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PubMed1996

Effect of high-dose pentoxifylline on acute radiation-induced lung toxicity in a rat lung perfusion model.

PURPOSE: The purpose of this study was to study the effect of high-dose oral pentoxifylline on radiation-induced acute lung injury as assessed with a rat lung perfusion model. METHODS AND MATERIALS: Adult male Sprague-Dawley rats were used throughout this study. A preliminary experiment determined that treatment with 2 g/liter pentoxifylline in drinking water resulted in an average consumption of 1.38 g/m2/day, which is comparable to the maximum tolerated dosage in humans. Seventy-two rats were irradiated to the left hemithorax with single fraction doses ranging from 10 through 18 Gy. Half were treated with 2 g/liter pentoxifylline in drinking water from 1 week before radiation through 8 weeks after radiation. Lung vascular perfusion scanning was performed at 3, 4, 5, 6, and 8 weeks after radiation using 99mTc-macroaggregated albumin. The lung perfusion ratio was defined as the number of counts due to radioactivity within the irradiated left lung region of interest divided by the number of counts within the region of the nonirradiated right lung. This lung perfusion ratio has been shown to decrease with radiation-induced lung injury. RESULTS: Although radiation led to a decreased lung perfusion ratio in all groups, those receiving pentoxifylline maintained higher ratios than irradiated controls from 3-5 weeks, especially for those receiving 15 or 18 Gy. However, from 6 through 8 weeks the irradiated controls exhibited partial recovery of lung perfusion ratio, whereas the pentoxifylline groups did not. By 8 weeks after 15 and 18 Gy, lung perfusion ratios were significantly higher for the irradiated controls than for pentoxifylline-treated rats-a reversal of the pattern observed at 3-5 weeks. CONCLUSIONS: The protection by pentoxifylline against radiation-induced acute lung injury was transient and limited to the first 5 weeks after radiation. Subsequent recovery from lung injury was inhibited by this drug at later times within the acute phase.

Acute Disease↗
PubMed2004

Acute respiratory distress syndrome of the contralateral lung after reexpansion pulmonary edema of a collapsed lung.

STUDY OBJECTIVE: To report that leukocyte-mediated acute injury may develop in a nonhypoxic lung after hypoxia-reoxygenation injury of the hypoxic lung and in other systemic organs in patients with reexpansion pulmonary edema. DESIGN: Case report analysis with examination of the literature. SETTING: Intensive care unit of a university hospital. PATIENTS: Three patients who developed leukocyte-mediated acute lung injury in the contralateral lung and systemic organ injury after ipsilateral reexpansion pulmonary edema of a collapsed lung. MEASUREMENTS: To rule out the possibility that the acute lung injury in the contralateral lung was an extension of the hypoxia-reoxygenation injury, we analyzed changes in leukocyte and platelet count in the peripheral blood in relation to the development of pulmonary edema in each lung. Changes in liver enzymes were also analyzed to detect hepatic dysfunction as evidence of systemic organ injury. MAIN RESULTS: Both leukocyte and platelet counts decreased when reexpansion pulmonary edema developed, and decreased further when acute lung injury developed in the contralateral lung (F = 8.42, p = 0.037 for leukocytes, and F = 17.66, p = 0.01 for platelets). Significant hepatic dysfunction developed, as evidenced by increases in both serum bilirubin (p = 0.001) and lactic dehydrogenase, indicating the presence of systemic organ injury. CONCLUSIONS: The hypoxia-reoxygenation injury of one lung can induce acute lung injury in the other lung and systemic organ injury.

Adult↗
PubMed2006

Cytostatic lung perfusion results in heterogeneous spatial regional blood flow and drug distribution: evaluation of different cytostatic lung perfusion techniques in a porcine model.

OBJECTIVES: Comparison of doxorubicin uptake, leakage and spatial regional blood flow, and drug distribution was made for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), as opposed to intravenous administration in a porcine model. METHODS: White pigs underwent single-pass lung perfusion with doxorubicin (320 mug/mL), labeled 99mTc-microspheres, and Indian ink. Visual assessment of the ink distribution and perfusion scintigraphy of the perfused lung was performed. 99mTc activity and doxorubicin levels were measured by gamma counting and high-performance liquid chromatography on 15 tissue samples from each perfused lung at predetermined localizations. RESULTS: Overall doxorubicin uptake in the perfused lung was significantly higher (P = .001) and the plasma concentration was significantly lower (P < .0001) after all isolated lung perfusion techniques, compared with intravenous administration, without differences between them. Pulmonary artery infusion (blood flow occlusion) showed an equally high doxorubicin uptake in the perfused lung but a higher systemic leakage than surgical isolated lung perfusion (P < .0001). The geometric coefficients of variation of the doxorubicin lung tissue levels were 175%, 279%, 226%, and 151% for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), respectively, compared with 51% for intravenous administration (P = .09). 99mTc activity measurements of the samples paralleled the doxorubicin level measurements, indicating a trend to a more heterogeneous spatial regional blood flow and drug distribution after isolated lung perfusion and blood flow occlusion compared with intravenous administration. CONCLUSIONS: Cytostatic lung perfusion results in a high overall doxorubicin uptake, which is, however, heterogeneously distributed within the perfused lung.

Animals↗
PubMed2005

Evidence for reduced arterial plasma input, prolonged lung retention and reduced lung monoamine oxidase in smokers.

UNLABELLED: We have previously found that smokers have reduced brain monoamine oxidase (MAO) A and B using positron emission tomography (PET) and the irreversible mechanism-based radiotracers [(11)C]-labeled clorgyline (CLG) and deprenyl (DEP) and their deuterated analogs (D CLG, D DEP). More recently, we have estimated MAO A and B activity in other organs using the deuterium isotope effect to determine binding specificity for MAO and a three-compartment model to estimate k(3), the model term proportional to MAO A activity. Here, we have investigated the robustness of the model term k(3) for estimating lung MAO A and B in light of our unexpected finding that lung MAO activity (k(3)) was reduced for smokers relative to nonsmokers, although radiotracer uptake in the lungs was similar at peak and plateau for the two groups. METHODS: Time-activity data from lung and arterial plasma were used from seven nonsmokers and seven smokers scanned previously with CLG and D CLG, and five nonsmokers and nine smokers scanned previously with DEP and D DEP. The measured time-activity curves for lung and plasma and the integrals for the arterial plasma time-activity curves were compared at an early time point (2.5 min) and at the end of the study (55 min). A three-compartment irreversible model was used to estimate the differences between smokers and nonsmokers, and the stability of the parameter (k(3)) while varying model assumptions for the relative fractions of lung tissue, blood and air in the PET voxel. RESULTS: The peak in the arterial plasma input function and the integral of the arterial plasma time-activity curve over the first 2.5 min after radiotracer injection were significantly lower for smokers relative to nonsmokers for all four tracers. However, although the peak and plateau of the lung time-activity curves were similar for smokers and nonsmokers, the decline in radioactivity from peak to plateau was slower for smokers for all tracers. Using a three-compartment irreversible model, we estimated the ratio of MAO subtypes A and B in normal lung tissue to be on the order of 3 to 1 (MAO A to B) and that smokers have reduced MAO levels for both subtypes as measured by the model parameter, k(3). The values of k(3) are insensitive to model assumptions of variations in air and tissue fraction in the PET voxel. Most of the effects of changes in these fractions are absorbed into the parameter K(1), which governs the plasma-to-tissue transfer of tracer and is a function of blood flow. K(1) was found to be larger in smokers, although the values depend upon model assumptions of air and tissue fractions. k(3) was found to be significantly lower in smokers; for CLG, a 50% reduction in MAO A for both CLG and D CLG was observed. For DEP, k(3) was also significantly lower in smokers with a reduction of approximately 80% in lung MAO B, although there was a very large coefficient of variation in the smoker's k(3). We also found larger values of lambda (K(1)/k(2)) for smokers relative to nonsmokers for all tracers consistent with a longer lung retention of the nonenzyme-bound tracer, which explains the slower decline in uptake from peak radioactivity for smokers. CONCLUSIONS: The measured arterial input function values for smokers and nonsmokers are significantly different for these two tracer pairs for nonsmokers and smokers particularly for the first few minutes after radiotracer injection. Model estimates of k(3) that indicate that smokers have lower lung MAO A and B activity than nonsmokers are robust and insensitive to variations in model assumptions for relative fractions of lung tissue, blood and air in the PET voxel. Although we have only investigated the behavior of [(11)C]clorgyline and [(11)C]l-deprenyl and their deuterium-substituted analogs in this report, the extent to which reduced arterial input and longer lung retention also hold for other tracers for subjects who smoke merits investigation.

Arteries↗
PubMed1999

Assessing lung deposition of inhaled medications. Consensus statement from a workshop of the British Association for Lung Research, held at the Institute of Biology, London, U.K. on 17 April 1998.

In vitro measurements of aerosol fine particle fraction (FPF) using particle-sizing apparatus (e.g. the twin impinger, multi-stage liquid impingers, cascade impactors) have a key role to play in the development of new pharmaceutical products and in quality control. However, use of in vitro methodology to attempt to predict lung deposition in vivo is of limited value due, in part, to the inability of current apparatus to mimic upper and lower airway anatomy satisfactorily. Estimates of FPF based on cut-off points ranging from 5-7 microns generally overestimate lung deposition as measured in vivo by gamma scintigraphy. We recommend that: 1. multistage apparatus (minimum five stages) be used to characterize particle size distribution adequately, over the range 0.5-5.0 microns; 2. where possible, measurements should be made at a range of rates and profiles of flow reflecting those likely to be generated using the inhalation device in clinical practice (including use by young and elderly patients with varying degrees of airflow obstruction); 3. encouragement should be given to the further development, standardization, and validation of apparatus with a 'throat' which more closely resembles the human oropharynx and larynx. Pharmacokinetic methods can give a good estimate of total, but not regional, lung deposition, with drugs which are either not absorbed via the gastrointestinal tract, or whose absorption can be blocked by co-administration of charcoal, thus avoiding confounding by absorption of drug substance deposited in the oropharynx and subsequently swallowed. Techniques which rely on evaluation of a timed fractional output of drug substance in the urine are susceptible to the inherent variability of rate of absorption across the respiratory epithelium. We recommend that consideration should be given to the further refinement and validation of PK methods which would more clearly identify the fractional dose deposited in the lung. Lung-imaging methodology, e.g. gamma scintigraphy, employing formulations radiolabelled with gamma-ray-emitting radionuclides such as 99mTc, can measure total lung deposition and oropharyngeal deposition, provided that the radiolabelling process is appropriately validated and suitable corrections are made for attenuation of gamma rays by body tissues. An estimate of regional lung deposition can be made by drawing 'regions of interest' on the scintigraphic image; the precision of this measure is limited by the two-dimensional (2-D) nature of most images which mean that there is an overlay of structures of interest (alveoli, small and large airways), which is most marked centrally. Three-dimensional (3-D) imaging techniques (e.g. single photon emission computed tomography, SPECT, and positron emission tomography, PET) have the potential to give more detailed data on regional lung deposition, but are currently more expensive, employ higher radiation doses, and are less well validated than 2-D (planar) imaging. We consider that, of the available imaging modalities, planar gamma scintigraphy represents current best practice for the assessment of lung deposition from inhaler devices where regional differences may be important. The methodology should be optimized by the adoption of generally accepted standards for radiolabelling, imaging, attenuation correction, and interpretation. It is important that deposition in all sites (device, oropharynx, lungs, stomach) should be quantified. Consideration should be given to refining the concept of regions of interest to coincide more closely with anatomical lung structures. Statistical methods to compare the size distributions of drug and radiolabel in validation experiments should be developed. In the longer term it is envisaged that three-dimensional imaging may play a more important part in evaluating lung deposition; an optimal three-dimensional anatomical model of lung zones of interest needs to be developed.

Administration, Inhalation↗
PubMed2000

DNA adduct level in lung tissue may act as a risk biomarker of lung cancer.

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.

Adenocarcinoma↗
PubMed2004

Prior lung disease and risk of lung cancer in a large prospective study.

OBJECTIVES: While 75-90% of people who develop lung cancer are smokers, only a small proportion of smokers develop lung cancer. Identifying factors that increase a smoker's risk of developing lung cancer may help scientists to better understand the etiology of lung cancer and more effectively target high-risk groups for screening. METHODS: Information on physician-diagnosed non-malignant lung diseases [asbestosis, asthma, chronic bronchitis or emphysema (CB/E), pneumonia, and tuberculosis] was obtained at baseline from 17,698 men and women involved in CARET, a randomized lung cancer prevention trial of beta-carotene and vitamin A among heavy smokers and asbestos-exposed workers. Hazard ratios for lung cancer were estimated through Cox regression models, after controlling for potential confounding factors, included smoking. Analyses were restricted to former and current smokers. RESULTS: During a median follow up of 9.1 years, 1028 cases of lung cancer occurred. Those who developed lung cancer were more likely to report a history of CB/E than controls (adjusted HR = 1.29, 95% CI: 1.09-1.53). In subgroup analyses, the association between a history of CB/E and lung cancer was stronger for those who were younger at diagnosis/reference, men in the heavy smoker cohort, former smokers, and those with squamous cell carcinomas. There was little association between a history of other lung diseases and lung cancer. CONCLUSIONS: Smokers with a history of CB/E may be at higher risk of developing lung cancer, independent of their smoking history.

Adult↗
PubMed2001

Outcome of bilateral lung volume reduction in patients with emphysema potentially eligible for lung transplantation.

OBJECTIVE: Between January 1993 and May 1998, we performed 200 consecutive bilateral lung volume reduction operations. After initial assessment, 99 of these patients were eligible for lung volume reduction and potentially eligible for immediate or eventual lung transplantation on the basis of age and absence of contraindications. All chose to proceed with lung volume reduction surgery. The outcomes of these 99 patients are reviewed to assess the consequences of proceeding with lung volume reduction surgery on patients potentially eligible for lung transplantation. METHODS: A retrospective study was performed with the use of a prospectively assembled computer database. RESULTS: The 61 men and 38 women were 55 +/- 7 years old at evaluation for lung volume reduction. Mean values for first second expired volume, total lung capacity, and residual volume were 24% +/- 8%, 141% +/- 19%, and 294% +/- 54% predicted. There were 4 operative deaths and 17 late deaths. Two-year and 5-year survival after evaluation for lung volume reduction are 92% and 75%. The 32 patients who have been listed for transplantation after lung volume reduction include 15 who have undergone transplantation, 14 who remain on the list, and 3 who have been removed from the list. All 15 transplant recipients survived transplantation and 3 have subsequently died of rejection or late infection. The 12 living recipients have a median post-transplantation follow-up of 1.7 years. The age at transplantation was 58 +/- 5 years with transplantation occurring 3.8 +/- 1.1 years after lung volume reduction. Sixteen of 99 patients underwent lower lobe volume reduction with an increased rate of listing (63%, P =.008) and transplantation (38%, P =.003) compared with patients undergoing upper lobe volume reduction. Patients listed for transplantation were younger, more impaired, and experienced less benefit from lung volume reduction than patients not yet listed for transplantation. CONCLUSIONS: The preliminary use of lung volume reduction in patients potentially suitable for transplantation does not appear to jeopardize the chances for subsequent successful transplantation.

Contraindications↗
PubMed1979

Quantitation of phosphatidylcholine secretion in lung slices and primary cultures of rat lung cells.

Rat lung slices and isolated rat lung cells were used to study the secretion of phosphatidylcholine by the lung in vitro. The rate of incorporation of [(3)H]choline by lung slices was 20-fold greater than by liver slices and 4-fold greater in lung cells compared to confluent skin fibroblasts. Labeling lung slices or cells with [(3)H]choline for up to 8 hr failed to reveal a significant amount of labeled phosphatidylcholine in the medium of either system compared to the medium from liver slice or fibroblast controls. Labeling of isolated lung cells for up to 24 hr, with or without 10% fetal calf serum, also showed no significant difference in the amount of labeled phosphatidylcholine in the medium compared to control fibroblast cultures. Washing labeled lung slices or cells with a nonlysing concentration of Triton X-100 (0.05%) did not selectively release labeled phosphatidylcholine, indicating that any secreted phosphatidylcholine did not adhere to the surface of the lung slices or cells. Experiments were performed to determine whether the small amount of phosphatidylcholine in the medium and detergent-released phosphatidylcholine was similar to the tissue and cell phosphatidylcholine. The saturated fatty acid composition of the phosphatidylcholine released by Triton X-100 and in the medium (from lung slices) was identical to that of the tissue phosphatidylcholine. In addition, the relative labeling rates of the phospholipids released by Triton X-100 and in the medium (labeled with [(14)C]glycerol) were identical to those of the tissue and cell phospholipids. Based on these results, we conclude that phosphatidylcholine is not secreted by lung slices and lung cells in large amounts compared to controls. The implication of these data is that pulmonary surfactant material may actually not be secreted by the lung in vitro, and perhaps in vivo, in the manner that is currently generally accepted.

Animals↗
PubMed1997

Annexin I in fibrotic rat lung and cultured lung fibroblasts following irradiation.

Radiation-induced lung fibrosis is a result of collagen accumulation in the interstitium, partly due to increased collagen synthesis by fibroblasts. One feature of active collagen synthesis is increased membrane trafficking in the fibroblasts. A group of proteins called annexins is believed to play a regulatory role in membrane fusion and exocytosis. Therefore, increased annexin activity might be expected in the fibrotic lung. We tested this hypothesis by measuring annexin I levels, hydroxyproline content and ultrastructural changes in radiation-induced pulmonary fibrosis in rat. Three months after a single exposure to 30 Gy of X-rays to the right hemithorax, the right lung of the rat was atrophied and fibrotic with a concomitant increase in size of the shielded left lung. Electron micrographs revealed that the irradiated lung was ladened with interstitial collagen fibrils, with increased number of fibroblasts amongst them. Hydroxyproline concentration in the irradiated lung was nearly twice that in the sham-irradiated lung. Annexin I in the irradiated lung, on the other hand, was markedly reduced, and barely detectable on immunoblots. Since increased annexin I might precede enhanced collagen production, we also measured annexin I levels in rat lungs 3 days after 30 Gy irradiation and correlated that with hydroxyproline concentration. We found no appreciable difference in annexin I levels and hydroxyproline content between sham-irradiated and irradiated lungs at 3 days. To determine whether annexin I levels in cultured fibroblasts were altered by irradiation, we assayed annexin I in cultured rat lung fibroblasts 3 days after 0.10 Gy exposure, with concomitant measurement of 14C-proline incorporation. The annexin I level in fibroblasts irradiated with 10 Gy X-rays was 55% higher than in sham-irradiated fibroblasts. However, incorporation of 14C-proline into collagenase-sensitive macromolecules in the culture medium and extracellular matrix was not different between these two groups of cells. These data demonstrate a radiation-induced increase in immunoreactive annexin I in cultured lung fibroblasts, but fail to support the hypothesis of a positive correlation between annexin I concentration and fibrosis in irradiated rat lung.

Animals↗
PubMed1996

Retention of asbestos fibres in lungs of workers with asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos township.

OBJECTIVE: To conduct a mineralogical study on the particles retained in the necropsied lungs of a homogenous group of asbestos miners and millers from Asbestos township (and a local reference population) and to consider the hypothesis that there is a difference in size between fibres retained in the lungs of patients with asbestosis with and without lung cancer. METHODS: Samples of lung tissue were obtained from 38 patients with asbestosis without lung cancer, 25 with asbestosis and lung cancer, and 12 with mesothelioma, from necropsied Quebec chrysotile miners and millers from Asbestos township. Fibre concentrations in the lungs of these patients were compared with those in tissue from necropsies carried out on a local reference population: men who had died of either accidental death or acute myocardial infarction between 1990 and 1992. 23 were born before 1940 and 26 after 1940. RESULTS: Geometric mean (GM) concentrations were higher in cases than in the controls for chrysotile fibres 5 to 10 microns long in patients with asbestosis with or without lung cancer; for tremolite fibres 5 to 10 microns long in all patients; for crocidolite, talc, or anthophyllite fibres 5 to 10 microns long in patients with mesothelioma; for chrysotile and tremolite fibres > or = 10 microns long in patients with asbestosis; and crocidolite, talc, or anthophyllite fibres > or = 10 microns long in patients with mesothelioma. However, median concentrations of each type of fibre in the lungs did not show any significant differences between the three disease groups. Average length to diameter ratios of the fibres were calculated to be larger in patients with asbestosis and lung cancer than in those without lung cancer for crocidolite fibres > or = 10 microns long, for chrysotile, amosite, and tremolite fibres 5 to 10 microns long, and for chrysotile and crocidolite fibres < 5 microns long. However, there was no statistical difference in the median length to diameter ratios for any type of fibres across the disease groups when they were calculated in each patient. Cumulative smoking index (pack-years) was higher in the group with asbestosis and lung cancer but was not statistically different from the two other disease groups. CONCLUSION: Lung cancers occurred in workers with asbestosis from Asbestos township who had an equal concentration of retained fibres but a tendency to a higher length to diameter ratio of amphiboles. These workers had a 29% higher average cumulative smoking index.

Adult↗
PubMed1987

Hypoxia enhances unilateral lung injury by increasing blood flow to the injured lung.

We hypothesized that in unilateral lung injury, bilateral hypoxic ventilation would induce vasoconstriction in the normal lung, redirect blood flow to the injured lung, and cause enhanced edema formation. Unilateral left lung injury was induced by intrabronchial instillation of 1.5 ml/kg of 0.1 N HCl. After HCl injury, blood flow to the injured left lung decreased progressively from 0.70 +/- 0.04 to 0.37 +/- 0.05 l/min and percent of flow to the injured left lung (QL/QT) decreased from 37.7 +/- 2.2 to 23.6 +/- 2.2% at 240 min. Exposure to hypoxia (12% O2) for three 10-min episodes did not affect QL/QT in normal animals, but after unilateral HCl injury, it caused blood flow to the injured left lung to increase significantly. A concomitant decrease in blood flow occurred to the noninjured right lung, resulting in a significant increase in QL/QT. The enhanced blood flow to the injured lung was associated with a significant increase in the wet-to-dry lung weight ratio in the dependent regions of the injured lung. These findings demonstrate that in unilateral HCl-induced lung injury, transient hypoxia can enhance blood flow to the areas of injury and increase lung edema formation.

Animals↗
PubMed1989

Relationship between lung injury and lung lipid peroxidation caused by recurrent endotoxemia.

We compared the relationship between lung lipid peroxidation and the histologic and physiologic changes seen after repeated doses of low dose endotoxin in unanesthetized sheep. Thirty-two sheep with lung lymph fistula were given from 1 to 10 doses of 1 micrograms/kg Escherichia coli endotoxin, 12 h apart. Animals were killed 5 h after 1, 3, 5, or 9 doses of endotoxin or 3 to 5 days after the tenth dose of endotoxin. The lipid peroxidation process was monitored by circulating conjugated dienes and lung tissue malondialdehyde (MDA) content. We found that conjugated dienes and MDA were increased after one dose of endotoxin corresponding in time with the increased prostanoid production and increased permeability. Acute lung inflammation was also evident histologically. Lipid peroxidation was not increased, however, when 3 to 7 doses were given. The permeability change was also markedly attenuated whereas severe lung inflammation was still present on histologic examination. After 9 doses, we noted a fourfold increase in lung tissue MDA that corresponded histologically with a marked mononuclear cell infiltration. Physiologic changes included a sustained 50% increase in oxygen consumption. However, lung lymph flow was not increased, again, reflecting lung inflammation with no change in lung vascular permeability. The MDA remained increased 5 days after the last dose of endotoxin along with a marked lung mononuclear cell infiltration. The lung MDA content corresponded with the level of increase in VO2, but not with changes in pulmonary vascular permeability. Conjugated dienes were increased only after the first injection of endotoxin. The lung lipid peroxidation process does not appear to correspond to physiologic or histologic lung changes after recurrent exposures to endotoxin.

Animals↗
PubMed1980

Lung solute permeability and lung liquid absorption in premature ventilated fetal goats.

In 21 premature fetal goats ventilated at low tidal volumes, measurements were made of alveolar surfactant activity by bubble stability tests on alveolar liquid, lung epithelium solute permeability using radiolabeled tracer molecules, lung liquid absorption from wet and dry lung weights, effectiveness of lung gas exchange, and lung mechanics. Arterial pO2 and residual gas volume were higher and arterial pCO2 and specific compliance were lower in animals whose bubble stability test was greater than 1:5 on alveolar liquid aspirated following one hr of ventilation. Animals without detectable surfactant in fetal lung liquid before ventilation had transfer of all size tracer solutes between alveolar liquid and blood, whereas those with detectable surfactant did not allow tracers 14 A or larger in radius to cross the lung epithelium. Lung liquid absorption rate in animals without lung liquid surfactant in fetal lung liquid before ventilation averaged 25% hr, whereas those with surfactant absorbed liquid at only 2%/hr in this protocol. All differences in solute permeability and lung liquid absorption were related to preventilation surfactant levels in fetal lung liquid, and not to postventilation surfactant levels or to lung function.

Absorption↗
PubMed1997

Release of lactate by the lung in acute lung injury.

UNLABELLED: The pathogenesis of hyperlactatemia during sepsis is poorly understood. We have previously described an increase in lactate concentration across the lung in the dog during early endotoxemia. Accordingly, we sought to determine if the lung releases lactate in humans and what relation this has with lung injury. METHODS: We measured lactate concentrations across the lung and lung injury scores (LIS) in two groups of patients. Group 1 consisted of nine patients with acute lung injury (LIS > or = 2.0) and elevated lactate concentrations (> 2.0 mmol/L). Group 2 contained 12 patients with no acute lung injury (LIS scores < or = 1.5), with or without increased lactate concentrations. Simultaneous measurements of plasma lactate and blood gases were obtained from indwelling arterial and pulmonary artery catheters. Measurements of cardiac output were also obtained. Lactate measurements were done using a lactate analyzer (YSI; Yellow Springs, Ohio). RESULTS: For each patient with acute lung injury and hyperlactatemia, an arterial-venous lactate gradient existed demonstrating release of lactate by the lung. This gradient persisted after correction for changes in hemoconcentration across the lung. The lactate gradient across the lung was 0.4 +/- 0.2 mmol/L for group 1 vs 0.05 +/- 0.1 mmol/L for group 2 (p = 0.001). This corresponded to a mean pulmonary lactate flux of 231.3 +/- 211.3 vs 5.0 +/- 37.2 mmol/h (p = 0.001). The lactate flux and the arterial-venous lactate difference correlated with LIS both for the entire sample and for the subgroup with hyperlactatemia (r = 0.69, p < 0.01). Pulmonary lactate flux was not related to arterial lactate levels (r = 0.25). CONCLUSION: In patients with acute lung injury and hyperlactatemia, the lung is a major source of lactate and lactate flux correlates with LIS. This lactate flux could explain some of the hyperlactatemia seen in sepsis.

Adult↗
PubMed2006

Threshold of lung injury required for the appearance of marrow-derived lung epithelia.

Bone marrow-derived cells (BMDCs) can adopt an epithelial phenotype in the lung following bone marrow transplantation (BMT). This phenomenon has been assumed to result from the lung injury that occurs with myeloablative radiation. To date, no study has related the degree of epithelial chimerism following bone marrow transplantation to the lung damage induced by preconditioning for BMT. Such a goal is crucial to understanding the local host factors that promote the engraftment of BMDCs as lung epithelia. We undertook this aim by performing sex-mismatched bone marrow transplantation using a variety of preconditioning regimens and comparing measurements of lung injury (bronchoalveolar lavage [BAL] cell count, alveolar-capillary leak assayed by BAL protein levels, and terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis on epithelial cells) with rigorous methods to quantify bone marrow-derived lung epithelia (costaining for epithelial and donor markers on tissue sections and isolated lung epithelia in recipient mice). We found that only at doses that induced lung injury could marrow derived lung epithelium be identified following BMT. With irradiation doses less than 1,000 centigray (cGy), there was little to no apparent injury to the lung, and there were no marrow-derived pneumocytes despite high levels of hematopoietic chimerism. In contrast, 4 days after either split or single-dose 1,000 cGy irradiation, nearly 15% of lung epithelia were apoptotic, and with this dose, marrow-derived type II pneumocytes (0.2%) were present at 28 days. These data indicate a critical relationship between lung injury and the phenotypic change from BMDCs to lung epithelial cells.

Animals↗
PubMed2005

Ultrastructure of immediate microvascular lung injury induced by bacterial endotoxin in the isolated, no-deficient lung perfused with full blood.

NOS-2-derived NO is involved in hypotension, vasoplegia, metabolic disorders and lung injury in endotoxic shock. On the other hand, NOS-3-derived NO protects against LPS-induced lung injury. We have previously shown that NO limits lung injury in the isolated blood-perfused rat lung. Here we characterize the ultrastructure of microvascular lung injury induced by LPS in the absence of endogenous NO and summarize our data on the mechanisms of immediate lung response to LPS in the presence and absence of endogenous NO. Injection of LPS (from E.Coli, 300 microg/ml) into the isolated blood-perfused rat lung induced an immediate transient constriction of airways and vessels that was not associated with lung edema and pulmonary microcirculation injury. In contrast, in the presence of the NOS inhibitor L-NAME (300 microg/ml), LPS produced an enhanced constriction of airways and vessels, which was accompanied by profound lung edema and capillary-alveolar barrier injury, as evidenced by optic and electron microscopy. Microvascular lung injury was confirmed by the following findings: edema of pulmonary endothelium with low electronic density of endothelial cytoplasm, presence of protein-rich fluid and numerous erythrocytes in alveolar space, concentric figures of damaged tubular myelin of surfactant (myelin-like bodies), edema of epithelium type I cells with low electronic density of their cytoplasm and alterations in ultrastructure of basal membrane of vascular-alveolar barrier. Interestingly, epithelial type II cells did not show signs of injury. It is worth noting that capillary-alveolar barrier injury induced by L-NAME+LPS was associated with sequestration of platelets and neutrophils in pulmonary microcirculation and internalization of LPS by neutrophils. In conclusion, in the absence of endogenous nitric oxide LPS induces injury of microvascular endothelium and vascular-alveolar barrier that leads to fatal pulmonary edema. Mechanisms of immediate lung response to LPS in presence of NO and those leading to acute microvascular lung injury in response to LPS in absence of NO are summarized. In our view, immediate lung response to bacterial endotoxin represents a phylogenetically ancient host defence response involving complement-dependent activation of platelets and neutrophils and subsequent production of lipid mediators. This response is designed for a quick elimination of bacterial endotoxin from the circulation and is safeguarded by endothelial NO.

Animals↗
PubMed2006

[Differential response of developing human fetal lung explants to hyperoxia and the effects of dexamethasone on hyperoxia-exposed lungs].

OBJECTIVE: This study aimed to explore the effects of hyperoxia on the development of fetal lung by investigating the changes of morphological and cell proliferation induced by hyperoxia in cultured fetal lungs as well as the effects of dexamethasone on hyperoxia-exposed lungs. METHODS: Human fetal lung explants at the pseudoglandular stage of development were cultured randomly either in normoxia (21% O2/5% CO2) or hyperoxia (95% O2/5% CO2) for 72 hrs. Dexamethasone was added into the feeding medium at the concentration of 10(-6)M. Harvested tissues were stained for pancytokeratin to identify epithelial cells, with Ki-67 as a marker of proliferation. The effects of lung morphometry were analyzed using computer assisted image analysis. The mean airway thickness, the proportion of the surface area occupied by airways, the mean airway surface area and the index of the epithelium proliferation were measured. RESULTS: The lung architectures remained unchanged after 72 hrs normoxia culture, whereas hyperoxia culture resulted in significant dilation of airways and thinning of epithelium, with the surface area of airways of 6662 microm(2) vs 2728 microm(2) and the thickness of airways of 7.8 microm vs 8.1 microm (P < 0.05). Hyperoxia culture also resulted in an increase in the proportion of the surface area occupied by airways than normoxia culture (35.2% vs 23.4%; P < 0.05). The surface area of airways (3174 microm(2)) and the proportion of the surface area occupied by airways (23.9%) decreased significantly in hyperoxia-cultured lungs after dexamethasone administration (P < 0.05). The epithelium proliferation index in hyperoxia-cultured lungs (21.8%) was higher than that in normoxia-cultured lungs (5.1%) and dexamethasone-treated hyperoxia-cultured lungs (7.4%) (P < 0.05). CONCLUSIONS: The exposure of pseudoglandular lungs to hyperoxia modulates the lung architecture to resemble saccular lungs with higher epithelium proliferation index. Dexamethasone may inhibit the effects induced by hyperoxia.

Cell Differentiation↗