Lung Tissue Concentrations Research Articles

Cholinergic Regulation of Hamster Pulmonary Neuroendocrine Cell Calcitonin

The lung content of the peptide hormone calcitonin (iCT) has been localized to discrete and clustered pulmonary neuroendocrine cells. We have undertaken a study of the effect of the autonomic ganglionic agent nicotine on the iCT of hamster lung. The acute subcutaneous administration of nicotine raised serum iCT, while lung tissue concentration of the hormone changed reciprocally to that of the serum. One week following right-sided vagotomy, total (left plus right side) iCT levels decreased following nicotine; the concentration of iCT on the denervated right lung was more markedly decreased than that from the left lung. Hamster serum levels of iCT were significantly reduced following thyroid ablation. As in the intact animals, the subsequent subcutaneous injection of nicotine to these animals raised serum iCT. Further pharmacological evaluations revealed that subcutaneously administered nicotinic cholinergic antagonists, but not muscarinic cholinergic antagonists, prevented the nicotine-evoked increase in serum iCT. Furthermore, the subcutaneous injection of acetylcholine was found to mimic the effect noted for nicotine; this was also abolished by prior administration of a nicotinic antagonist, but not by a muscarinic antagonist. The present study suggests that the nicotinic effect on pulmonary iCT secretion is ganglionically mediated, presumably via vagal innervation of the pulmonary neuroendocrine cells.

PYY-like material and its spatial relationship with NPY, CGRP and 5-HT in the lung of the Syrian golden hamster

We investigated the presence of peptide YY, neuropeptide Y, calcitonin gene-related peptide and serotonin in the hamster lung by radioimmunoassay, high performance liquid chromatography and immunocytochemistry. Lung-tissue concentrations of peptide YY and neuropeptide Y were 1.3 +/- 0.2 and 2.5 +/- 0.2 pmol/g wet weight, respectively. These two closely related pancreatic peptides were demonstrated in separate peaks with high performance liquid chromatography. The peptide YY appeared fragmented as immunoreactive peptide YY eluted primarily late in the gradient but showed additional peaks early in the gradient. Peptide YY-like immunoreactivity (PYY-LI) was predominantly observed in one or more cells of neuroepithelial bodies in all airways peripheral to bronchioles, and in solitary neuroendocrine cells primarily located in the same peripheral areas. Neuropeptide Y-LI was seen in individual, thin nerve fibers around arteries and veins, in the airway lamina propria, and in the airway epithelium; in the latter also immunopositive nerve terminals were located. This pattern did not appear to coincide with that of calcitonin gene-related peptide-LI in epithelial nerve fibers and terminals. Peptide YY-LI, calcitonin gene-related-LI and serotonin-LI were present in cells of one and the same neuroepithelial body. However, peptide YY-LI was never found to be co-localized with calcitonin gene-related-LI or serotonin-LI, but the latter two were co-localized as previously reported.

Fluoroquinolone antimicrobial agents.

The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers' diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

Respiratory cancer in chrysotile textile and mining industries: exposure inferences from lung analysis.

In an attempt to explain the much greater risk of respiratory cancer at the same cumulative exposure in asbestos textile workers in Charleston, South Carolina, than in Quebec miners and millers, both exposed to chrysotile from the same source, 161 lung tissue samples taken at necropsy from dead cohort members were analysed by transmission electron microscopy. Altogether 1828 chrysotile and 3270 tremolite fibres were identified; in both cohorts tremolite predominated and fibre dimensions were closely similar. Lung fibre concentrations were analysed statistically (a) in 32 paired subjects matched for duration of employment and time from last employment to death and (b) in 136 subjects stratified by the same time variables. Both analyses indicated that the Quebec/Charleston ratios for chrysotile fibre concentration in lung tissue were even higher than the corresponding ratios of estimated exposure intensity (mpcf). After allowance for the fact that regression analyses suggested that the proportion of tremolite in dust was probably 2.5 times higher in Thetford Mines, Quebec, than in Charleston, the results from both matched pair and stratification analyses of tremolite fibre concentrations in lung were almost the same as for chrysotile. It is concluded that neither fibre dimensional differences nor errors in estimation of exposure can explain the higher risks of lung cancer observed in asbestos textile workers. The possible co-carcinogenic role of mineral oil used in the past in asbestos textile plants to control dust provides an alternative hypothesis deserving consideration.

Enoxacin concentrations in lung tissue

For successful treatment of bacterial lung infections the administered antibiotic must reach sufficiently high concentrations in lung tissue. Therefore, the concentrations of enoxacin in this tissue were measured in ten patients requiring pulmonary surgery. In order to prevent postoperative infection, the patients received 400 mg enoxacin b.i.d. for three days. Eight h after the final dose samples of venous blood were drawn and a sample of lung tissue was removed. Using a microbiological assay, we found the following concentrations (mean +/- S.D.):serum 2.36 (+/- 0.65) mg/l, lung 6.48 (+/- 1.54) mg/kg. With the HPLC-technique the corresponding values method were 2.37 (+/- 0.80) mg/l and 7.41 (+/- 3.01) mg/kg. Thus concentrations of enoxacin in lung tissue are about three times higher than the corresponding serum concentrations.

DETECTION OF REACTIVE FREE RADICALS IN FRESH COAL MINE DUST AND THEIR IMPLICATION FOR PULMONARY INJURY <xref ref-type="fn" rid="fn1"><sup>*</sup></xref>

Freshly ground and aged anthracite and bituminous coal samples were investigated by electron spin resonance (ESR) spectroscopy to detect the presence, concentration and reactivity of free radicals. Freshly ground anthracite coal produced greater concentration of free radicals than the bituminous coal, and the radical reactivity was also greater for the anthracite. The reactivity of the newly produced free radicals in the anthracite dust correlated with the dust's toxicity. Furthermore, similar coal-based free radicals were detected in the lung tissue of autopsied coal miners, suggestive of persistent reactivity by the embedded coal dust leading to the progressive disease process. Results of the studies on the severity of coal workers' pneumoconiosis (CWP) and free radical concentration in lung tissue support this hypothesis.

Mineral fiber concentration in lung tissue of mesothelioma patients in Finland.

The mineral fibers in lung tissue samples of 19 mesothelioma patients and 15 randomly selected autopsy cases were analyzed using low-temperature ashing, scanning electron microscopy (SEM) and x-ray microanalysis. The fiber concentration ranged from 0.5 to 370 million fibers per gram of dry tissue in the mesothelioma group and from less than 0.01 to 3.2 million fibers per gram of dry tissue in the autopsy group. In 80% of the mesothelioma patients and in 20% of the autopsy cases, the fiber concentration exceeded 1 million fibers per gram of dry tissue. Amphibole asbestos fibers predominated in both groups, and only a few chrysotile fibers were found. In the lungs of six mesothelioma patients, anthophyllite was the main fiber type. The overall analytical precision of sample preparation and fiber counting with SEM was 22%.

Associations between high chromium and nickel concentrations in lung tissue and lung cancer : Kollmeier H, Seemann J, Muller K-M et al. Bundesanstalt fur Arbeitsschutz, D-4600 Dortmund. Prax Klin Pneumol 1988;42:142-8

Associations between high chromium and nickel concentrations in lung tissue and lung cancer : Kollmeier H, Seemann J, Muller K-M et al. Bundesanstalt fur Arbeitsschutz, D-4600 Dortmund. Prax Klin Pneumol 1988;42:142-8

Serum and tissue trace metal levels in lung cancer.

Copper, zinc, magnesium, calcium and iron were measured in serum and lung tissue - tumor mass and histologically nonneoplastic tissue - from lung cancer patients and compared with serum concentrations in healthy subjects and control lung tissue obtained from patients with nonmalignant lung disease. Lung cancer patients showed a significant increase in serum Cu and Cu/Zn ratio levels and decrease in serum Zn and Fe concentrations. These findings were correlated with TNM stage of the disease, but not with histologic type of tumor. Malignant lung tissue showed a higher level of Cu, Ca, Mg, and Cu/Zn ratio and lower Zn level than that found in control samples, as well as an increase in Cu, Mg and Cu/Zn ratio concentrations with regard to histologically nonneoplastic tissue samples from the same patient. Tissue concentration of trace metals was not significantly influenced either by histologic type of tumor or clinical TNM stage. Significant correlation coefficients between serum and tissue trace metal levels were not found.

Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress

The physiological significance of the enzyme indoleamine 2,3,-dioxygenase (IDO) (EC 1.13.11.17), which consumes superoxide anion ( O 2 • ) , is not known. Since this enzyme is found in high concentrations in lung tissue, we examined the possibility that IDO may protect against chemically induced oxidative stress in the lung. The induction of IDO by bacterial lipopolysaccharide (LPS) was found to be 20-fold in the mouse and 4-fold in the rat, but did not confer protection against paraquat-induced pulmonary toxicity. Moreover, paraquat, when dosed to rats or mice, did not induce pulmonary IDO activity. An elevation in the intracellular O 2 • concentration was sought by incubating lung slices with 5 m m diethyldithiocarbamate (DDTC) (to inhibit SOD), paraquat (10 −4 m), or methylene blue (10 −4 m) or under an atmosphere of 100% oxygen. These attempts did not enhance the IDO activity in lung slices prepared from control or LPS-treated rats and mice. There was also no evidence that the uptake of an IDO substrate, tryptophan, was limiting for IDO activity in rat and mouse lung slices. We have concluded in the case of rats and mice that the pulmonary IDO activity, even following induction, is too low for O 2 • to be the rate-limiting factor. For this reason IDO cannot act as a protective enzyme by scavenging O 2 • in the lung of these species. However, in the rabbit, a species comparatively resistant to paraquat- and oxygen-induced lung damage, pulmonary IDO activity is 170 times that of rats or mice. IDO activity in rabbit lung slices was increased 4-fold by incubation with 5 m m DDTC and 10-fold by incubation with methylene blue (10 −4 m). However, paraquat (10 −4 m and oxygen (100% atmosphere) were able to enhance IDO activity (5-fold) only when SOD had previously been inhibited. We have concluded that in the rabbit lung IDO is able to scavenge O 2 • and therefore has the potential to act as a protective enzyme in this species.

Spiramycin concentrations in lung tissue.

Spiramycin concentrations in lung tissue were studied in patients undergoing pulmonary surgical procedures. The first group of six patients received 500 mg spiramycin iv 16 h before surgery and 500 mg at anaesthetic induction (total 1 g). The second group of six patients received three doses of 500 mg spiramycin iv 24, 16 and 8 h before surgery, and 500 mg at anaesthetic induction (total 2 g). Samples were taken from lung tissue, pleura, fat tissue and muscle. In group 1, the mean lung tissue concentration of spiramycin was 1.15 +/- 0.14 mg/kg and 7.99 +/- 2.02 mg/kg in group 2 (P less than 0.02). The differences in concentration in pleura, fat tissue and muscle samples between treatment groups 1 and 2 were not statistically significant.

The effect of lung concentrations of glutathione and vitamin E on the pulmonary toxicity of 3-methylindole.

The relative roles of tissue glutathione and vitamin E concentrations in the pneumotoxicity of 3-methylindole were studied. Thirty-two goats were divided into four groups and pretreated with (i) vitamin E + cysteine, (ii) vitamin E + diethylmaleate, (iii) cysteine, and (iv) diethylmaleate to vary tissue concentrations of glutathione and (or) vitamin E. Lung tissue concentrations of glutathione, vitamin E, and cytochrome P-450 were measured after pretreatments in four of eight animals in each group. Groups pretreated with cysteine had higher glutathione levels in the lung than those of diethylmaleate-pretreated goats. Goats receiving vitamin E had significantly higher concentrations of vitamin E than unsupplemented groups. After pretreatments the other four goats in each group were challenged with 3-methylindole (0.03 g/kg body weight) by intrajugular infusion. The severity of lung lesions was evaluated and scored by gross and microscopic examination at 72 h after infusion. 3-Methylindole-induced lung lesions were severe when tissue glutathione was reduced and were mild when tissue glutathione was induced. Enhancement of tissue vitamin E did not significantly affect 3-methylindole toxicity. These results indicate that the initial toxicological event is likely to be the result of binding of 3-methylindole free radical covalently to cellular protein rather than lipid peroxidation.

The penetration of ofloxacin into lung tissue.

After a single oral 600 mg dose, ofloxacin concentrations were measured in lung tissue, whole blood and plasma in 11 patients undergoing thoracotomy for a bronchial malignancy. To correct for blood contamination in the tissue samples, the tissue haemoglobin content was measured using a method based on the binding of haemoglobin by haptoglobin. Ofloxacin concentrations in plasma and whole blood did not differ significantly. The calculated blood content in the tissue samples was 0.12 +/- 0.05 ml/g lung tissue. After correction for blood admixture, the mean lung tissue concentration 2 h after administration of ofloxacin was 17.7 +/- 9.2 micrograms/g. At the same time the mean plasma concentration was 8.7 +/- 4.2 mg/l (P less than 0.02). The high concentration of ofloxacin obtained in lung tissue does not result from the preparation technique. After a single 600 mg dose the tissue concentrations proved to exceed MIC values for most pathogens frequently involved in respiratory tract infections.

Spiramycin concentrations in the human respiratory tract: a review.

Spiramycin has exceptionally good distribution properties, especially in respiratory tract tissues and fluids. Three hours after a single oral dose of 3 g spiramycin, the serum concentration ranged from 1.6 to 2.8 mg/l and the reported half-life was approximately 8 h. Studies of lung tissue concentrations showed that high pulmonary levels were achieved after a loading dose of 3 g; the levels were higher after multiple doses and reached approximately 30 to 45 mg/kg in lung tissue and 6.5 to 36 mg/kg in bronchial mucosa; in bronchial secretions and in sputum the concentrations of spiramycin ranged from 1.5 to 7.3 mg/l (after 1 g, multiple doses). In upper respiratory tract tissues and fluids, high levels of spiramycin were reached as well: 8 to 13 mg/kg in sinus mucosa; 15 to 29.5 mg/kg in tonsils or adenoids.

Pulmonary edema after Escherichia coli peritonitis correlates with thiobarbituric-acid-reactive materials in bronchoalveolar lavage fluid.

We developed a new model of acute lung injury caused by live Escherichia coli peritonitis in guinea pigs. Arterial blood gas determinations, arterial blood pressure, and white blood cell counts were monitored serially for 12 h after the injection of either 2 x 10(9) E. coli J96 or saline. Lung water, albumin concentration in bronchoalveolar lavage fluid (BALF) and in lung tissue, WBC counts in BALF, and thiobarbituric-acid-reactive materials (TBARM) in plasma, lung tissue, and BALF were examined. Increased TBARM might be associated with pulmonary injury and are produced either by the generation of lipoperoxides secondary to oxygen-free radicals or as metabolic byproducts of prostanoid metabolism. Lung tissue sections were studied by light microscopy. E. coli peritonitis, as compared with control animals, caused significant peripheral neutropenia, histopathologic evidence of lung inflammation, acidosis, and hypotension. The wet-to-dry lung ratio was increased in the peritonitis group when compared with that in the control group (p less than 0.01). Pulmonary edema in the peritonitis group was associated with significantly increased albumin concentrations in BALF and lung tissue. We report the new finding of increased TBARM concentrations in BALF after E. coli peritonitis (p less than 0.01 and p less than 0.05, respectively). In contrast, plasma TBARM concentrations were unchanged. The levels of TBARM in the BALF correlated significantly with both lung water (p less than 0.01) and lung tissue albumin concentration (p less than 0.01). The measurement of elevated TBARM in BALF may allow acute lung injury to be detected. We conclude that this model may be useful for further studies of acute lung injury caused by E. coli peritonitis.

Determination of gold accumulation in human tissues caused by gold therapy using x-ray fluorescence analysis

Human autopsy tissues from five patients with rheumatoid arthritis, who had been treated with aqueous solutions of gold and from an untreated control cadaver with the same disease, were analysed by x-ray fluorescence spectrometry using a conventional Si(Li) detection system. The gold and zinc concentrations of tissues were determined and compared to some results available in the literature. Correlation has been found between Zn and Au concentrations in heart, lung, kidney and liver tissues.

Pharmacokinetics of enoxacin and its penetration into bronchial secretions and lung tissue.

Pharmacokinetic data were obtained from four healthy volunteers after oral administration of a single 400 or 600 mg dose of enoxacin. Enoxacin was absorbed quickly and absorption was increased when enoxacin was ingested after a meal. Renal clearance of enoxacin and 4-oxo-enoxacin decreased after simultaneous administration of probenecid. In addition, pharmacokinetic parameters of enoxacin and its 4-oxo metabolite were determined for plasma and sputum from 19 patients treated with enoxacin, 400 or 600 mg bd, for a respiratory tract infection. The half-life of both enoxacin and 4-oxo-enoxacin was 5-6 h; during treatment with 400 and 600 mg bd, the plasma concentrations exceeded MIC values for most bacteria isolated in respiratory tract infections, including most Pseudomonas aeruginosa strains; Streptococcus pneumoniae was an exception. Diffusion from plasma to sputum was approximately 100%. Of an ingested dose, 60-65% was recovered in the urine in 24 h. In a third study, a single 600 mg dose of enoxacin was given to 15 patients undergoing thoracotomy. Subsequent lung tissue concentrations of enoxacin were significantly higher than plasma concentrations at the same time after ingestion.

Interstitial distribution of charged macromolecules in the dog lung: a kinetic model.

A mathematic model was constructed to investigate conflicting physiologic data concerning the charge effect of continuous capillaries to macromolecules in the lung. We simulated the equilibration kinetics of lactate dehydrogenase (MR 4.2 nM) isozymes LDH 1 (pI = 5.0) and LDH 5 (pI = 7.9) between plasma and lymph using previously measured permeability coefficients, lung tissue distribution volumes (VA) and plasma concentrations (CP) in lung tissue. Our hypothesis is that the fixed anionic charges in interstitium, basement membrane, and cell surfaces determine equilibration rather than charged membrane effects at the capillary barrier, so the same capillary permeability coefficients were used for both isozymes. Capillary filtration rates and protein fluxes were calculated using conventional flux equations. Initial conditions at baseline and increased left atrial pressures (PLA) were those measured in animal studies. Simulated equilibration of isozymes over 30 h in the model at baseline capillary pressures accurately predicted the observed differences in lymph/plasma concentration ratios (CL/CP) between isotopes at 4 h and equilibration of these ratios at 24 h. Quantitative prediction of isozyme CL/CP ratios was also obtained at increased PLA. However, an additional cation selective compartment representing the surface glycocalyx was required to accurately simulate the initial higher transcapillary clearances of cationic LDH 5. Thus experimental data supporting the negative barrier, positive barrier, and no charge barrier hypotheses were accurately reproduced by the model using only the observed differences in interstitial partitioning of isozymes without differences in capillary selectivity.

Increased chromium and nickel content in lung tissue and bronchial carcinoma.

In 25 random autopsies, chromium (Cr) and nickel (Ni) in lung tissue and regional lymph nodes were analysed by means of flameless atomic absorption spectrometry (AAS). The subjects originate from Bochum in the Ruhr District, which is defined as a particular pollution area with locally high Cr and Ni emissions. The subjects examined from Bochum (BO) and vicinity have Cr and Ni concentrations about 5 and 6 times higher than those in a previous series form Münster (MS) and vicinity (outside the particular pollution area), which is used for comparison purposes. BO and MS data showed an age-dependent increase of chromium and nickel in the lung, and in both data sets as well as in the combined, the Cr and Ni values showed extremely high correlations (r greater than 0.9). The Cr and Ni concentrations (BO) in lung (3.47 +/- 2.53 micrograms Cr/g, 1.09 +/- 1.43 micrograms Ni/g dry weight) and lymph node tissue (6.30 +/- 3.72 micrograms Cr/g, 1.00 +/- 0.58 micrograms Ni/g dry weight) do not show any correlation. The BO data contained four cases of bronchial carcinoma (all male), three of which showed pulmonary Cr and Ni concentrations that lie clearly above the predicted level. One case of bronchial carcinoma had extremely high Cr and Ni values; an occupational exposure as dental laboratory technician is taken into consideration.

Elimination of paraquat.

There is a striking discrepancy between the efficacy of the kidneys, haemodialysis and haemoperfusion in removing paraquat from the body and the poor prognosis of paraquat poisoning even when the blood and urine concentrations (which are good indices of concentrations in lung and other tissues) are very low. Extracorporeal elimination techniques have been used world-wide in paraquat poisoning. Do they remove paraquat effectively? Certainly. Do they increase the survival rate? Probably not. The reason being that when these techniques of elimination are initiated, potentially lethal concentrations of paraquat have already been attained in the highly vascular tissues of vital organs and in pneumocytes. The data presented here suggest that the successful treatment of paraquat poisoning will not be achieved by modification of toxicokinetics.