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Penetration of clarithromycin into lung tissues from patients undergoing lung resection.

The concentrations of clarithromycin and its active principal metabolite, 14-(R)-hydroxy-clarithromycin, were determined in lung tissue obtained during lung resection and compared with concomitant concentrations in plasma. Concentrations of the parent and metabolite were determined by high-performance liquid chromatography. The 15 patients studied were given 500 mg orally every 12 h for a minimum of five doses to achieve steady-state concentrations. The mean concentrations of clarithromycin and 14-(R)-hydroxy-clarithromycin in plasma just prior to the final dose were 1.38 and 0.67 micrograms/ml, respectively, and those 4 h after the final dose (at the time of lung resection) were 1.89 and 0.80 microgram/mL, respectively. The concentrations of the parent and metabolite in lung tissue at the time of lung resection averaged 54.3 and 5.12 micrograms/g, respectively, with a mean calculated ratio of concentrations of the parent to metabolite being 11.3 in lung tissue and 2.4 in plasma. Clarithromycin and its active metabolite are extensively distributed into human lung tissue.

Adolescent↗

High frequency of K-ras mutations in normal appearing lung tissues and sputum of patients with lung cancer.

To evaluate the possible use of mutant ras as a biomarker for lung cancer, we have analyzed "normal appearing" lung tissue, lung tumor, lung metastases and sputum samples from patients with non-small cell lung cancer (NSCLC). As a control, we used lung tissue and sputum samples from patients without oncological diseases or lung disorders. Our analyses were performed with the aid of enriched PCR (EPCR), a method which enables detection of ras mutation even if present at low incidence. EPCR identified K-ras codon 12 mutations in 10% of lung tissues obtained from patients with no lung diseases, whereas the same mutation was detected in 60% of samples of normal appearing lung tissues obtained from patients with NSCLC, 62% of NSCLC tumors and 80% of metastases. Analysis of sputum samples of patients with NSCLC identified 47% to harbor mutant ras allele, whereas 12.5% of controls diagnosed with non-oncological lung diseases carried this mutation. Most of these mutations were detected with the aid of EPCR only, indicating that a minority of cells in a given sample harbor this mutation. The ability to detect K-ras codon 12 mutation in 60% of lung tissue samples and in 47% of sputum samples taken from patients with lung cancer (as compared with 10% and 12.5% of respective controls) points to the potential use of ras mutation as a biomarker for exposure and possible identification of patients who may be at higher risk of developing lung cancer.

Aged↗

Ultrastructural changes in the contralateral lung tissue following unilateral lung ischemia: an experimental study in rabbits.

PURPOSE: To investigate the acute ultrastructural changes that may occur in the contralateral nonischemic lung tissue after unilateral ischemia of a lung in a rabbit model. METHODS: The animals were divided into three main groups of eight; namely, a 2-h procedure group, a 4-h procedure group, and an 8-h procedure group. Each of these groups was further divided into two subgroups of four rabbits each; namely, a control group, given a sham operation without any ischemic insult, and an ischemia group, in which the main pulmonary arteries, the pulmonary veins, and the main bronchi of the left lungs were ligated after thoracotomy. Tissue samples were taken from the left and right lungs to examine the ultrastructural changes after 2, 4, and 8 h of ischemia. Each sample was given a semiquantitative histological injury score. Statistical analysis was done by the Mann-Whitney U-test. RESULTS: Contralateral ultrastructural damage, evident by heterochromatin in the nuclei, mitochondrial degeneration, cisternal widening of the endoplasmic reticulum, increased lipid droplets, and lysosomes, was determined by electron microscopy after unilateral lung ischemia. The contralateral lung injury was significantly correlated with the duration of ischemia. CONCLUSIONS: Unilateral lung ischemia affected the bilateral lungs in a rabbit model. Therefore, in operations such as single-lung transplantation, pulmonectomy, or lobectomy, if the procedure is unnecessarily prolonged, the contralateral lung may be damaged, which could seriously affect the prognosis of the patient.

Animals↗

Expression of intercellular adhesion molecule in lung tissues of experimental acute lung injury and the affect of Rhubarb on it.

OBJECTIVE: To approach the relation and the possible mechanism between the expression of intercellular adhesion molecule (ICAM-1) mRNA and acute lung injury (ALI) and the mechanisms of rhubarb in the prevention and treatment of the lung injury. METHODS: Lipopolysaccharide (LPS) was injected into the sublingual vein of male Wistar rats to perform ALI animal model. The rats were divided into 4 groups: LFS group, control group, rhubarb group and dexamethasone group. Macroscopic and histopathological examinations were performed and biological markers were measured for the lung specimens. The markers included lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary vascular permeability and pulmonary alveolar permeability index. Molecular hybridization method was used to determine the expression of ICAM-1 mRNA. RESULTS: In the lung tissues, the ICAM-1 mRNA expression was increased in the endothelial cells of pulmonary veins and capillaries, rhubarb and dexamethasone had the action of decreasing the expression. The light reflex value in the gray scale scanning showed that in the comparison between the LPS and the control group, the gray scale value of the lung tissues in ALI was significantly increased, thus the light reflex value was markedly decreased (P < 0.01), demonstrating the expression of ICAM-1 mRNA was increased. In comparison with the LPS group, dexamethasone and rhubarb could decrease the gray scale value of the lung tissue significantly, thus the light reflex value was elevated (P < 0.01, P< 0.05); the corresponding pathologic change of lung tissue and the biological markers of the lung injury were significantly decreased or ameliorated. CONCLUSIONS: The increase of the expression of ICAM-1 mRNA in the lung tissues of ALI plays the roles in ALI. The application of rhubarb and dexamethasone can decease the expression and ameliorate the lung damage; its mechanism is possibly via the inhibition of ICAM-1 mRNA expression.

Animals↗

Two different types of granulocyte colony-stimulating factor produced by bovine lung tissue.

Bovine lung tissue produces two different types of granulocyte colony-stimulating factor (CSF). The high molecular weight (MW) type (CSF-F) of 70,000 d by Sephadex G-100 gel filtration is only found in conditioned medium of homogenized tissue incubated in sealed glass bottles. The species of CSF exclusively stimulates CFU-C of mouse bone marrow, human bone marrow only hardly. The low MW type CSF (CSF-M) of approximately 29,000 d by gel filtration is found mainly in conditioned medium of slightly minced tissue incubated in Petri dishes. It stimulates both human and mouse CFU-C. Methods to prepare both types of CSF are described. By propagating a fibroblast cell line from bovine lung tissue it was found that fibroblasts are the source of the 70,000 d CSF. Indirect evidence suggests that macrophages produce the 29,000 d CSF species.

Animals↗

Metal concentrations in human lung tissue, with special reference to age, sex, cause of death, emphysema and contamination of lung tissue.

Nine element concentrations in the lung tissues of 2,274 autopsies were determined in Japan by atomic absorption spectrometry. The metals determined were iron, calcium, magnesium, zinc, copper, cobalt, nickel, lead, and chromium. The range, mean, standard deviation, mode and median are described for each metal. Moreover, these data were analyzed statistically, based on their sex, age, degree of lung contamination (color and the amount of particle deposition), severity of pulmonary emphysema and cause of death. Iron, calcium, magnesium, zinc, copper and cobalt concentrations in the lung tissue seemed to be affected mostly by physiological variation and the levels in the blood. On the other hand, nickel, lead and chromium concentrations might reflect environmental exposure. Chromium concentration especially increased with age and showed a significantly positive correlation with the degree of contamination and severity of emphysema.

Age Factors↗

[Effect of glucocorticoid on lung tissue and bronchus-associated lymphoid tissue of experimental granulomatous lung].

The effect of glucocorticoid on the immunological response in the delayed type hypersensitivity reaction of granulomatous disorders was investigated in order to elucidate the mechanism of glucocorticoid on the suppressive course of the reaction. Experimental pulmonary granuloma model in rats was induced by an intravenous injection of heat killed BCG, and the effects of methylprednisolone (MPSL) on the granulomatous lung tissue, bronchus associated lymphoid tissue (BALT) and the population of cells from bronchoalveolar lavage fluid (BALF) and peripheral blood were examined by the cytological and immunohistochemical methods. The pulmonary granulomatous reaction was reduced effectively by the administration of MPSL. A remarkable reduction of the number of Ia antigen positive alveolar macrophages (Ia+ A.M phi) and T lymphocytes in the granulomatous lung tissue and BALF was observed. T helper cells to non-helper cells (TH/TNH) ratio in BALF decreased remarkably. Furthermore, a reduction of Ia antigen positive macrophages (Ia+ M phi) and T cells was noted in the parafollicular area of BALT. These findings suggest that glucocorticoid may suppress the immunological activity of M phi and T cell through its inhibitory effect on the differentiation of Ia+ M phi and activated T cells, which result in the diminishment of pulmonary granulomatous reaction through the disorder of M phi - T cell interaction. On the other hand, lymphocytopenia with decreased TH/TNH ratios in peripheral blood was observed simultaneously with the reduction of the pulmonary granulomatous reaction. Thus, the mechanism of reduced pulmonary granulomatous reaction after MPSL administration may be not only due to local immunosuppression, but also to impaired systemic immune response. In addition, the disappearance of the germinal center and the reduction of surface IgM-positive cells in the follicular area of BALT occurred with the reduction of pulmonary granulomatous reaction. These results suggest that glucocorticoid also suppress the humoral immune responses in BALT during the course of delayed type hypersensitivity reaction.

Animals↗

PEEP decreases atelectasis and extravascular lung water but not lung tissue volume in surfactant-washout lung injury.

OBJECTIVE: To examine the effects of positive end-expiratory pressure (PEEP) on extravascular lung water (EVLW), lung tissue, and lung volume. DESIGN AND SETTING: Experimental animal study at a university research facility. SUBJECTS: Fifteen adult sheep. INTERVENTIONS: All animals were studied before and after saline washout-induced lung injury while ventilated with sequentially increasing PEEP (0, 7, 14, or 21 cmH(2)O). MEASUREMENTS AND RESULTS: Lung volume was determined by computed tomography and EVLW by the thermal dye dilution technique. Saline washout significantly increased lung tissue volume (21+/-3 to 37+/-5 ml/kg) and EVLW (9+/-2 to 36+/-9 ml/kg). While increasing levels of PEEP reduced EVLW (30+/-7, 24+/-8, and 18+/-4 ml/kg), lung tissue volume remained constant. Total lung volume significantly increased (50+/-8 ml/kg at PEEP 0 to 77+/-12 ml/kg at PEEP 21). Nonaerated lung volume significantly decreased and was closely correlated with the changes in EVLW ( r=0.67). In addition, a highly significant correlation was found between PEEP-induced decrease in nonaerated lung volume and decrease in transpulmonary shunt ( r=0.83). CONCLUSIONS: The main findings are as follows: (a) PEEP effectively decreases EVLW. (b) The decrease in EVLW is closely correlated with the PEEP-induced decrease in nonaerated lung volume, making EVLW a valuable bedside parameter indicating alveolar recruitment, similar to measurements of transpulmonary shunt. (c) As excess tissue volume remained constant, however, EVLW may not be suitable to reflect overall severity of lung disease

Animals↗

Mesothelioma and asbestos fiber type. Evidence from lung tissue analyses.

Lung tissue samples from 78 cases from autopsy of mesothelioma in Canada, 1980 through 1984, and from matched referents were examined by optical and analytical transmission electron microscopic study. Concentrations of amosite, crocidolite, and tremolite fibers, and of typical asbestos bodies discriminated sharply between cases and referents. The distributions of chrysotile and anthophyllite/talc fibers and of all other natural and man-made inorganic fibers (greater than or equal to 8 microns) in the two series were quite similar. Relative risk was related to the concentration of long (greater than or equal to 8 microns) amphibole fibers with no additional information provided by shorter fibers. The proportion of long fibers was much higher for amphiboles than chrysotile and, except for chrysotile, systematically higher in cases than referents. Amphibole asbestos fibers could explain most mesothelioma cases in Canada and other inorganic fibers, including chrysotile, very few. Fibrous tremolite, contaminant of many industrial minerals including chrysotile, probably explained most cases in the Quebec mining region and perhaps 20% elsewhere.

Asbestos↗

Metal concentrations in lung tissue of subjects suffering from lung cancer.

Concentrations of nine metals (Fe, Ca, Mg, Zn, Cu, Co, Ni, Pb and Cr) concentrations in lung tissues from 224 lung cancer cases were compared with those in other cases to achieve an understanding of their contribution to the development of lung cancer and the varieties after the development of cancer. Comparisons of metal concentrations in each cell type of lung cancer were also performed. All cases were collected from routine autopsies in Tokyo and Saitama, Japan. The copper concentration in tissue from lung cancers was significantly higher than that in other specimens, although calcium, magnesium, zinc and cobalt concentrations in lung cancers were significantly lower than those in other cases. There were no significant differences in the 99% intervals (excluding extremely high values for occupationally exposed cases) for chromium, nickel and lead concentrations between lung cancers and other cases, although these values were lower in lung cancers. However, in comparisons of men only, the chromium concentration, the degree of lung contamination and the severity of pulmonary emphysema in lung cancer cases were significantly higher than those in other specimens. Moreover, percentages of lung cancer in men at each degree of contamination and each severity of emphysema increased with increasing grades. Thus, this finding could be evidence that the exposure to contaminants other than chromium and nickel in the air had affected the development of lung cancer, except for occupationally exposed individuals. Therefore, almost all chromium and nickel in lung tissue might not deposit in carcinogenic forms such as hexavalent chromium or nickel subsulfide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Topographic analysis of K- ras mutations in histologically normal lung tissues and tumours of lung cancer patients.

Mutations in the K- ras gene are very common in lung tumours and are implicated in the development of lung cancer, but the timing of their occurrence remains poorly understood. We investigated K- ras mutations in cell samples microdissected by laser capture microscopy at multiple sites from lung tissue sections representing tumour tissue and matched histologically normal tissue obtained from 48 lung cancer patients. K- ras mutations were detected in cell samples from 10 of 38 (26.3%) lung adenocarcinomas and in none of the histologically normal or tumour cell samples taken from 10 lung squamous cell carcinomas. Of the K- ras mutation-positive adenocarcinomas, in 4 cases a mutation was found in only the tumour tissue, in 1 case a mutation was found only in the histologically normal tissue, and in 5 cases mutations were found in both the tumour tissue and histologically normal tissue. Among these 5 cases, 2 had identical mutations in both the tumour tissue and histologically normal tissue, 2 had 1 mutation in the tumour tissue and 2 mutations in the histologically normal tissue, 1 of which was identical to the mutation found in the tumour, and 1 case had 2 codon 12 mutations in tumour tissue and 2 mutations, in codons 9 and 11, in histologically normal tissue. These results showed that K- ras mutations are frequent in histologically normal cells taken from outside lung adenocarcinomas and suggest that some of these mutations may represent early events which could pave the way of lung carcinogenesis.

Adenocarcinoma↗

Inorganic fibres in the lung tissue of Hungarian and German lung cancer patients.

OBJECTIVE: To ascertain the lung burden of asbestos fibres in Hungarian lung cancer patients in comparison with the cumulative asbestos exposure estimated from the occupational history. METHODS: For 25 Hungarian lung cancer patients, lung tissue fibre analysis was performed by scanning transmission electron microscopy (STEM) and counting of ferruginous bodies (FBs) by light microscopy. Cumulative asbestos exposure in fibre-years was assessed from a standardised occupational history using the report "fibre years" of the German Berufsgenossenschaften. RESULTS: Median and maximum concentrations of fibres longer 5 microns per gram dry lung tissue (g dry) were 0.03 and 7.38 million fibres/g dry for chrysotile, 0.00 and 0.21 million fibres/g dry for amphibole and 0.22 and 0.62 million fibres/g dry for other mineral fibres (OMFs). The maximum values were observed in one patient for whom a high asbestos exposure was evident in advance from the occupational history. CONCLUSIONS: In comparison with reference values obtained by the same method for German patients with no indication of workplace asbestos exposure, increased concentrations of more than 0.2 million chrysotile fibres/g dry were obtained for six of the 25 Hungarian patients (24%). For one of them, the second highest estimate of a workplace exposure of 60 fibre-years and the highest tissue concentration of 7.38 million chrysotile fibres/g dry substantiate a high probability of a causal relationship to asbestos. A further comparison can be made with the results for 66 German patients treated by surgical lung resection for a disorder other than mesothelioma, mainly lung cancer. For the Hungarian lung cancer patients, similar amounts of chrysotile but distinctly lower amounts of amphibole fibres and distinctly higher amounts of OMFs were observed. A correlation between exposure estimates from occupational history and concentration of fibres in the lung tissue was observed for amphibole (Spearman: R = 0.66, P < 0.001, Pearson: R = 0.50, P = 0.01) and for chrysotile (Pearson: R = 0.48, P = 0.02).

Adult↗

Microsatellite alteration in histologically normal lung tissue of patients with non-small cell lung cancer.

Microsatellite alteration (MSA) has been observed in a fraction of non-small cell lung cancer (NSCLC). Most prior studies regarding MSA in lung cancer have usually used adjacent non-malignant lung tissues as a source of constitutional DNA. However, these normal tissues might have genetic alterations because the entire field of bronchial tree is exposed to the same carcinogenic insult. The aim of this study was to search if MSA is present in the histologically normal lung tissue of patients with NSCLC. Tumor and corresponding normal lung tissue specimens were obtained from 20 patients with NSCLC. Normal lung tissue specimens were obtained from either the opposite end of resected surgical samples or as distant from the tumor as possible. They were examined histopathologically and confirmed as normal by H-E stain. Patients' peripheral lymphocytes were used as the source for the normal DNA. Sixteen markers on 3p and 9p (nine and seven markers, respectively) were used. MSA was detected in seven of 20 (35%) histologically normal lung tissue specimens at a frequency similar to that observed in tumor tissue (eight of 20, 40%). Five cases showed MSA in both normal lung tissue and the corresponding tumor. In these five cases, MSA in normal lung tissue was detected at the same microsatellite markers which MSA was detected in the corresponding tumor. The number and size of novel bands in normal lung tissue was identical to that in tumor tissue except in one case. In which case, the same pattern of MSA was found in both normal lung tissue and corresponding tumor tissue at two markers. However, at one marker, while one identical novel band was detected in normal lung tissue and corresponding tumor tissue, another novel band was found only in tumor tissue. In two of 12 patients whose tumor was negative for the presence of MSA, MSA was detected in normal lung tissue. These results indicate that genetic alterations are widely distributed in the lung tissue of patients with lung cancer and provide considerable support for the field cancerization theory. Screening for MSA in resected normal lung tissue might be a new method to identify patients at high risk for developing second primary lung cancers.

Adult↗

Reperfusion liver injury induces down-regulation of eNOS and up-regulation of iNOS in lung tissues.

OBJECTIVES: Acute lung injury and inflammation can occur after hepatic ischemia/reperfusion (I/R). Little is known regarding the possible role of nitric oxide synthase expression in this complex type of lung injury. METHODS: Real-time polymerase chain reactions and immunohistochemistry were used to assess the mRNA and protein expression of eNOS and iNOS in lung tissue after I/R challenge to the liver. Ischemia was induced by clamping the hepatic artery and portal vein for 40 minutes. After flow was restored, the liver was reperfused for 300 minutes. Blood samples were collected to assay three inflammatory parameters: tumor necrosis factor (TNF)-alpha, hydroxyl radicals, and NO. Lung lavage samples were assayed for protein and myeloperoxidase. The expression of eNOS and iNOS in lung tissues (n = 3) was also evaluated after I/R challenge to the liver. The iNOS inhibitor aminoguanidine was also tested in this I/R model. RESULTS: Reperfusion of the liver produced increased blood concentrations of TNF, hydroxyl radicals, and NO (P < .001; n = 8). Bronchial lavage fluids showed higher levels of protein and myeloperoxidase in the I/R than in the sham-treated group (P < .01). eNOS expression was down-regulated and iNOS expression up-regulated in I/R lung tissues (n = 3). The iNOS inhibitor aminoguanidine (10 mg/kg) significantly attenuated the lung injury. CONCLUSIONS: I/R injury to the liver induced lung injury involving systemic inflammatory responses and iNOS expression. Administration of aminoguanidine significantly attenuated the injury, suggesting that iNOS expression may play a critical role in lung injury induced by I/R of the liver.

Animals↗

[Fatty acid composition of lipids in lung tissue of patients with lung cancer].

The fatty acid (FA) spectrum of lung tissue fragments was studied versus distance of malignant cells from lesion focus in lung cancer patients. Decreased polyunsaturated FA levels in all samples were attributed, chiefly, to linoleic, (linoleic-new) and eicosatrienoic acid deficiency. Both in tumor tissue and areas of intensive cell proliferation, accumulation of monounsaturated C18:1 and C15:1 fatty acids, low C20:4(6 and C 20:5(3 and an FA with 19 carbon atoms were detected. The total concentration of (-6 and (-3 series fatty acids was relatively low, too, the deficit of the latter being remarkably low. Those changes are likely to be related to certain peculiarities of the structure and functions of tumor cells.

Adult↗

Mechanical interactions between collagen and proteoglycans: implications for the stability of lung tissue.

Collagen and elastin are thought to dominate the elasticity of the connective tissue including lung parenchyma. The glycosaminoglycans on the proteoglycans may also play a role because osmolarity of interstitial fluid can alter the repulsive forces on the negatively charged glycosaminoglycans, allowing them to collapse or inflate, which can affect the stretching and folding pattern of the fibers. Hence, we hypothesized that the elasticity of lung tissue arises primarily from 1) the topology of the collagen-elastin network and 2) the mechanical interaction between proteoglycans and fibers. We measured the quasi-static, uniaxial stress-strain curves of lung tissue sheets in hypotonic, normal, and hypertonic solutions. We found that the stress-strain curve was sensitive to osmolarity, but this sensitivity decreased after proteoglycan digestion. Images of immunofluorescently labeled collagen networks showed that the fibers follow the alveolar walls that form a hexagonal-like structure. Despite the large heterogeneity, the aspect ratio of the hexagons at 30% uniaxial strain increased linearly with osmolarity. We developed a two-dimensional hexagonal network model of the alveolar structure incorporating the mechanical properties of the collagen-elastin fibers and their interaction with proteoglycans. The model accounted for the stress-strain curves observed under all experimental conditions. The model also predicted how aspect ratio changed with osmolarity and strain, which allowed us to estimate the Young's modulus of a single alveolar wall and a collagen fiber. We therefore identify a novel and important role for the proteoglycans: they stabilize the collagen-elastin network of connective tissues and contribute to lung elasticity and alveolar stability at low to medium lung volumes.

Animals↗

Asbestos exposure among Finnish lung cancer patients: occupational history and fiber concentration in lung tissue.

In a series of 65 surgically treated lung cancer patients, past exposure to asbestos was evaluated by personal interviews, and by scanning electron microscopy analyses of the mineral fibers in lung tissue. Lung tissue samples of 17 autopsied male office workers were analyzed as referents. According to occupational history, 37% of the lung cancer patients had definite or probable, 31% possible, and 32% unlikely exposure to asbestos. The fiber concentration in the lung tissue ranged from < 0.1 to 65 million fibers per gram dry tissue in the lung cancer group, and from < 0.1 to 0.8 million fibers per gram dry tissue in the reference group. In 26% of the lung cancer patients, but in none of the referents, the fiber concentration exceeded 1 million fibers per gram dry tissue. Most of the exposed patients had been employed in various construction jobs, and valuable information about the exposure levels could be obtained by the mineral fiber analyses. In general, there was a good accord between the exposure categorization and the fiber burden measured in the lung.

Adenocarcinoma↗