epithelial lining fluid (ELF) of the normal human lower respiratory tract. Although plasma contained small amounts of TGF-beta, the concentrations of TGF-beta in normal ELF were in the 200 to 300 pM range, more than 15-fold higher. This ELF TGF-beta had similar physical characteristics to purified human platelet TGF-beta, competed with platelet TGF-beta for its receptor on A549 carcinoma cells, and stimulated the anchorage-independent growth of NRK cells in soft agar in the presence of epidermal growth factor. Furthermore, ELF TGF-beta suppressed diploid lung fibroblast proliferation in a dose-dependent fashion similar to platelet TGF-beta. In the context of these observations and with the known biologic properties of this molecule, TGF-beta in ELF has the potential to play a role in a variety of cellular processes in the lower respiratory tract.

Adult↗
PubMed1990

Changes in surfactant in bronchoalveolar lavage fluid after hemithorax irradiation in patients with mesothelioma.

Experimental studies have shown that the surfactant system of the lung is affected shortly after irradiation. It is unclear, however, whether surfactant plays a role in the pathogenesis of radiation pneumonitis. In the present study surfactant components (saturated phosphatidylcholine, surfactant protein A, phosphatidylglycerol, and phosphatidylinositol) and other phospholipids of bronchoalveolar lavage fluid (BAL) were studied in four patients with pleural mesothelioma before and during hemithorax irradiation (70 Gy) as well as zero, 1, 2, 3, and 4 months following irradiation. The concentrations of these same components and of soluble proteins were also estimated in the epithelial lining fluid (ELF) using urea as a marker of dilution. After radiotherapy, the concentrations of the surfactant components in ELF decreased to 12 to 55% of the control values before radiation, whereas the concentration of sphingomyelin in ELF increased ninefold. There were small changes in the other phospholipids. The concentration of soluble protein in ELF increased sevenfold. The minimum surface activity of crude BAL increased from 12 +/- 4 to 32 +/- 6 mN/m, and that of the sediment fraction of BAL increased from 7 +/- 4 to 22 +/- 6 mN/m, p less than 0.001. The protein-rich supernatant fraction of BAL from irradiated lung had a inhibitory effect on normal surfactant. There were significant correlations between the increasing severity of the radiologic changes on the one hand and, on the other, the saturated phosphatidylcholine/sphingomyelin ratio (p less than 0.001), the concentrations of soluble protein (p less than 0.001), and the concentrations of the surfactant components (p less than 0.02-0.001) in ELF.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Leukotriene B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis.

Persistent neutrophil infiltration into the airways of patients with cystic fibrosis (CF) results in lung destruction. Eicosanoid lipid mediators, particularly leukotriene B4 (LTB4), may play a role in neutrophil influx and activation. We compared the eicosanoid content of epithelial lining fluid (ELF) obtained by bronchoalveolar lavage (BAL) from 17 patients with CF and 10 healthy subjects. LTB4 was the predominant eicosanoid in the CF airway (16.7 +/- 9.1 ng/ml ELF in CF versus 0.5 +/- 0.1 ng/ml ELF in healthy subjects). Prostaglandins (PG) and thromboxane (TX) were also elevated in CF (PGE2, 8.5 +/- 2.2; PGF2 alpha, 6.0 +/- 2.0; and TXB2, 14.0 +/- 3.0 ng/ml ELF) compared with healthy subjects (PGE2, 0.4 +/- 0.2; PGF2 alpha, 0.5 +/- 0.2; and TXB2, 1.2 +/- 0.4 ng/ml ELF). We also developed a protocol for the storage and subsequent analysis of BAL fluid that assures accurate and reproducible measurements of these eicosanoids. BAL samples stored for up to 8 months retain greater than 80% of their original eicosanoid content if the BAL fluid is immediately treated with methanol, concentrated, and stored at -70 degrees C without further purification. These data suggest that CF airways contain sufficient amounts of LTB4 both to recruit additional neutrophils into the airways and to stimulate neutrophils to release their injurious products. Therapies aimed at interfering with the production or action of LTB4 may be beneficial in CF and other lung diseases with a significant neutrophil response.

Adolescent↗
PubMed1987

Comparison of alpha-1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha-1-antitrypsin phenotype null-null before and during alpha-1-antitrypsin augmentation therapy.

The null-null phenotype of alpha 1-antitrypsin (alpha 1AT), a phenotype characterized by no detectable alpha 1AT in serum, presents a rare opportunity to examine the contribution of alpha 1AT to the antineutrophil elastase protection of the lower respiratory tract. The subject, a 35-yr-old lifetime non-smoker with moderate emphysema, has been characterized as having alpha 1AT serum levels of zero resulting from the homozygous inheritance of alpha 1AT genes that do not express detectable alpha 1AT mRNA transcripts. Evaluation of the antineutrophil elastase capacity of the null-null serum showed it was less than 5% of normal, whereas that of the epithelial lining fluid (ELF) of the lower respiratory tract was 13% of normal. However, after 60 mg/kg of intravenously administered alpha 1AT augmentation therapy once weekly for 4 wk, the serum alpha 1AT levels peaked at greater than 300 mg/dl, trough levels just prior to the next infusion were 81 +/- 2 mg/dl, and the average serum level integrated for the month of infusions was 138 mg/dl. Consistent with this serum rise in alpha 1AT, the serum antineutrophil elastase capacity increased in parallel(r = 0.98). Importantly, evaluation of the ELF 2 and 6 days after infusion demonstrated increases of alpha 1AT levels (range, 1.4 to 2.1 microM) and antineutrophil elastase capacity (range, 1.6 to 2.5 microM), values within the lower range of normal. Furthermore, the lung ELF alpha 1AT levels rose in direct proportion to the serum alpha 1AT levels, and the ELF antineutrophil elastase capacity rose in direct proportion to the ELF alpha 1AT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Limitations of using urea to quantify epithelial lining fluid recovered by bronchoalveolar lavage.

The quantitation of substances in the epithelial lining fluid (ELF) of the lower respiratory tract, as obtained by bronchoalveolar lavage (BAL), is not precise because of the variable dilution of the ELF by the instilled lavage fluid. It has been reported that the absolute concentration of proteins in ELF can be determined by using the ratio of urea concentration in BAL fluid to that in serum as a method to calculate the volume of ELF recovered by BAL. Furthermore, it has been suggested that the error caused by diffusion of urea into the instilled lavage fluid can be minimized by instilling only 100 ml (5 X 20 ml) of saline rather than 300 ml (6 X 50 ml). We tested the validity of this method by collecting and individually analyzing aliquots from 2 different BAL protocols--a 100-ml (5 X 20 ml) BAL and a 300-ml (6 X 50 ml) BAL--performed in 6 healthy, nonsmoking subjects. Total protein, albumin, and urea were measured in each aliquot and in pooled fluid from each BAL procedure, and urea was measured in serum. In the 300-ml BAL, total protein and albumin concentrations tended to decrease progressively from the second to the sixth aliquots. In contrast, the urea concentration increased progressively from the first to the sixth aliquots. The concentration of albumin in ELF, calculated from the concentration of urea and albumin in each BAL aliquot, tended to decrease in each successive aliquot, becoming significant by the fourth aliquot.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed2002

A role for vascular endothelial growth factor in acute and resolving lung injury.

We have previously reported, in patients with acute respiratory distress syndrome (ARDS), elevated plasma levels of vascular endothelial growth factor (VEGF) that became reduced in those who recovered. To examine the potential effect of VEGF on the epithelial side of the alveolar-capillary membrane, we compared VEGF levels in the epithelial lining fluid (ELF) of the same 40 patients with ARDS, and in 28 patients at risk of ARDS. We measured intrapulmonary VEGF levels in 23 patients on Days 1 and 4 after admission to the intensive therapy unit and related these levels to recovery. ELF from subjects with ARDS contained lower levels of VEGF than did ELF from at-risk subjects (1,076 and 7,674 pg/ml, respectively, p = 0.0004) and increased ELF levels at Day 4 were associated with recovery (p = 0.001). Alveolar macrophages from subjects with ARDS produced significantly less VEGF than those from at-risk subjects (6.3 and 13.0 pg/ml, respectively, p = 0.005). Similarly, alveolar neutrophils from subjects with ARDS produced significantly less VEGF than those at risk (13.9 and 31.5 pg/ml, respectively, p = 0.03). ELF VEGF levels inversely correlated with Lung Injury Score (p = 0.003). These studies suggest that VEGF in the alveolar space may reflect the development of, and recovery from, acute lung injury in a manner opposite to that in plasma.

Adolescent↗