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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.
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OBJECTIVE: To evaluate the distribution in lung tissue of ulifloxacin, the active metabolite of prulifloxacin, a new once-daily fluoroquinolone administered orally in a single 600mg dose. DESIGN: Open-label, randomised study. PATIENTS: Twenty-seven patients (25 males, 2 females; mean age 65.7 years [range 49-79 years]) with a lung neoplasm requiring lobectomy or pneumonectomy. METHODS: Patients were randomly assigned to five treatment groups and received a single oral dose of prulifloxacin 600mg at 2, 4, 6, 12 or 24 hours preoperatively. During surgery, blood and healthy lung (based on macroscopic appearance) samples were collected at the same time. Ulifloxacin concentrations in plasma and lung tissue were determined by a validated reversed-phase high-performance liquid chromatography assay. Lung tissue ulifloxacin concentrations were adjusted for blood contamination, by measuring haemoglobin in the supernatant of each tissue sample and applying a corrective equation. RESULTS: Ulifloxacin concentration in lung tissue exceeded plasma concentration at every timepoint. Following administration of prulifloxacin 600mg, the overall mean corrected lung/plasma ratio over the 24-hour period was 6.9 (range 1.2-14.1). When sampling intervals were assessed, the corrected lung/plasma ratios were 7.5 (2 hours after dosing), 6.3 (4 hours), 4.3 (6 hours), 7.0 (12 hours) and 9.2 (24 hours). The mean corrected lung/plasma area under the concentration-time curve ratio was 6.3, demonstrating the ability of the drug to penetrate lung tissue and confirming the high exposure of this target tissue to ulifloxacin. However, the limitation of the lung tissue sampling method and the high interpatient variability should be considered. Over the 24-hour period, the concentrations of ulifloxacin in lung tissue were higher than the minimum inhibitory concentration (MIC) values for pathogens frequently involved in community-acquired respiratory tract infections. CONCLUSION: Lung tissue penetration data may have a supportive value when considered jointly with MICs and efficacy results. The findings from this lung penetration study could explain the efficacy of once-daily prulifloxacin 600mg observed in clinical trials conducted in patients with exacerbation of chronic bronchitis.
The objective of this study was to investigate the effects of 3-aminobenzamide (3-AB) on tissue damage in lung after hind limb ischemia-reperfusion (I/R), by assessing blood biochemical assay and histopathological analysis. Thirty-five adult Wistar rats were divided into five groups. After application of anaesthesia both hind limbs were occluded with tourniquets. Following ischemia period for 60 min, the tourniquets were removed allowing reperfusion for 120 min. The IR group received 0.5 ml of saline while the IR+AB group received 3-AB (10 mgkg(-1) intraperitoneally). The IR+DMSO group was given 0.5 ml 10% DMSO 30 min before the removal of the tourniquets. The control group received 0.5 ml saline and the AB group received 0.5 ml 3-AB (10 mgkg(-1)) intraperitoneally. At the end of the reperfusion period, mid-line sternotomy was performed. Blood samples were taken with cardiac puncture. Bronchoalveolar lavage (BAL) of the left lung was performed with saline. Right lung was preserved for histopathological evaluation and biochemical examination. Lung tissue malondialdehyde (MDA) and 3-nitrotyrosine levels, myeloperoxidase and Na+/K+ ATP-ase activities, wet to dry weight ratios, and plasma and BAL fluid MDA levels were determined. Histopathological evaluation was performed, too. Hind limb IR caused significant increase in the lung tissue 3-NT to total tyrosine ratio (p = 0.014), wet to dry weight ratio (p = 0.000), MPO activity (p = 0.000), and MDA levels (p = 0.000). The animals treated with 3-AB showed a statistically significant decrease in these values (p < 0.05). Na+/K+ ATP-ase activity which was found to be decreased significantly with IR, returned to near normal levels with 3-AB treatment. Additionally, lung tissue injury in IR group characterized with moderate interstitial congestion and neutrophil infiltration, showed remarkable amelioration following 3-AB treatment. Our results strongly support the view that poly(ADP-ribose) polymerase (PARP) plays an important role in the inflammatory process in hind limb I/R-induced lung injury and as a PARP inhibitor, 3-AB seems to have a potential to treat this inflammatory injury.
The rate of collagen synthesis was measured in vivo and in vitro in both normal and damaged mouse lung tissue. Acute lung damage was induced by the administration of butylated hydroxytoluene (BHT). The production of labeled hydroxyproline, following the administration of labeled proline, was used as an index of collagen production. Total and labeled hydroxyproline in normal and damaged lung tissue were solubilized equally following digestion with purified collagenase. Assuming that the extent of hydroxylation was not altered, this indicated that hydroxyproline was an accurate index of collagen content and production in damaged as well as normal lung tissue. The quantities of hydroxyproline formed at various times both in vivo and in vitro were calculated from the specific activity of free proline in lung tissue. The specific activity of free proline in normal and damaged lung tissue remained constant in vivo for at least 90 minutes after the intravenous injection of labeled proline. Hydroxyproline production was a linear function of time for up to 90 minutes in vivo and three hours in vitro. The in vivo rate of hydroxyproline production was significantly greater than the in vitro rate in lung tissue from similarly treated mice. The difference ranged from five-fold in normal lung tissue to eight-fold in lung tissue damaged by the administration of BHT. Comparable differences were seen between the in vivo and in vitro rates of non-collagen protein synthesis. Despite these differences in rates, the percentage of total protein synthesis committed to collagen in vivo was the same as in vitro in normal lung, and identical increases were seen in damaged lung. These data show that in vivo rates of both collagen and non-collagen protein synthesis are significantly higher than those measured in mouse lung tissue in vitro. Although the relative increases in collagen synthesis that occur in response to lung damage are larger in vivo, measurements of collagen synthesis in vitro do accurately reflect the general changes that accompany acute lung damage.
Lung cancer is a leading cause of mortality in Taiwan. We hypothesised that high susceptibility to DNA damage in the target organ acts as a risk biomarker for the development of lung cancer. To verify this hypothesis, the aromatic/hydrophobic DNA adduct levels of non-tumorous adjacent lung tissues from 73 primary lung cancer patients and 33 non-cancer controls were evaluated by 32P-postlabelling assay. Wilcoxon rank sum test showed that DNA adduct levels in lung cancer patients (49.58+/-33.39 adducts/10(8) nucleotides) were significantly higher than those in non-cancer controls (18.00+/-15.33 adducts/10(8) nucleotides, P<0.001). The DNA adduct levels among lung cancer and non-cancer samples were not influenced by smoking behaviour and cigarette consumption. Our data also showed that the polymorphisms of cytochrome P4501A1 (CYP1A1) Msp1, glutathione S-transferase M1 (GSTM1) and the combination of both genetic polymorphisms were not related to the DNA adduct levels. Interestingly, positive association between CYP1A1 protein expression and DNA adduct levels was found when CYP1A1 protein expression in lung specimens from lung cancer patients was examined by immunohistochemistry. Multivariate linear regression analysis indicated that the DNA adduct level was not associated with gender, smoking behaviour, or genetic polymorphisms of CYP1A1 and GSTM1. Moreover, multivariate logistic regression analysis showed that persons with high DNA adduct levels (>48.66 adducts/10(8) nucleotides) had an approximately 25-fold risk of lung cancer compared with persons with low DNA adduct levels (</=48.66 adducts/10(8) nucleotides). In conclusion, DNA adduct levels in lung tissue may be a more reliable lung cancer susceptibility biomarker than DNA adduct levels in leucocytes. In addition, higher susceptibility to DNA damage in lung cancer patients may partly play a role in the development of lung cancer.
Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in human disease processes, including pulmonary disorders. However, the role of the Fas/FasL system in acute lung injury (ALI) and in the acute respiratory distress syndrome (ARDS) is poorly defined. Accordingly, we investigated both the soluble and cellular expression of the Fas/FasL system in patients with ALI or ARDS. The major findings are summarized as follows. First, the soluble expression of the Fas/FasL system was assessed in undiluted pulmonary edema fluid and simultaneous plasma. Pulmonary edema fluid obtained from patients with ALI or ARDS (n = 51) had significantly higher concentrations of both soluble Fas (27 ng/ml; median; P < 0.05) and soluble FasL (0.125 ng/ml; P < 0.05) compared to control patients with hydrostatic pulmonary edema (n = 40; soluble Fas, 12 ng/ml; soluble FasL, 0.080 ng/ml). In addition, the concentrations of both soluble Fas and soluble FasL were significantly higher in the pulmonary edema fluid of the patients with ALI or ARDS compared to simultaneous plasma samples (soluble Fas, 16 ng/ml; soluble FasL, 0.058 ng/ml; P < 0.05), indicating local release in the lung. Higher soluble Fas concentrations were associated with worse clinical outcomes. Second, cellular expression of the Fas/FasL system was assessed by semiquantitative immunofluorescence microscopy in lung tissue obtained at autopsy from a different set of patients. Both Fas and FasL were immunolocalized to a greater extent in the patients who died with ALI or ARDS (n = 10) than in the patients who died without pulmonary disease (n = 10). Both proteins were co-expressed by epithelial cells that lined the alveolar walls, as well as by inflammatory cells and sloughed epithelial cells that were located in the air spaces. Semiquantitative immunohistochemistry showed that markers of apoptosis (terminal dUTP nick-end labeling, caspase-3, Bax, and p53) were more prevalent in alveolar wall cells from the patients who died with ALI or ARDS compared to the patients who died without pulmonary disease. These findings indicate that alveolar epithelial injury in humans with ALI or ARDS is in part associated with local up-regulation of the Fas/FasL system and activation of the apoptotic cascade in the epithelial cells that line the alveolar air spaces.
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The slope of the lung tissue CO2 dissociation curve and the rate of storage of CO2 in the lung tissue were studied at 22 degrees C and at 37 degrees C in 21 isolated, bloodless dog lungs with a total of 465 separate observations. Results at the two temperatures were similar. The slope of the tissue dissociation curve of lung tissue at a PCO2 of 40 torr was approximately 0.3 ml CO2 X 100 g wet tissue-1 X torr-1. Normally, this storage was 90% complete in about 5 seconds. After carbonic anhydrase inhibition by acetazolamide, the total storage capacity was unchanged, but the rate at which storage occurred decreased significantly, so that it took about 25 seconds for 90% of the storage to be completed.
OBJECTIVES: Injury causes the disruption of homeostatic cell-cell interactions and epithelial regeneration is part of the threshold response. Due to the lack of a good animal model for the investigation of these mechanisms, the kinetics of cell proliferation after injury to the human respiratory tract are poorly understood. METHODS: To create a better model of human bronchioloalveolar epithelial regeneration, we engrafted adult human lung tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Then the lung tissue was studied at various times up to 20 weeks after implantation. RESULTS: The xenografts of bronchiolar epithelium showed characteristic features, including positivity for specific human antigens, and extensive regeneration was observed within 8 weeks after implantation. In addition, a few alveolar type II epithelial cells expressing prosurfactant protein C were detected in some areas. The distal alveolar spaces were filled with protein-rich material and were markedly dilated. Abundantly ciliated secretory epithelium, which was similar to normal adult bronchiolar epithelium, was observed within 16 weeks after implantation in the mice. All of the human lung tissue specimens that were implanted subcutaneously into the backs of the mice developed well and remained viable for 20 weeks. Each type of adult human lung epithelial cell showed a different mode of proliferation. Bronchiolar epithelial cells proliferated earlier, with MIB-1 labeling of up to 20% of the cells in the grafts at 8 weeks, while alveolar type II cells proliferated later, with labeling of up to 5% of graft cells at 12 weeks. CONCLUSION: This model seems to allow adult human lung epithelial regeneration to be investigated in vivo over the long term.
The mechanical properties of lung tissue are important contributors to both the elastic and dissipative properties of the entire organ at normal breathing frequencies. A number of detailed studies have shown that the stress adaptation in the tissue of the lung following a step change in volume is very accurately described by the function t-k, for some small positive constant k. We applied step increases in length to lung parenchymal strips and found the ensuing stress recovery to be extremely accurately described by t-k over almost 3 decades of time, despite the quasi-static stress-length characteristics of the strips being highly nonlinear. The corresponding complex impedance of lung tissue was found to have a magnitude that varied inversely with frequency. We note that this is highly reminiscent of a phenomenon known as 1/f noise, which has been shown to occur ubiquitously throughout the natural world. 1/f noise has been postulated to be a reflection of the complexity of the system that produces it, something like a central limit theorem for dynamic systems. We have therefore developed the hypothesis that the t-k nature of lung tissue stress adaptation follows from the fact that lung tissue itself is composed of innumerable components that interact in an extremely rich and varied manner. Thus, although the constant k is no doubt determined by the particular constituents of the tissue, we postulate that the actual functional form of the stress adaptation is not.
Rat lung homogenates heavily infected with Pneumocystis carinii were digested with trypsin and pronase. Pneumocystis carinii cysts were examined by light and electron microscopy, and by an indirect fluorescent antibody (IFA) technique. Cysts digested with trypsin exhibited swelling of their cell wall but stained brightly by IFA; cysts digested with pronase lost their cell wall and ability to stain by IFA. These effects were related to the concentration of the enzyme and duration of exposure. The data suggest that the antigenic determinants of P. carinii cysts reside in the cell wall.
Angiotensin-converting enzyme activity and its kinetic parameters were determined in both serum and lung tissue samples obtained from 17 patients with lung cancer and 21 control subjects, regardless of ethical base. The specific activities for cancerous and normal lung tissues were 67.2 +/- 27.3 (mean +/- SD) U/g protein and 28.5 +/- 5.4 U/g protein, respectively (P less than 0.001). Serum enzyme activity, on the other hand, was found to be higher in controls (198 +/- 42 U/L) than in patients (237 +/- 68 U/L) (P less than 0.01). The effects of chloride and zinc ions, pH and temperature on the enzyme activity were investigated as kinetic parameters in both serum and tissue samples.
1. Human lung tissue, passively sensitized with reaginic antibodies, released prostaglandins E(1), E(2) and F(2alpha) in addition to histamine and slow reacting substance (SRS-A), when exposed to the appropriate antigen. No rabbit aorta contracting substance (RCS) was detected.2. Experiments with rats and guinea-pigs showed that the release of RCS is not confined to anaphylactic reactions mediated by non-reaginic antibodies but may be a feature of anaphylaxis in guinea-pigs alone.3. Human lung tissue gently agitated with a blunt nylon rod liberated an E-type prostaglandin and RCS in addition to histamine and SRS-A.4. Human isolated bronchial muscle was contracted by RCS.5. Disodium cromoglycate antagonized the release of prostaglandins during anaphylaxis but not during agitation of human lung tissue, whereas indomethacin blocked the release of prostaglandins during agitation and anaphylaxis.6. The release of an E-type prostaglandin during anaphylaxis in human lung tissue, which inhibits the further release of histamine could be another example of the regulatory role of prostaglandins in body functions.
In many species including man, the second most abundant lipid in lung surfactant is phosphatidylglycerol (PG) which may comprise 10% of the total lipid in surfactant from mature lungs. Infants delivered before their surfactant contained a large amount of PG are at greater risk of succumbing to hyaline membrane disease. Regulation of the PG content of lung surfactant is not understood completely, but the reciprocal changes in the amount of phosphatidylinositol (PI) and PG in surfactant as the lung mature are suggestive of regulation at the level of a common precursor. The immediate common precursor of PI and PG is CDP-diacylglycerol which is found in only small amounts in most mammalian cells and likely restricts the biosynthesis of both PI and PG. It has been observed in several species that the enzymes that synthesize PI and PG compete for the limited amount of CPD-diacylglycerol and this competition is influenced by the availability of myo-inositol. We and others have presented evidence that myo-inositol availability in the developing lung may be an important factor in the regulation of lung surfactant composition. In the present investigation, myo-inositol was administered chronically to nonpregnant and to pregnant rats and the effect of this treatment on the glycerophospholipid composition of lung tissue and lung lavage was measured. In addition, the influence of myo-inositol administration to pregnant rats on the glycerophospholipid composition of lung tissue of their fetuses was investigated. The concentration of myo-inositol in adult and fetal blood was measured by gas-liquid chromatography of its trimethylsilyl derivative. For determination of glycerophospholipid composition, the total lipid extracts of lung tissues and lung lavage were separated by 2-dimensional thin-layer chromatography and quantified by lipid phosphorus assay of individual spots. The concentration of myo-inositol in the serum of pregnant rats was significantly higher than in nonpregnant rats (Tab. I, Fig. 1). Treatment of the rats with myo-inositol resulted in a significant elevation of serum concentrations of myo-inositol throughout the experimental period. Between day 18 and day 21 of the gestation there was a significant decrease in serum myo-inositol concentrations in fetuses of saline treated rats. Treatment of the pregnant dams with myo-inositol resulted in a significant elevation in fetal serum concentrations of myo-inositol on both day 18 and day 21 of gestation (Tab. I).(ABSTRACT TRUNCATED AT 400 WORDS)
Concentrations of cefpiramide (CPM) in human lung tissues were determined after 1 g intravenous bolus injection in 6 patients with lung tumors and pyothorax. Concentrations of the CPM in blood and lung tissues were determined and analyzed pharmacokinetically. Levels of CPM in the lung tissues reached 38.4 micrograms/g at 2 hours and declined to 27.7 micrograms/g in 6 hours. Levels of CPM in the lung tissues were higher than 50% of those in the serum between 100 minutes and 360 minutes after the administration of CPM.