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PubMed2004

Oxidized low-density lipoproteins accumulate in rat lung after experimental lung edema induced by alpha- naphthylthiourea (ANTU).

Oxidation of the low-density lipoprotein (LDL) results in the production of modified LDLs. Oxidation of LDL cholesterol plays a role on the pathogenesis of endothelial dysfunction. This study was designed to investigate the possible participation of the oxidative modification of low density lipoprotein in the lung edema induced by alpha-naphthylthiourea (ANTU), which is a well-known noxious chemical agent on the lung endothelium. When ANTU injected intraperitoneally into rats (15 mg kg(-1)), it produced lung edema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. A significant lung edema was observed 4 h after intraperitoneally injection of alpha-naphthylthiourea when compared with olive oil-injected control rats. On microscopic examination of alpha-naphthylthiourea-treated rats were shown to have severe lung injury, while no change was observed in olive oil-treated control rats. While there were no staining in control lungs, positive oxidized low-density lipoproteins immune-fluorescent staining were observed in lung edema group. Our study showed that oxidized low-density lipoprotein (oxLDL) accumulated in ANTU-induced lung damage. This is the first study in which accumulation of oxLDL molecules in the intact lung tissue were shown by fluorescent immune-staining method in experimental lung edema. The potential role of oxLDL in this pathology are still under investigation.

Animals↗
PubMed1998

Down-regulation of ET(B) receptor, but not ET(A) receptor, in congestive lung secondary to heart failure. Are marked increases in circulating endothelin-1 partly attributable to decreases in lung ET(B) receptor-mediated clearance of endothelin-1?

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ET(A) receptors and ET(B) receptors. We previously reported that an ET(A) receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ET(A) receptor mRNA expression but also ET(B) receptor mRNA expression in the congestive lung because lung ET(B) receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-1 and circulating ET-1 levels. The expression of ET(B) receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ET(A) receptor mRNA did not differ between the two groups. The protein level of ET(B) receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ET(A) receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ET(B) receptor, but not ET(A) receptor, occurs in the congestive lung. Since lung ET(B) receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ET(B) receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.

Animals↗
PubMed1999

Discountinuous lung sounds and hysteresis in control and Tween 20-rinsed excised rat lungs.

In the past, the relationship between pulmonary hysteresis and a model of the recruitment-derecruitment of lung units has been explored (Cheng, W., DeLong, D.S., Franz, G.N., Petsonk, E.L., Frazer, D.G., 1995, Resp. Physiol. 102, 205-215). The recruitment process is characterized by a sequence of events which represents discrete configurational changes in lung structure. It is assumed that energy released during the opening of lung units is associated with the formation of discontinuous lung sounds. The goal of this study was to record tracheal sounds for lungs inflated from different end-expiratory pressures and to relate the sound power to the normalized hysteresis of individual pressure-volume (PL-VL) loops. PL-VL curves and lung sounds were recorded for control lungs and lungs rinsed with Tween 20 in order to estimate the role of alveolar surfactant on the recruitment-derecruitment process. Results indicate that there may be two populations of lung units, one which is altered by Tween 20 and another which is not. The population not affected by Tween 20 appears to be responsible for producing discrete lung sounds and may represent the opening of larger conducting airways. The second population, possibly within the respiratory zone, is affected by alterations in surface tension and contributes to pulmonary hysteresis, but, apparently, does not contribute significantly to lung sound power measured at the trachea.

Animals↗
PubMed2003

Usefulness of TA02 (napsin A) to distinguish primary lung adenocarcinoma from metastatic lung adenocarcinoma.

TA02 (napsin A) associated with primary lung adenocarcinoma detected by the two-dimensional polyacrylamide gel electrophoresis (2-DE), has a molecular weight of 35.0 kDa and an isoelectric point 5.29. We developed a mouse monoclonal antibody against the N-terminal of the TA02 molecule (clone TMU-Ad02 (6A1)) and attempted to investigate its immunohistochemical reactivity for nodular lesions of the peripheral lung, and evaluate its usefulness for making a differential diagnosis between primary and metastatic lung adenocarcinomas. The TA02-immunohistochemical evaluation was carried out using surgically resected materials of 109 cases of lung cancer (76 cases of primary lung cancer and 33 cases of metastatic lung adenocarcinoma from other organs), five cases with mesothelioma, four cases with atypical adenomatous hyperplasia (AAH) and five cases with tuberculoma of the lung. In 39 out of 43 (90.7%) primary lung adenocarcinomas, positive immunohistochemical reactivity with a granular cytoplasmic staining pattern was observed. Even though two out of seven (28.6%) large cell carcinomas showed positive results with a granular staining pattern, the immunohistochemical staining intensity was weak. The other cancerous lesions containing metastatic lung adenocarcinoma and mesothelioma were all completely negative. In comparison with the immunohistochemical reactivity of TA02 and SpA, TA02 was superior to SpA both in terms of positive rate and immunohistochemical intensity. We concluded that the evaluation of TA02 expression in lung tumorous lesions was very valuable for discriminating between primary and metastatic lung adenocarcinoma, and TA02 was superior to SpA as a discriminating marker.

Adenocarcinoma↗
PubMed1996

Some lifestyle factors in human lung cancer: a case-control study of 792 lung cancer cases.

In order to investigate the relationship between some lifestyle factors and lung cancer, a case-control study involving all lung cancer deaths registered in 1986 was performed. The results show that among males, 92.5% of the cases and 75.5% of controls were smokers, implying that cigarette smoking is a primary risk factor for lung cancer in males. By contrast, among females only 60.6% of the cases and 30.8% of the controls were smokers, implying factors other than cigarette smoking must be involved in the development of lung cancer in females. The risk of lung cancer in nonsmoking females was found to be unaffected by exposure to environmental tobacco smoke (ETS). A study of diet and eating habits showed that in males the risk of lung cancer was reduced by the intake of vegetables and fruits, but was significantly increased by a frequent intake of fried foods. The positive association between the intake of fried food and the risk of lung cancer could result from cooking practices and from inappropriate methods used in food preparation. No association can be demonstrated between the consumption of high protein or high fat diets, salty and smoked food items and the incidence of lung cancer. Thus, it is not likely that sufficient lung cancer inducing carcinogens can be generated through the intake of food. In addition, the positive association found to exist between the living index and the risk of lung cancer in females is consistent with the notion that coal smoke or cooking practices may generate sufficient indoor air pollutants to significantly increase the risk of lung cancer in females.

Air Pollution, Indoor↗
PubMed1999

Lung injury following pulmonary resection in the isolated, blood-perfused rat lung.

Lung resection may be complicated by postpneumonectomy pulmonary oedema. Oxidant generation following surgery-induced ischaemia-reperfusion may be responsible. This hypothesis was tested utilizing isolated, in situ, blood perfused rodent lungs subjected to continuous perfusion (control subjects); one lung ventilation followed by pneumonectomy (group 1); or one lung ventilation followed by reinflation of the collapsed lung (group 2). In control subjects, no significant changes in markers of oxidant damage, oxygenation, pulmonary artery pressure or extravascular albumin extravasation were detected. In group 1 lungs, hydroxyl radical-like damage was detected in association with impaired oxygenation (p<0.05), and increased pulmonary artery pressure and extravascular albumin accumulation in both lungs. In group 2, there was evidence of hydroxyl radical-like damage, and a fall in oxygenation (p<0.05) occurred during one lung ventilation. There was a transient rise in pulmonary artery pressure following lung reinflation and extra vascular albumin accumulation was significantly increased in both lungs (right>left, p<0.05). Both changes were attenuated (p<0.05) following treatment with the reactive oxygen species (ROS) scavenger superoxide dismutase (group 2a) and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (group 2b). Hydroxyl radical-like damage was undetectable following nitric oxide synthase inhibition. Oxidant stress may contribute to the pathologies seen in this model of lung injury.

Animals↗
PubMed2001

Lung recruitment at birth does not improve lung function in immature lambs receiving surfactant.

BACKGROUND: In mature animals with surfactant deficiency induced by lung lavage, the therapeutic effect of exogenous surfactant is enhanced by a lung recruitment maneuver. We then tested whether a lung recruitment maneuver at birth immediately before surfactant treatment would improve lung function also in preterm lambs with surfactant deficiency due to immaturity. METHODS: Ten newborn lambs with a gestational age of 127 days were randomized to receive surfactant either before the first breath or immediately after a lung recruitment maneuver consisting of five sustained inflations of 8, 16 or 32 ml/kg. Functional residual capacity was measured by sulfur hexafluoride washout, and inspiratory capacity as well as maximal compliance were obtained from a static expiratory pressure-volume curve after the lungs had been inflated to 35 cm H2O. In addition, blood gases were obtained. Measurements were made at 15, 45, 175, 135, 170 and 230 min after birth. Post mortem histological examinations of the lungs were performed in a blinded fashion. RESULTS: The lung recruitment maneuvers did not improve oxygenation. Inspiratory capacity, static compliance and functional residual capacity at 4 h, as well as post mortem intrapulmonary air volume, had an inverse relation to the size of inflations given at birth. There was also a negative correlation between size of inflations at birth and response to surfactant therapy, as assessed by lung microscopy. CONCLUSION: Lung recruitment at birth does not improve the response to surfactant in immature lambs, but may instead have an adverse effect on lung function and morphology.

Animals↗
PubMed1998

Relation between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema.

BACKGROUND: Surgery to reduce lung volume has recently been reintroduced to alleviate dyspnea and improve exercise tolerance in selected patients with emphysema. A reliable means of identifying patients who are likely to benefit from this surgery is needed. METHODS: We measured lung resistance during inspiration, static recoil pressure at total lung capacity, static lung compliance, expiratory flow rates, and lung volumes in 29 patients with chronic obstructive lung disease before lung-volume-reduction surgery. The changes in the forced expiratory volume in one second (FEV1) six months after surgery were related to the preoperatively determined physiologic measures. A response to surgery was defined as an increase in the FEV1 of at least 0.2 liter and of at least 12 percent above base-line values. RESULTS: Of the 29 patients, 23 had some improvement in FEV1 including 15 who met the criteria for a response to surgery. Among the variables considered, only preoperative lung resistance during inspiration predicted changes in expiratory flow rates after surgery. Inspiratory lung resistance correlated significantly and inversely with improvement in FEV1 after surgery (r=-0.63, P<0.001). A preoperative criterion of an inspiratory resistance of 10 cm of water per liter per second had a sensitivity of 88 percent (14 of 16 patients) and a specificity of 92 percent (12 of 13 patients) in identifying patients who were likely to have a response to surgery. CONCLUSIONS: Preoperative lung resistance during inspiration appears to be a useful measure for selecting patients with emphysema for lung-volume-reduction surgery.

Adult↗
PubMed2002

Gain and subsequent loss of lung function after lung volume reduction surgery in cases of severe emphysema with different morphologic patterns.

OBJECTIVE: Surgical lung volume reduction improves lung function and dyspnea in advanced emphysema to a variable degree. Because long-term results with this procedure are scant, we prospectively investigated lung function over several years after lung volume reduction surgery with regard to emphysema morphology. METHODS: Bilateral video-assisted thoracoscopic lung volume reduction surgery was performed in severely symptomatic patients with marked hyperinflation caused by advanced nonbullous emphysema. Emphysema heterogeneity was visually graded on chest computed tomography. Symptoms and lung function were assessed before the operation and 3, 6, and then every 6 months after the operation. RESULTS: A total of 115 patients with a median forced expiratory volume in 1 second of 0.73 L (27% of predicted value) underwent lung volume reduction surgery. Follow-up extended over a median of 37 months. Median forced expiratory volume in 1 second significantly increased within 6 months after the operation by 37% in homogeneous (n = 27), by 38% in intermediately heterogeneous (n = 37), and by 63% in markedly heterogeneous emphysema (n = 51, P <.05 vs. other morphologies). Maximal forced expiratory volume in 1 second was reached within 6 months after lung volume reduction surgery and decreased in the first postoperative year by 0.16 L per year in homogeneous, by 0.19 L per year in intermediately heterogenous, and by 0.32 L per year in markedly heterogeneous emphysema (P <.01 vs. other morphologies). The decline in forced expiratory volume in 1 second over subsequent years decelerated according to an exponential decay and was similar for all morphologic types (median annual decrease of 0.09 L [9%]). CONCLUSIONS: Lung volume reduction surgery improves lung function in severe homogeneous and, to an even greater extent, heterogeneous emphysema. Forced expiratory volume in 1 second peaks within 6 months postoperatively. The subsequent decline is most rapid in the first year and slows down in succeeding years according to an exponential decay. Therefore, long-term functional results of lung volume reduction surgery may be more favorable than expected from linear extrapolations of short-term observations.

Adult↗
PubMed2006

Accumulation of chromium and nickel metals in lung tumors from lung cancer patients in Taiwan.

Metallic carcinogenicity is generally thought to generate of free radicals, and thus some metals were reported to play a role in lung tumorigenesis. In order to verify the role of heavy metals in the development of Taiwanese lung cancer, a case-control study was conducted to compare heavy metal contents between 60 tumor and 42 normal lung tissues surgically resected from lung cancer and noncancer patients. The tissue concentration of heavy metals, including cadmium (Cd), chromium (Cr), cobalt (Co), lead (Pb), and nickel (Ni), was measured using by atomic absorption spectrometry (AAS). Our results indicated that Cr and Ni contents in lung tumors of lung cancer patients were significantly higher than those in normal lung tissue of noncancer controls, but Co content was markedly lower in lung tumors. Additionally, Pb content in lung tumors was associated with nodal involvement, and Co amounts in squamous-cell carcinomas were relatively higher than those in adenocarcinomas. Data suggest that accumulation of Cr and Ni in lung tumors may play a role, at least in part, in the development of lung cancer in Taiwan.

Adenocarcinoma↗
PubMed2006

Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis.

BACKGROUND: A troubling aspect of cancer screening is the potential for overdiagnosis, i.e., detection of disease that, in the absence of screening, would never have been diagnosed. Overdiagnosis is of particular concern in lung cancer screening because newer screening modalities can identify small nodules of unknown clinical significance. Previously published analyses of data from the Mayo Lung Project, a large randomized controlled trial conducted among 9211 male cigarette smokers in the 1970s and early 1980s indicated that overdiagnosis might exist in lung cancer screening. At the end of follow-up (July 1, 1983), no difference in lung cancer mortality was observed, but an excess of 46 cases in the intervention arm suggested overdiagnosis. Because that excess could instead have resulted from short follow-up time, we investigated this possibility by conducting long-term lung cancer incidence follow-up. METHODS: We investigated the lung cancer status through 1999 of the 7118 participants in the Mayo Lung Project who were alive and without diagnosed lung cancer in 1983 by use of medical records, surveys mailed to participants or next-of-kin, and state death certificates. RESULTS: Information was available for 6101 participants, including 811 with inconclusive lung cancer status. From November 1971 through December 31, 1999, 585 participants in the intervention arm and 500 in the usual-care arm were diagnosed with lung cancer. CONCLUSIONS: The persistence of excess cases in the intervention arm after 16 additional years of follow-up provides continued support for overdiagnosis in lung cancer screening.

Death Certificates↗
PubMed1991

A morphometric study of the lungs of different sized bats: correlations between structure and function of the chiropteran lung.

1. The lungs of four species of bats, Phyllostomus hastatus (PH, mean body mass, 98 g), Pteropus lylei (PL, 456 g), Pteropus alecto (PA, 667 g), and Pteropus poliocephalus (PP, 928 g) were analysed by morphometric methods. These data increase fivefold the range of body masses for which bat lung data are available, and allow more representative allometric equations to be formulated for bats. 2. Lung volume ranged from 4.9 cm3 for PH to 39 cm3 for PP. The volume density of the lung parenchyma (i.e. the volume proportion of the parenchyma in the lung) ranged from 94% in PP to 89% in PH. Of the components of the parenchyma, the alveoli composed 89% and the blood capillaries about 5%. 3. The surface area of the alveoli exceeded that of the blood-gas (tissue) barrier and that of the capillary endothelium whereas the surface area of the red blood cells as well as that of the capillary endothelium was greater than that of the tissue barrier. PH had the thinnest tissue barrier (0.1204 microns) and PP had the thickest (0.3033 microns). 4. The body mass specific volume of the lung, that of the volume of pulmonary capillary blood, the surface area of the blood-gas (tissue) barrier, the diffusing capacity of the tissue barrier, and the total morphometric pulmonary diffusing capacity in PH all substantially exceeded the corresponding values of the pteropid species (i.e. PL, PA and PP). This conforms with the smaller body mass and hence higher unit mass oxygen consumption of PH, a feature reflected in the functionally superior gas exchange performance of its lungs. 5. Morphometrically, the lungs of different species of bats exhibit remarkable differences which cannot always be correlated with body mass, mode of flight and phylogeny. Conclusive explanations of these pulmonary structural disparities in different species of bats must await additional physiological and flight biomechanical studies. 6. While the slope, the scaling factor (b), of the allometric equation fitted to bat lung volume data (b = 0.82) exceeds the value for flight VO2max (b = 0.70), those for the surface area of the blood-gas (tissue) barrier (b = 0.74), the pulmonary capillary blood volume (b = 0.74), and the total morphometric lung diffusing capacity for oxygen (b = 0.69) all correspond closely to the VO2max value. 7. Allometric comparisons of the morphometric pulmonary parameters of bats, birds and non-flying mammals reveal that superiority of the bat lung over that of the non-flying mammal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

De novo ICAM-1 synthesis in the mouse lung: model of assessment of protein expression in lungs.

Because most studies addressing the regulatory mechanisms of intercellular adhesion molecule (ICAM)-1 expression have used cultured endothelial cells, we set out to develop an isolated mouse lung preparation to study gene and protein expression in its proper cellular context in the organ. Lungs from CD1 mice were isolated and perfused (2 ml/min, 37 degrees C) with a recirculating volume of RPMI 1640 solution supplemented with 3 g/100 ml albumin. Lungs maintained their isogravimetric state for 4 h. Tumor necrosis factor (TNF-alpha; 2,000 U/ml) was added to the perfusate for 0.5, 1, 2, or 3.5 h to induce ICAM-1 expression or lungs received no treatment (control). After quick-freezing the lungs using liquid nitrogen at different time points, the prepared tissue homogenates were analyzed for ICAM-1 protein expression by Western blotting and NF-kappaB activation by electrophoretic mobility shift assay. TNF-alpha caused a progressive increase in NF-kappaB activity after 0.5 h and ICAM-1 protein expression two- to threefold of basal after 2 h. Untreated lungs expressed a low and constant level of ICAM-1 between 0 and 3.5 h. TNF-alpha failed to induce NF-kappaB activation and ICAM-1 expression in lungs of NADPH oxidase-deficient mice lacking p47(phox). We disaggregated mouse lungs using collagenase and stained the cells for ICAM-1 and VE-cadherin (used as an endothelial marker) to assess the in situ endothelial-specific expression of ICAM-1. We observed that TNF-alpha challenge resulted in increased ICAM-1 expression in endothelial cells freshly isolated from lungs. These data show the role of NADPH oxidase-derived oxidant signaling in the mechanism of NF-kappaB activation and ICAM-1 expression in mouse lung endothelial cells. Moreover, the general method presented herein has potential value in assessing mechanisms of gene and protein expression in the isolated-perfused mouse lung model.

Animals↗
PubMed1994

Interleukin-1-induced lung neutrophil accumulation and oxygen metabolite-mediated lung leak in rats.

We found that intratracheal administration of recombinant interleukin-1 alpha (IL-1) into rats rapidly (< 5 h) increased neutrophils in lung lavages and caused an acute edematous lung injury which was reflected by lung albumin accumulation (lung leak) and histological abnormalities (perivascular cuffing). These IL-1-dependent processes were inhibited by prior administration of recombinant IL-1 receptor antagonist and did not occur following administration of heated IL-1. Several lines of evidence suggested that neutrophil-derived oxygen metabolites contributed to lung leak. First, lung leak did not occur in rats rendered neutropenic by vinblastine treatment 4 days before IL-1 administration but did occur in neutrophil-replete rats given vinblastine 1 day before IL-1 administration and control rats given IL-1. Second, treatment with a hydroxyl radical scavenger, dimethyl sulfoxide (DMSO) or a superoxide anion scavenger, manganese superoxide dismutase, decreased lung leak, lung lavage neutrophils, and histological abnormalities in rats given IL-1 intratracheally. Third, intratracheal IL-1 administration increased lung oxidized glutathione (GSSG) levels and expired H2O2 concentrations, and these two indices of oxidative stress were decreased by dimethyl sulfoxide or manganese superoxide dismutase treatment. We conclude that intratracheal administration of IL-1 increases neutrophils in the lung and causes a neutrophil and oxygen metabolite-dependent acute edematous lung injury.

Animals↗
PubMed2006

Impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes.

RATIONALE: One of the limitations associated with lung transplantation is the lack of available organs. OBJECTIVE: To determine whether a lung donor-management protocol could increase the number of lungs for transplantation without affecting the survival rates of the recipients. METHODS: We implemented the San Antonio Lung Transplant protocol for managing potential lung donors according to modifications of standard criteria for donor selection and strategies for donor management. We then compared information gathered during a 4-yr period, during which the protocol was used with information gathered during a 4-yr period before protocol implementation. Primary outcome measures were the procurement rate of lungs and the 30-d and 1-yr survival rates of recipients. MAIN RESULTS: We reviewed data from 711 potential lung donors. The mean rate of lung procurement was significantly higher (p < 0.0001) during the protocol period (25.5%) than during the pre-protocol period (11.5%), with an estimated risk ratio of 2.2 in favor of the protocol period. More patients received transplants during the protocol period (n = 121) than during the pre-protocol period (n = 53; p < 0.0001). Of 98 actual lung donors during the protocol period, 53 (54%) had initially been considered poor donors; these donors provided 64 (53%) of the 121 lung transplants. The type of donor was not associated with significant differences in recipients' 30-d and 1-yr survival rates or any clinical measures of adequate graft function. CONCLUSIONS: The protocol was associated with a significant increase in the number of lung donors and transplant procedures without compromising pulmonary function, length of stay, or survival of the recipients.

Adult↗
PubMed2002

The Liverpool Lung Project: a molecular epidemiological study of early lung cancer detection.

Lung cancer is the major cause of death from neoplastic disease in the world, and even with politically-motivated smoking cessation campaigns throughout Europe, the disease remains the major cause of death. The development of molecular epidemiological population-based research into early lung cancer detection, such as the Liverpool Lung Project (LLP), may provide a way forward. This is the first major molecular epidemiological study of detection of early lung cancer. The use of molecular epidemiological risk assessments prior to clinical diagnosis and markers of preclinical carcinogenesis in patients with a high risk of developing lung cancer will reduce the incidence of clinically-detectable lung cancer, given the appropriate intervention strategies. The aims are as follows: 1) to prepare a molecular genetic and epidemiological risk assessment model based on environmental exposures and genetic predisposition; 2) to develop an archive of specimens relating to at-risk individuals and those with lung cancer; 3) to redefine lung cancer based on molecular pathology using the fields of expression profiling, genetic instability and molecular cytogenetics; 4) to identify and assess novel markers of precarcinogenesis in high-risk populations; and 5) to facilitate the development of new treatment strategies (e.g. chemoprevention programmes and targeted drug therapies). The LLP has two components: 1) a case-controlled study of newly-diagnosed cases of lung cancer that will provide a baseline, risk assessment; and 2) a prospective cohort study to be carried out over a 10-yr period that will identify markers of preclinical carcinogenesis. In-depth interviews are carried out using structured and semi-structured questionnaires. Sputum, blood and tumour specimens are collected and will be assessed for specific molecular markers (e.g. genetic instability, mutation and expression profiling, and methylation status). Conclusions from The Liverpool Lung Project will be based around molecular-epidemiological and genotyping risk assessment models, as well as redefining the disease, and ultimately contributing to the development of new early lung cancer detection and treatment strategies.

Age Factors↗
PubMed2000

Chronic lung injury in preterm lambs: abnormalities of the pulmonary circulation and lung fluid balance.

Chronic lung disease of early infancy, or bronchopulmonary dysplasia, is a frequent complication of prolonged mechanical ventilation after premature birth. Pulmonary hypertension and edema are common features of this condition, which is often attributed to long-term, repetitive overinflation of incompletely developed lungs. The overall objective of this work was to examine the effects on the pulmonary circulation and lung fluid balance of different ventilation strategies using large versus small inflation volumes in an animal model of bronchopulmonary dysplasia. We studied 16 newborn lambs that were delivered prematurely (124+/-3 d gestation, term = 147 d) by cesarean section and mechanically ventilated for 3 to 4 wk. Ten lambs were ventilated at 20 breaths/min, yielding a tidal volume of 15+/-5 mL/kg, and six lambs were ventilated at 60 breaths/min, yielding a tidal volume of 6+/-2 mL/kg. All lambs received surfactant at birth and had subsequent surgery for closure of the ductus arteriosus and catheter placement to allow serial measurements of pulmonary vascular resistance and lung lymph flow. Chronic lung injury, documented by serial chest radiographs and postmortem pathologic examination, developed in all lambs irrespective of the pattern of assisted ventilation. Pulmonary vascular resistance, which normally decreases during the month after birth at term, did not change significantly from the first to the last week of study. Lung lymph flow, an index of net transvascular fluid filtration, increased with time in lambs that were ventilated at 20 breaths/min, but not in lambs ventilated at 60 breaths/min. Lymph protein concentration decreased with time, indicative of increased fluid filtration pressure, without evidence of a change in lung vascular protein permeability. Postmortem studies showed interstitial lung edema, increased pulmonary arteriolar smooth muscle and elastin, decreased numbers of small pulmonary arteries and veins, and decreased capillary surface density in distal lung of chronically ventilated lambs compared with control lambs that were killed either 1 d (same postconceptional age) or 3 wk (same postnatal age) after birth at term. Thus, chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance and leads to lung edema from increased fluid filtration pressure. These abnormalities of the pulmonary circulation may contribute to the abnormal respiratory gas exchange that often exists in infants with bronchopulmonary dysplasia.

Animals↗
PubMed1977

Pulmonary insulin responsivitiy: in vivo effects of insulin on the diabetic rat lung and specific insulin binding to lung receptors in normal rats.

Adult rats were rendered diabetic by a single iv injection of streptozotocin (70 or 75 mg/kg). In these rats, serum insulin fell to minimal levels during the 48 h following drug treatment, and this was roughly paralleled by a progressive decrease in the ability of the lung to oxidize glucose. The addition of insulin to diabetic rat lung slices in vitro had no restorative effect on the depressed glucose oxidative rate during a 2 h incubation period; however, two daily treatments of the rats with 1 unit of protamine, zinc insulin completely restored lung glucose oxidation rate to normal, without significantly reducing the hyperglycemic state of the rats. An examination of the temporal changes in glucose utilization by the rat lung after acute insulin treatment revealed that the diabetic lung responded directly to serum levels of insulin, whereas the normal lung appeared to be unaffected by serum insulin levels as hihg as 87 ng/ml. The reduced rate of glucose oxidation in the diabetic lung was apparent after perfusion of the lung with glucose-free medium, and was characterized by a significant reduction in Vmax without an alteration in Km. This was attended by a depressed ability of the lung to incorporate [3H]leucine into protein and an increased ability to produce lactate, but hexose monophosphate shunt activity was normal. Specific receptors for insulin have been identified and partially characterized in crude membrane preparations of normal rat lung. The interaction of insulin with these receptors was rapid, reversible, saturable, and was dependent upon time and temperature. The binding of labeled insulin was inhibited by low concentrations of unlabeled insulin and by high concentrations of proinsulin, whereas it was unaffected by the presence of glucagon, gastrin, prolactin, ACTH, or growth hormone in microgram amounts. These observations suggest that insulin regulates the transport and utilization of glucose in the rat lung, and that this tissue contains specific receptors for insulin.

Animals↗