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Lung size matching for double lung transplantation based on the submammary thoracic perimeter. Accuracy and functional results. The Joint Marseille-Montreal Lung Transplant Program.

The present study evaluates the accuracy of submammary thoracic perimeter for lung size matching between donor and recipient and analyzes the influence of donor lung size discrepancies on functional outcome after double lung transplantation. The population is composed of 18 double lung graft recipients, 16 of whom had cystic fibrosis. The lung size match was assessed by comparison of predicted total lung capacity of donor and recipient: five patients were matched in a 10% confidence interval; four received smaller lungs, and nine received larger ones. The functional outcome was assessed with the spirometric values measured at 3 and 6 months after transplantation. The final functional result was not influenced by the lung size (r = 0.142 for total lung capacity; r = 0.372 for vital capacity; r = 0.378 for forced expiratory volume in 1 second). For larger lungs the final result tended to the recipient's predicted, whereas for smaller lungs, spirometry tended to the donor's predicted (r = 0.906 for total lung capacity; r = 0.875 for vital capacity; r = 0.874 for forced expiratory volume in 1 second). The thoracotomy effect, that is, restrictive syndrome at 3 months that resolves at 6 months, was not correlated with the lung size (r = 0.07 for total lung capacity; r = 0.436 for vital capacity). It is concluded that respiratory functional result is not affected by larger lungs; despite the wide range of error, the submammary thoracic perimeter appeared to be a satisfactory selection parameter in this group of patients.

Adolescent↗

Magnetic resonance imaging of lung signal intensity and dimensions in patients with advanced lung disease before and after single lung transplantation.

A retrospective analysis of lung signal intensity normalized for fat and lung cross-sectional area normalized for body surface area was obtained from cardiac gated spin-echo (echo time 40 ms) images before and after single-lung transplantation in 12 patients with pulmonary airway disease (seven emphysema, two bronchiectasis and three obliterative bronchiolitis) and 14 with interstitial lung disease (three pulmonary fibrosis, four fibrosing alveolitis and seven lymphangioleiomyomatosis). Nine healthy volunteers were studied for comparison. The native lung in pulmonary airway disease without inflammatory processes has normalised signal intensity (79 +/- 12%) similar to that of the control (100 +/- 6%) while interstitial lung disease had a higher normalised signal intensity (172 +/- 33%; P = < 0.05). The transplanted lung had a similar normalised signal intensity (103 +/- 12%) to that of the control except when there was a rejection reaction (one patient) or infection (two patients). Compared with the control, the native lung was smaller in pulmonary fibrosis (50 +/- 8%) and fibrosing alveolitis (78 +/- 8%), while larger in lymphangioleiomyomatosis (136 +/- 6%) and pulmonary airway disease (165 +/- 8%). The cross-sectional area of the transplanted lung was comparable to that of the control (100 +/- 13%). Distinctive features of lung normalised signal intensity and cross-sectional area were demonstrated in patients with pulmonary airway disease and interstitial lung disease before lung transplantation. These measurements could be useful noninvasive indices for assessment of the transplanted lung and for frequent follow-up of patients without exposure to ionizing radiation. Future developments are required to enhance lung signal sufficiently to detect less severe diseases.

Adult↗

Pentoxifylline and lung ischemia-reperfusion injury: application to lung transplantation. Université Paris-Sud Lung Transplant Group.

Pentoxifylline (PTX) attenuates neutrophil-mediated lung injury in several models of acute lung inflammation. Because pulmonary neutrophil sequestration is the main determinant of ischemia-reperfusion (IR) injury in lung transplantation, we sought to determine whether or not PTX prevented IR injury in isolated perfused rat and rabbit lungs submitted to IR, and in pigs after left lung allotransplantation. In rat lungs after IR, the coefficient of lung endothelial permeability (Kfc) increased by 112 +/- 12% in controls and by 27 +/- 8% (p < 0.001) in PTX-treated lungs. After IR, lung myeloperoxidase and blood neutrophil count decrease were lower with PTX than in controls, and the changes in Kfc were correlated with the percentage decrease in blood neutrophils during reperfusion. In rabbit lungs, endothelium-dependent relaxation in isolated pulmonary arterial rings was decreased in the control group and normal in the PTX group. In pigs ventilated with pure oxygen, the PaO2 was greater in the PTX group than in the control group (423 +/- 49 vs. 265 +/- 43 mm Hg; p < 0.05), whereas the total pulmonary vascular resistance was lower (15 +/- 1 vs. 30 +/- 9 mm Hg/L/min; p < 0.02). After reperfusion, the decrease in circulating leukocyte count fell by 35 +/- 3% in the control group and remained unchanged in the PTX group, and the leukocyte count per microscopic field in the transplanted lung was lower in the PTX group than in the control group (p < 0.02). In conclusion, PTX prevented IR lung endothelium injury and improved post-IR lung function by decreasing neutrophil lung sequestration, and this agent might be useful in clinical lung transplantation.

Animals↗

Lung function associated with histologically diagnosed acute lung rejection and pulmonary infection in heart-lung transplant patients.

A group of 34 heart-lung transplant patients were studied with serial pulmonary function measurements, chest radiographs, and transbronchial biopsies from the time of surgery. These investigations were carried out routinely at 3 and 6 months and then annually after transplantation as well as on clinical suspicion of acute lung rejection or infection. A total of 61 transbronchial biopsies and concurrent lung function and chest radiographs were obtained. Of the biopsies, 30 (49.2%) showed histologic evidence of lung rejection, 12 (19.7%) demonstrated various opportunistic infections, and 19 (31.1%) were normal. Compared to during episodes of normal biopsies, FEV1 decreased significantly with lung rejection (p less than 0.001) and with infection (p less than 0.01). Vital capacity (VC) and DLCO also fell with these acute lung complications. Using histologic diagnosis as a standard, lung function testing had a sensitivity of 86% in detecting lung rejection in the first 3 months postoperation and 75% in the subsequent period. Its sensitivity for detecting lung infection was 75%. Although not distinguishing between these two complications, lung function had a specificity of 84% for detecting occurrence of an acute lung complication. Chest radiographs, although of similar sensitivity in the first 3 months postsurgery, had a sensitivity of only 19% for rejection in subsequent months and 58% for infection. Its specificity was 100%. Lung function testing changes in a predictable fashion with lung rejection and infection, offers an improvement over chest radiographs, and provides a quantitative measurement to aid the decision of when to undertake transbronchial lung biopsy.

Biopsy↗

The effect of recipient lung size on lung physiology after heart-lung transplantation.

We studied the postoperative course of lung volumes in 32 heart-lung transplant recipients relative to the predicted total lung capacity of the individual donors, to assess the degree of inaccuracy likely to result from the radiological method of matching of donor and recipient lung sizes. There was a tendency for recipients with large preoperative lung volumes--from, for example, emphysema--to receive smaller lungs, while those with smaller volumes from pulmonary vascular disease received bigger donor lungs, but no immediate problems were incurred. After an initial fall in total lung capacity, the postoperative value of the total lung capacity approached the recipients' pretransplant value about one year after the operation irrespective of the size of the donor lungs. This suggests that chest wall compliance is the major determinant of postoperative lung volume and not the donor lung size or compliance. Exact matching of donors' and recipients' lung sizes may not be necessary, and if required can be simply achieved by comparing the measured total lung capacity in the recipient with the predicted value of the donor based on sex, age, and height.

Anthropometry↗

Assessment of PEEP-induced reopening of collapsed lung regions in acute lung injury: are one or three CT sections representative of the entire lung?

OBJECTIVES: To study whether PEEP-induced reopening of collapsed lung regions--defined as the decrease in nonaerated lung volume measured on a single or three computerized tomographic (CT) sections--is representative of the decrease in overall nonaerated lung volume. DESIGN: Review of 39 CT scans obtained in consecutive patients with Acute Lung Injury. SETTINGS: Fourteen-bed surgical intensive care unit of a University Hospital. MEASUREMENTS AND RESULTS: PEEP-induced decrease in nonaerated lung volume was measured in 39 patients with ALI on a single juxtadiaphragmatic CT section, on three CT sections--apical, hilar, and juxtadiaphragmatic--and on contiguous apex-to-diaphragm CT sections. The percentage of decrease in nonaerated lung volume following PEEP, was compared between one, three and all CT sections using a linear regression analysis and Bland and Altman's method. The decrease in nonaerated lung volume measured on a single and three CT sections was significantly correlated with the decrease in nonaerated lung volume measured on all CT sections: R=0.83, P<0.0001 for one CT section and R=0.92, P<0.0001 for three CT sections. However, measurements performed on a single CT section were poorly representative of the overall lung: bias -6%, limits of agreement ranging between -37% and +25%. Measurements performed on three CT sections overestimated by 11% the overall decrease in nonaerated lung volume: bias -11%, limits of agreement ranging between -29% and +7%. CONCLUSIONS: PEEP-induced reopening of collapsed lung regions measured on a single or three CT sections sensibly differs from the reopening of collapsed lung regions measured on the overall lung. The inhomogeneous distribution of PEEP-induced reopening of collapsed lung regions along the cephalocaudal axis probably explains these discrepancies.

Adult↗

Increased intensity of lung infiltrates at the side of lung cancer in patients with lung cancer associated with pulmonary fibrosis.

It has been reported that lung cancer is frequently associated with idiopathic pulmonary fibrosis (IPF). The purpose of this study was to compare the intensity of lung infiltrates between the side associated with lung cancer and the side without lung cancer. Twenty-three patients (24 lung cancers) with primary lung cancer associated with pulmonary fibrosis were retrospectively evaluated. Chest CT findings were evaluated by three expert radiologists using the intensity scores. In 16 of the 23 patients, it was possible to compare the intensity of lung infiltrates between both sides of the lungs. As a result, increased intensity at the side in which lung cancer developed was demonstrated in 12 of 16 patients (75%). In the remaining four patients, intensity of lung infiltrates was the same in both lungs. In operated patients as well as autopsied patients, it was possible to evaluate the pathological findings of lung tissues around cancer cells. This study clearly demonstrates that the intensity of lung infiltrates increased at the side in which lung cancer developed.

Adenocarcinoma↗

Changes in lung volume and volume of emphysema after unilateral lung reduction surgery: analysis with CT lung densitometry.

PURPOSE: To evaluate changes in volume of the lungs and volume of emphysema after unilateral lung reduction surgery (ULRS) by using computed tomographic (CT) lung densitometry. MATERIALS AND METHODS: Twenty-eight patients underwent CT before and 3 months after ULRS. With use of a density mask software program and a three-dimensional graphics workstation, CT scans were analyzed to define the volume of the lungs and the volume of emphysema. Pre- and postoperative mean CT numbers were determined. RESULTS: After ULRS, the surgically reduced lung volume decreased 22%, and the intact opposite lung volume increased 4%. Emphysema in the surgically reduced lung decreased 14% and was unchanged in the intact opposite lung. Mean CT numbers in the surgically reduced lung increased 26 HU but were unchanged in the intact opposite lung. CONCLUSION: The effects of ULRS on each lung can be evaluated by using CT lung densitometry and a three-dimensional graphics workstation. ULRS reduces emphysema and lung volume in the surgically reduced lung without statistically significant worsening of contralateral emphysema at 3 months.

Adult↗

The effect of lung biopsy on lung function in diffuse lung disease.

The aim of this study was to investigate the effect on lung function of lung biopsy used in the diagnosis of diffuse lung disease carried out by an open procedure or by video-assisted thoracoscopy. One hundred and sixteen patients with diffuse lung disease who attended the Royal Brompton Hospital were studied retrospectively. Thirty five patients underwent open lung biopsy, and 33 video-assisted thoracoscopic biopsy and 48 had their diagnosis made without biopsy. All patients underwent lung function tests before and after surgery, or at an interval of 3-6 months in those who did not undergo biopsy. No significant differences were found in changes in lung function between those who had and had not undergone biopsy, and the proportions of patients whose lung function improved or deteriorated were similar. Lung biopsy by an open procedure or by video-assisted thoracoscopy did not differ in its effects on lung function. The results for older patients, those with severe disease and those with fibrosing alveolitis were the same as for the whole group. Open lung biopsy for the diagnosis of diffuse lung disease does not deleteriously affect lung function whether carried out by an open or a minimally invasive procedure.

Adult↗

Increased lung clearance of 99mTcDTPA in allograft lung rejection. The Paris-Sud Lung Transplant Group.

To investigate whether lung 99mTc-DTPA clearance is altered during allograft lung rejection, a group of four double lung and 24 heart-lung transplant patients was studied using serial measurement of the clearance rate of aerosolized 99mTc-DTPA (DTPA-Cl), in association with pulmonary function tests, bronchoalveolar lavage, and transbronchial lung biopsies. Using histologic diagnosis as a standard, we compared 56 episodes with normal lung histology to 32 episodes with allograft lung rejection. A control group of 20 healthy nonsmokers was used to define normal DTPA-Cl. In patients with normal lung histology, DTPA-Cl was higher than in control subjects (2.62 +/- 0.25 versus 1.20 +/- 0.12 %/min; p less than 0.001). In the episodes of allograft lung rejection, DTPA-Cl increased to 3.65 +/- 0.41 %/min (p less than 0.02) as compared with episodes of normal lung histology. The change in DTPA-Cl during allograft lung rejection was correlated (r = 0.3, p less than 0.01) with the increased percentage of lymphocytes in bronchoalveolar lavage (27.8 +/- 3.5% in rejection versus 19.9 +/- 2.2% in normal histology; p less than 0.02). Sensitivity and specificity of DTPA-Cl measurement in detecting lung rejection were 69 and 82%, respectively, versus 45 and 85% for FEV1 measurement. These results suggest that DTPA-Cl monitoring could be used in conjunction with pulmonary function testing as a noninvasive approach for the detection of lung rejection.

Adult↗

Stimulation of lung growth in fetuses with lung hypoplasia leads to altered postnatal lung structure in sheep.

Increased lung expansion in the fetus stimulates lung growth and is being trialed clinically to reverse severe fetal lung hypoplasia. Our aim was to examine the effects of increased fetal lung expansion in the presence of lung hypoplasia on lung structure in sheep at term and 8 weeks after birth. Lung hypoplasia was induced in 15 fetal sheep by continuous drainage of tracheal fluid, commencing at approximately 113 days of gestation (term, approximately 148 days). In 10 of these fetuses, tracheal obstruction (TO) was performed from 137-147 days of gestation (treated lung hypoplasia, TLH), while lung liquid drainage continued until term in the remaining 5 fetuses (untreated lung hypoplasia, ULH). Lung tissues were obtained from 5 TLH, 5 ULH, and 5 control lambs at birth, and from 5 TLH and 5 control lambs at 8 weeks after birth. At birth, alveolar number, surface area, and interalveolar wall thickness were not different between TLH and control lambs, whereas airspace diameter was greater in TLH lambs (72.7 +/- 3.0 microm) than in controls (58.4 +/- 4.3 microm). Diameters of airspaces were not different between ULH and control lambs; however, alveolar numbers and surface area were reduced, while interalveolar wall thickness was increased in ULH lambs compared to controls. At 8 weeks after birth, alveolar number (928.0 +/- 66.1 x 10(6)) and surface area (30.3 +/- 2.2 m(2)) in TLH lambs were lower, whereas interalveolar wall thickness (83.0 +/- 3.1 microm) was greater than in control lambs (2,263.6 +/- 261.6 x 10(6), 46.7 +/- 4.8 m(2), and 68.6 +/- 2.1 microm, respectively). Our data show that TO restores most aspects of lung structure to normal in fetuses with lung hypoplasia but leads to altered alveolar development. The presence of fewer, larger alveoli in postnatal TLH animals may predispose these animals to respiratory complications during later life.

Analysis of Variance↗

Oleic acid vs saline solution lung lavage-induced acute lung injury: effects on lung morphology, pressure-volume relationships, and response to positive end-expiratory pressure.

OBJECTIVE: To compare two lung injury models (oleic acid [OA] and saline solution washout [SW]) regarding lung morphology, regional inflation, and recruitment during static pressure-volume (PV) curves, and the effects of positive end-expiratory pressure (PEEP) below and above the lower inflection point (Pflex). METHODS: Fourteen adult pigs underwent OA or SW lung injury. Lung volumes were measured using CT. PV curves were obtained with simultaneous CT scanning at lung apex and base. Fractional inflation and recruitment were compared to data on PEEP above and below Pflex. RESULTS: Severity of lung injury was comparable. At zero PEEP, SW showed an increased amount of edema and poorly aerated lung volume, recruitment during inspiration, and a better oxygenation response with PEEP. Whole-lung PV curves were similar in both models, reflecting changes in alveolar inflation or deflation. On the inspiratory PV limb, recruitment and inflation were on the same line, while there was a substantial difference between deflation and derecruitment on the expiratory limb. PEEP-induced recruitment at lung apex and base was at or above the derecruitment line on the expiratory limb and showed no relationship to the whole-lung expiratory PV curve. CONCLUSIONS: The following conclusions were made: (1) OA and SW models are comparable in mechanics but not in lung injury characteristics; (2) neither inspiratory nor expiratory whole-lung PV curves are useful to select PEEP in order to optimize recruitment; and (3) after recruitment, there is no difference in derecruitment between the models at high PEEP, while more collapse occurs at lower PEEP in the basal sections of SW lungs.

Animals↗

Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants.

BACKGROUND: Many preterm babies who survive, having had respiratory distress syndrome (RDS) or not, go on to develop chronic lung disease (CLD). This is probably due to persistence of inflammation in the lung. Corticosteroids have powerful anti-inflammatory effects and have been used to treat established CLD. However it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES: To determine if late (> 3 weeks) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the treatment of chronic lung disease (CLD) in the preterm infant. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Database of Controlled Trials, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment initiated at > 3 weeks of age in preterm infants with CLD were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality before discharge, failure to extubate, infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), gastrointestinal bleeding, bowel perforation, echodensities on ultrasound scan of brain, need for home oxygen, glycosuria, need for late rescue with dexamethasone, cerebral palsy in survivors and blindness in survivors were abstracted and analysed using Revman 4.0.4. MAIN RESULTS: Delayed steroid treatment had no effect on mortality. The only beneficial effects were reductions in failure to extubate by 7 or 28 days, need for late rescue treatment with dexamethasone, chronic lung disease at 36 weeks, and discharge to home on oxygen therapy. There was no increase in risk of infection, necrotising enterocolitis, or gastrointestinal bleeding. Short-term adverse affects included hyperglycaemia, glycosuria and hypertension. There was an increase in severe retinopathy of prematurity, but no effect on blindness. There were increases in long-term neurologic sequelae including abnormal neurologic examination and cerebral palsy, the latter of borderline statistical significance. REVIEWER'S CONCLUSIONS: The benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. There is a worrying increase in adverse neurological outcomes in infants treated with postnatal steroids (see also Review of Early Postnatal corticosteroids). Corticosteroids should be reserved for infants who cannot be weaned from mechanical ventilation. The dose of dexamethasone and the duration of any course of treatment should be minimised.

Anti-Inflammatory Agents↗

Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects. OBJECTIVES: To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in the preterm infant. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal steroids within 96 hours after birth. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, failure to extubate, pulmonary air leak, survival without chronic lung disease, CLD defined at 28 days postnatal age and 36 weeks post menstrual age, patent ductus arteriosus (PDA), severe intraventricular hemorrhage (IVH), infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), gastrointestinal bleeding and longterm outcome were abstracted and analysed using Revman 4.0.4. MAIN RESULTS: Fifteen randomised controlled trials of early postnatal corticosteroid treatment of preterm babies at risk of developing CLD were identified. A meta-analysis of these trials demonstrates benefits as regards earlier extubation, decreased risks of CLD at both 28 days and 36 weeks, death or CLD at 28 days, and PDA. There was an almost significant reduction in the risk of pulmonary air leak and in death or CLD at 36 weeks in the babies treated with early corticosteroids. There were no differences in the rates of neonatal mortality, infection, severe ROP, severe IVH, NEC and pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia and hypertension were also increased. Several adverse neurological effects were found at follow-up examinations of survivors treated with early steroids: abnormal neurological examination, cerebral palsy and developmental delay. REVIEWER'S CONCLUSIONS: The benefits of early postnatal corticosteroid treatment (< 96 hours) may not outweigh the known or potential adverse effects of this treatment. Gastrointestinal effects early in the neonatal period and neurological effects seen at follow-up mean that current use of early postnatal steroids needs to be reconsidered. There is a compelling need for the long term follow-up and reporting of late outcomes, especially neurologic and developmental outcomes, among surviving infants who participated in all randomized trials of early postnatal corticosteroid treatment. The role of inhaled steroids remains to be elucidated.

Anti-Inflammatory Agents↗

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↗

Evaluation of isolated lung perfusion as neoadjuvant therapy of lung metastases using a novel in vivo pig model: II. High-dose cisplatin is well tolerated by the native lung tissue.

OBJECTIVE: Efficacy of in vivo isolated lung perfusion (ILP) with cisplatin could be shown in different rodent tumor models. Despite the use of this alternative therapeutical strategy in very few patients with lung metastases, there are no systematic studies regarding the tolerance of the native lung tissue in large animal models or humans. METHODS: In a novel ILP pig model, groups with two different concentrations of cisplatin (group CP150: 150 mg/m(2) cisplatin, n=5; group CP300: 300 mg/m(2) cisplatin, n=5) were compared with a control group (n=5) and a Sham group (n=5) concerning the influence on hemodynamic, ventilatory and gas exchange parameters as well as on structural integrity of the lung. In the additional CP300-HT group the potentially cumulative effect of hyperthermia and high-dose cisplatin perfusion was evaluated (300 mg/m(2) cisplatin, 41.5 degrees C, n=5). Following the ILP of the left lung for 40 min, right main bronchus and right pulmonary arteries were clamped and survival as well as lung function parameters were dependent on the previously perfused lung for the 6-h-reperfusion period. Quantification of histological acute lung injury was performed using the score of Chiang. ANOVA, ANOVA with repeated measures and Pearson's correlation estimation were applied for statistical evaluation. RESULTS: All animals survived ILP and the entire reperfusion period. Platinum levels of the perfusate and lung tissue showed a significant correlation with the dose given (P<0.001) but no correlation with the very low plasma levels in all groups (P=0.825). ILP resulted in a slight deterioration of most functional parameters compared to the Sham group. Although there were no differences between the perfusion groups regarding hemodynamic and ventilatory parameters, gas exchange parameters (pO(2)/FiO(2)-index, pCO(2), AADO(2)) demonstrated a trend toward dose-related functional impairment. Histological evaluation confirmed a dose-depending damage of lung tissue (P<0.001, correlation coefficient 0.670). The hyperthermic ILP with high-dose cisplatin led to improved gas exchange parameters and a reduction of morphological lung damage. CONCLUSIONS: In vivo ILP with high-dose cisplatin represents a safe procedure in this pig model. Hyperthermic perfusion up to 41.5 degrees C was beneficial to reduce the acute lung injury. The promising results of this study might be used for initiation of clinical trials as an alternative treatment in patients with a very poor prognosis.

Animals↗

Metallothionein expression in human lung and its varying levels after lung transplantation. Toulouse Lung Transplantation Group.

The aim of this study was to determine the lung levels of metallothionein (MT), a free radical scavenger, because oxygen-derivated free radicals (ODFRs) have been involved both in reperfusion injury of transplanted lungs and in cardiac or renal allograft destruction. First, MT localization was evaluated in 14 normal human lung biopsy specimens. Then, in lung transplant recipients, MT content in BAL fluid (BALF) and its transcription rate in alveolar macrophages (AMs) were determined. The BALFs of 69 patients were separated into six groups: lung transplant recipients in clinically stable condition (CSR), those with acute rejection (AR), asymptomatic cytomegalovirus infection (ACMV), cytomegalovirus pneumonitis (CMVP), bronchiolitis obliterans syndrome (BOS), and patients without transplants who served as control subjects (NTCs). In normal lungs, 83% of AMs were positively stained. MT staining was also observed in pleural endothelial cells and basal cells from bronchial epithelium. In lung transplant recipients, MT levels in BALF were significantly higher in patients with CSR, AR, ACMV, and CMVP compared with NTCs, while during BOS, MT had a significantly lower level compared with other lung transplant groups. However, no difference among groups was found concerning MT-II messenger RNA expression in AMs, showing that, as in normal lung, AMs are not the only cells that produce MT. These data report for the first time to our knowledge MT cell distribution in human lung with specific emphasis on its enhanced levels after lung transplantation, even in the absence of complication. Possible correlation among MT levels, ODFRs, cytokine levels, and corticosteroid treatment during complications of lung transplantation are discussed.

Acute Disease↗

MRP is frequently expressed in human lung-cancer cell lines, in non-small-cell lung cancer and in normal lungs.

The multidrug resistance-associated protein (MRP), a new membrane transporter related to non-Pgp multidrug resistance, is overexpressed in some drug-selected cancer-cell lines. The role of MRP in unselected cell lines and in human cancer is unknown. MRP gene expression, determined by RNase protection assay and chemosensitivity to doxorubicin, etoposide and cisplatin, determined by MTT assay, were assessed in 18 non-drug-selected lung-cancer cell lines (10 small-cell lung cancer, 6 non-small-cell lung cancer, and 1 carcinoid). MRP gene expression was also investigated in normal lung tissue and primary non-small-cell lung cancer. All cell lines except one and all normal lung tissues and primary non-small-cell lung cancers expressed detectable levels of MRP. Expression was significantly lower in cell lines than in normal and neoplastic lung. MRP protein expression was also assessed by immunohistochemistry using the monoclonal antibody MRPr1; comparable levels of expression were observed between mRNA and protein in cell lines; however, in tumor samples intense staining was observed in tumor cells as well as in infiltrating normal cells in tumors, making the results less comparable to those obtained by RNase expression. MRP expression did not directly correlate with function in a calcein accumulation assay in 2 unselected cell lines. No gene amplification was observed by Southern-blot analysis, in the unselected cell lines or in tumor samples. In general, in cell lines, MRP gene expression was correlated with lower chemosensitivity to doxorubicin and etoposide, but not to cisplatin. However, MRP expression did not directly correlate with MRP function as assessed by a calcein accumulation assay in one of 2 unselected cell lines examined. Our results suggest that MRP may be implicated in drug resistance in unselected lung-cancer cell lines and its role in normal lung and primary lung cancer warrants further investigation in patients undergoing chemotherapy.

ATP-Binding Cassette Transporters↗