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PubMed2003

Gene expression signatures identify novel regulatory pathways during murine lung development: implications for lung tumorigenesis.

Oligonucleotide array based analysis was conducted to examine the temporal pattern of gene expression across the various stages of lung development to identify regulatory pathways at key developmental time points. Whole embryo total RNA or embryonic lung total RNA was harvested from A/J mice at seven developmental stages. To investigate changes in gene expression during lung development, four samples from each stage were examined using Affymetrix U74Av2 murine oligonucleotide microarrays. From the over 12,000 genes and ESTs represented on the array, 1346 genes and ESTs were identified as having a significant change in expression between at least one time point and the others (p<0.001, Kruskal-Wallis test). Within this group of approximately 1300 genes, four patterns of expression were seen: (1) upregulation during the embryonic period of development (up-down); (2) upregulation during the postnatal period of lung development (down-up) and (3) fluctuating expression, up initially, down for one or more time points, and then up again (up-down-up); and (4) vice versa (down-up-down). Expression patterns of genes previously reported to be involved in pulmonary development were also examined. Using the pathway visualisation tool, GenMapp, at least three regulatory pathways were found to contain clusters of differentially expressed genes: Wnt signalling, cell cycle, and apoptosis. Furthermore, we have shown that many of the genes involved in lung development are either known oncogenes or tumour suppressor genes altered in lung cancer, such as Cyr61, Rassf1a, and Dutt1/Robo1, or putative lung cancer genes. In addition, the genes identified pertinent to early development may also serve as candidate susceptibility genes for various inherited lung cancer disorders as well as for various heritable disorders of lung development. These results will contribute to our understanding of novel aspects of the regulatory machinery for embryonic lung development and of the genes involved in lung tumorigenesis.

Animals↗
PubMed2005

Differential expression of VASP in normal lung tissue and lung adenocarcinomas.

BACKGROUND: Vasodilator stimulated phosphoprotein (VASP) is associated with focal adhesions and is thought to have an important role in actin filament assembly and cell motility. We hypothesise that an increase in the expression of VASP is involved in the progression and invasion of lung adenocarcinomas in parallel to tumour progression. A study was undertaken to analyse VASP expression in normal lung tissue and lung adenocarcinomas. METHODS: Human lung tissues with adenocarcinomas (n = 26) were used. Normal lung tissue specimens (n = 14) were taken from areas a standard distance (3 cm) from resected adenocarcinomas of patients who underwent surgical lung resection. Adenocarcinomas were classified according to pathological staging and histopathological grades. Tissues were stained for VASP using immunohistochemistry. RESULTS: Normal lung pneumocytes showed no VASP expression while alveolar macrophages had the strongest immunoreactivity for VASP. Bronchial epithelium (surface epithelium, goblet cells) and bronchial gland cells had a very weak immunoreactivity for VASP. Adenocarcinomas had significantly greater VASP expression than normal epithelium (p < 0.001). Moreover, VASP expression in adenocarcinomas increased significantly with more advanced tumour stage (p < 0.001). CONCLUSIONS: The spatial and differential expression of VASP in normal lung tissue and lung adenocarcinomas suggests that it is likely to be involved in the differentiation of normal lung cells to adenocarcinomas. The significant increase in the expression of VASP in adenocarcinomas in parallel to pathological staging suggests that it may regulate the invasive behaviour of lung adenocarcinomas as adenocarcinoma invasion is increased in more advanced tumours.

Adenocarcinoma↗
PubMed2002

Acute lung injury and lung transplantation influence in vitro subtype conversion of pulmonary surfactant.

The effects of surfactant treatment on surfactant subtype conversion after lung injury were examined. Dogs were subjected to hyperventilation for 8 h with or without surfactant treatment. Lungs were stored for 17 h, and the right lung was transplanted and reperfused for 6 h. Conversion of large aggregate (LA) surfactant to small aggregates was investigated using in vitro surface area cycling. LA from transplanted lungs (Transplant-LA) from the nontreated group converted more rapidly than Transplant-LA from the treated group. Transplant-LA from both groups converted more rapidly than LA from normal lungs. Calculations based on [(3)H]dipalmitoylphosphatidylcholine in the administered surfactant [bovine lipid extract surfactant (BLES)] showed that the endogenous component of Transplant-LA converted more rapidly than the exogenous component. This indicates exogenous BLES did not equilibrate completely with endogenous surfactant. LA from hyperventilated, stored donor right lungs and from the recipients' native lungs from the nontreated group converted more rapidly than corresponding LA in the BLES-treated group. Similar relative conversions were observed with exogenous components from all lungs. Relative conversion of endogenous component from Transplant-LA was more rapid than that from LA from donor's stored right lung or from the recipient's native right lung. Low levels of phenylmethylsulfonyl fluoride inhibited conversion of Transplant-LA to a greater extent than normal LA. LA from all experimental groups had similar protein levels. These studies show acute lung injury, transplant, ischemia-reperfusion, and surfactant treatment have major effects on surfactant subtype integrity.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1979

Lung interdependence and lung-chest wall interaction of sublobar and lobar units in pigs.

In anesthetized and paralyzed pigs in the left decubitus position we obstructed, at functional residual capacity (FRC), either the right middle and lower lobes, or a small posterior basal lung unit, and then passively inflated the unobstructed remaining lung. Measurements were made of alveolar pressure in the obstructed and unobstructed lung regions as well as of esophageal pressure. The tendency of the obstructed lung region to inflate as the remainder of the lung was inflated was assessed by an index (A), which was the end-inspiratory pressure difference between unobstructed and obstructed alveolar pressures, normalized by the change in elastic recoil of unobstructed lung. With the chest wall intact, inflation of unobstructed lung resulted in a tendency to inflate the obstructed regions. This tendency was abolished with the chest wall removed. In a second group of pigs with the basilar lung unit obstructed, the height of the unit was changed by turning a pig from right to left decubitus positions. In each position A was assessed with both spontaneous and positive pressure ventilation. The magnitude of A was found to vary directly with the magnitude of caudal diaphragmatic motion and was greatest with the lung unit dependent and with spontaneous ventilation. These results suggest that lung-chest wall interaction was a more important factor tending to preserve homogenous inflation than lung tissue interdependence.

Animals↗
PubMed1993

Regional lung mechanics and gas transport in lungs with inhomogeneous compliance.

The effect of respiratory frequency (f) on the distributions of ventilation, regional gas transport, lung volume, and regional impedance was assessed with positron imaging in lungs with nonuniform lung mechanics after unilateral lung lavage. Supine dogs were studied during eucapnic oscillatory ventilation at f between 1 and 15 Hz and at a constant mean airway pressure of 5 cmH2O. Substantial differences in mean lung volume and tidal volume (VT) between lavaged and control lungs were found at all f values, but pendelluft never exceeded 2% of mouth flow. For f < or = 10 Hz, VT distributed in direct proportion to lung volume, whereas gas transport per unit of lung volume, measured from washout maneuvers, was reduced by 20% in the lavaged lung. At 15 Hz, however, the distributions of VT and gas transport approached equality between both lungs. Regional impedance was analyzed with a model that included a Newtonian resistance, an inertance, and Hildebrandt's model of tissue viscoelasticity. The data obtained from this work provide useful insights with respect to the mechanisms of gas transport during high-frequency ventilation and suggest the impact of operating frequency in clinical situations where substantial interregional heterogeneity in lung compliance could be expected.

Animals↗
PubMed1998

Dynamics of lung collapse and recruitment during prolonged breathing in porcine lung injury.

Oleic acid (OA) injection, lung lavage, and endotoxin infusion are three commonly used methods to induce experimental lung injury. The dynamics of lung collapse and recruitment in these models have not been studied, although knowledge of this is desirable to establish ventilatory techniques that keep the lungs open. We measured lung density by computed tomography during breath-holding procedures. Lung injury was induced with OA, lung lavage, or endotoxin in groups of six mechanically ventilated pigs. After a stabilization period, repetitive computed tomography scans of the same slice were obtained during prolonged expirations with and without positive end-expiratory pressure and during prolonged inspirations after 5 and 30 s of expiration. Lung collapse and recruitment occurred mainly within the first 4 s of breath-holding procedures in all three lung injury models, and some collapse and recruitment occurred even within 0.6 s. OA-injured lungs were significantly more unstable than lungs injured by bronchoalveolar lavage or endotoxin infusion. In this experimental setting, expiration times <0.6 s are required to avoid cyclic alveolar collapse during mechanical ventilation without extrinsic positive end-expiratory pressure.

Animals↗
PubMed1995

Mechanisms of lung liquid clearance during hyperoxia in isolated rat lungs.

Sodium transport across the lung epithelium is predominantly effected by apical amiloride-sensitive Na+ channels and basolaterally located ouabain-sensitive Na,K-ATPases. Previously, we reported that subacute hyperoxia caused an increase in active Na+ transport in rat lungs paralleling Na,K-ATPase upregulation in alveolar Type 2 cells isolated from the same lungs. In the present study we set out to quantify the amiloride-sensitive Na+ flux and ouabain-sensitive active Na+ transport in the isolated-perfused, fluid-filled lung model from rats exposed to 85% O2 for 7 d compared with normoxic control rats. We found increased transpulmonary albumin flux and permeability to small solutes (Na+ and mannitol) in hyperoxic rat lungs compared with controls. Amiloride (10(-5) M) instilled into rat airspaces inhibited active Na+ transport by approximately 62% in control rat lungs and by approximately 87% in lungs from rats exposed to hyperoxia, without further changing permeability for Na+ and mannitol. Ouabain (10(-5)M) perfused through the pulmonary circulation decreased active Na+ transport by approximately 40% in normal rat lungs and by approximately 52% in lungs from rats exposed to hyperoxia. We conclude that active Na+ transport and edema clearance are increased in the subacute hyperoxic lung injury in rats, caused in part by the upregulation of amiloride-sensitive apical Na+ channels and alveolar epithelial Na,K-ATPases. Conceivably, the upregulation of alveolar epithelial Na+ channels and Na,K-ATPases protects against the effects of lung injury in this model by contributing to effective edema clearance.

Albumins↗
PubMed1997

Lactate production by the lungs in acute lung injury.

Arteriovenous differences in lactate (AVLAC) across the lungs are usually small and close to zero. However, it has recently been reported that the lungs can produce increased amounts of lactate in some patients with acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate lactate production in various types of acute lung injury requiring mechanical ventilation and hemodynamic monitoring. Since the differences involved are usually small, minor errors in lactate measurement could greatly influence AVLAC. Based on an analysis of these errors (see text for details), we averaged five arterial and venous samples for each measurement. We investigated 122 patients: 43 with acute lung injury (ALI), nine with cardiogenic pulmonary edema (CPE), 37 with bronchopneumonia (BPN), seven with single lung transplantation (LTX), and 26 with other causes of respiratory failure (OTHER). There was no difference in arterial lactate between the various groups. AVLAC was higher in patients with ALI than in the other groups (0.20+/-0.23 versus 0.07+/-0.11 mEq/L). In patients with ALI, AVLAC was proportional to the Murray's lung injury score (-0.032+/-0.032x; r = 0.46, p < 0.01). Lung lactate production was calculated as the product of the cardiac index times AVLAC and was significantly higher in patients with ALI than in the other groups (0.69+/-0.88 versus 0.19+/-0.30 mEq/min; p < 0.05). In patients with ALI, lung lactate production was inversely related to the PaO2/FIO2 (1.42 - 0.005x; r = 0.35, p < 0.05) but directly related to the venous admixture (-0.36 + 0.003x; r = 0.49, p < 0.01) and the lung injury score (-0.19 + 0.36x; r = 0.45, p < 0.01). Lung lactate production was not significantly related to arterial lactate levels. These data indicate that AVLAC and lung lactate production can be increased in patients with ARDS but remain within the normal range in other types of respiratory failure.

Acute Disease↗
PubMed1998

A lung computed tomographic assessment of positive end-expiratory pressure-induced lung overdistension.

The aim of this study was to assess positive end-expiratory pressure (PEEP)-induced lung overdistension and alveolar recruitment in six patients with acute lung injury (ALI) using a computed tomographic (CT) scan method. Lung overdistension was first determined in six healthy volunteers in whom CT sections were obtained at FRC and at TLC with a positive airway pressure of 30 cm H2O. In patients, lung volumes were quantified by the analysis of the frequency distribution of CT numbers on the entire lung at zero end-expiratory pressure (ZEEP) and PEEP. In healthy volunteers at FRC, the distribution of the density histograms was monophasic with a peak at -791 +/- 12 Hounsfield units (HU). The lowest CT number observed was -912 HU. At TLC, lung volume increased by 79 +/- 35% and the peak CT number decreased to -886 +/- 26 HU. More than 70% of the increase in lung volume was located below -900 HU, suggesting that this value can be considered as the threshold separating normal aeration from overdistension. In patients with ALI, at ZEEP the distribution of density histograms was either monophasic (n = 3) or biphasic (n = 3). The mean CT number was -319 +/- 34 HU. At PEEP 13 +/- 3 cm H2O, lung volume increased by 47 +/- 19% whereas mean CT number decreased to -538 +/- 171 HU. PEEP induced a mean alveolar recruitment of 320 +/- 160 ml and a mean lung overdistension of 238 +/- 320 ml. In conclusion, overdistended lung parenchyma of healthy volunteers is characterized by a CT number below -900 HU. This threshold can be used in patients with ALI for differentiating PEEP-induced alveolar recruitment from lung overdistension.

Adult↗
PubMed1988

Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary-gonadal function in men.

We retrospectively determined serum total testosterone (T), fraction of T bound, free T index, LH, and FSH levels in 122 men with malignant lung disease, 32 men with benign lung disease, and 106 normal men. Men with malignant and, to a lesser extent, benign lung disease had decreased serum total T and free T index values at the 5th percentiles, with elevations of LH and FSH levels at the 95th percentiles. Linear regression analysis showed reductions in total T and free T index and increases in FSH, but not LH, levels with age in each group. Using multivariate analysis, we found stronger independent effects of disease than age on serum total T and fraction of T bound, but a greater influence of age on free T index. Serum LH values differed by diagnosis, whereas FSH differed by age. Relative to values in the normal men, mean serum total T levels were reduced in men with lung cancer; the fraction of T bound was decreased in the men with lung cancer and increased in the men with benign lung disease, the free T index was decreased in the men with both malignant and benign lung disease, and LH was increased in the men with lung cancer. The hormone and hormone binding results were similar in men with different types of lung cancer. Biochemical evidence of primary and secondary (or combined primary and secondary) hypogonadism was present in 50-59% and 28-32%, respectively, of the men with malignant and benign lung disease vs. 10% of the normal men. These data suggest that 1) there is an increased prevalence of both pituitary gonadotropic and testicular dysfunction in men with malignant and, to a lesser extent, benign chronic lung disease, and 2) the effects of illness are independent of, and quantitatively greater than, those due to age.

Adult↗
PubMed1991

Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease.

The purpose of this study was to characterize cardiovascular and ventilatory responses to exercise in single lung transplantation (SLT) recipients with nonseptic, severe obstructive lung disease (SLT-OB). We also investigated whether the hyperinflated native lung in SLT-OB recipients could limit normal increases in tidal volume by mechanically constraining the transplanted lung, resulting in ventilation-perfusion imbalance in the lung graft. Data from six SLT-OB recipients (five women, one man) and six age-matched SLT recipients (two women, four men) with severe interstitial lung disease (SLT-IN) were compared. Resting arterial O2 and CO2 tensions were normal and comparable between the SLT groups. Spirometry results were reduced but comparable between SLT groups. Total lung capacity was significantly larger in patients with SLT-OB than in patients with SLT-IN. Diffusion capacity was not different between SLT groups when differences in alveolar volume were accounted for. Quantitative perfusion to the lung graft was comparable between the SLT groups, but quantitative ventilation was greater in patients with SLT-OB than in patients with SLT-IN. Maximum exercise capacity following SLT-OB was decreased, but was comparable to that of SLT-IN recipients. None of the SLT-OB recipients reached predicted maximum minute ventilation and only one experienced mild arterial O2 desaturation, suggesting peripheral muscle abnormalities from corticosteroid use and deconditioning as limiting factors rather than a ventilatory limitation. Tidal volumes at end exercise in the SLT-OB recipients were normal. Our quantitative lung scan and exercise testing data suggest that ventilation-perfusion imbalance and resulting gas exchange abnormalities from lung graft constraint and compression do not occur at rest or with exercise after SLT for obstructive lung disease.

Anaerobic Threshold↗
PubMed1992

The role of transbronchial lung biopsy in the treatment of lung transplant recipients. An analysis of 200 consecutive procedures.

STUDY OBJECTIVE: The purposes of this study were as follows: (1) to establish the positivity rate and complication rate of transbronchial lung biopsies in the treatment of lung transplant recipients; (2) to determine the sensitivity of transbronchial lung biopsy specimens for the diagnosis of clinically suspected acute rejection and cytomegalovirus pneumonia; and (3) to examine the results of surveillance transbronchial lung biopsies in clinically and physiologically stable recipients. DESIGN: Retrospective review and analysis of 203 consecutive procedures. SETTING: Washington University Lung Transplantation Program, Washington University School of Medicine and Barnes Hospital, St. Louis, Mo. PATIENTS: Fifty-five lung transplant recipients. INTERVENTIONS: Biopsies were done with 2-mm fenestrated forceps using fluoroscopic guidance. Two hundred three bronchoscopies with transbronchial lung biopsy were performed for clinical indications (n = 88), routine surveillance (n = 90), or follow-up of a previous biopsy (n = 25). Biopsy specimens showing acute allograft rejection were classified according to the scheme recommended by the Lung Rejection Study Group. MEASUREMENTS AND RESULTS: The positivity rate and complication rate were determined for the procedures. In procedures performed for clinical indications, the sensitivity for the diagnosis of acute rejection and cytomegalovirus pneumonia was calculated by a decision-to-treat analysis. A specific histologic diagnosis was detected in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the follow-up procedures. For clinical indications, the sensitivity of transbronchial lung biopsy was 72 percent for the diagnosis of acute rejection and 91 percent for the diagnosis of cytomegalovirus pneumonia. Surveillance biopsy specimens often showed clinically inapparent rejection or cytomegalovirus pneumonia. The overall complication rate was 8.9 percent; none of the complications were life threatening. CONCLUSIONS: Transbronchial lung biopsy is a useful and safe procedure in the treatment of lung transplant recipients. When performed for clinical indications, the procedure proved to be sensitive for the diagnosis of acute rejection and cytomegalovirus pneumonia. When performed for surveillance in clinically and physiologically stable recipients, the incidence of rejection and cytomegalovirus pneumonia was unexpectedly high; the potential clinical implications of these findings will require further study.

Biopsy, Needle↗
PubMed1993

Regional distribution of lung perfusion and ventilation at rest and during steady-state exercise after unilateral lung transplantation.

Cardiopulmonary exercise testing has previously demonstrated a reduced maximum oxygen uptake and anaerobic threshold, as well as abnormal wasted ventilation fraction and gas exchange after unilateral lung transplantation. To further explain the mechanisms of these abnormalities, we assessed the regional distribution of pulmonary blood flow and ventilation at rest and during steady-state exercise in nine recipients of unilateral lung transplants. Krypton-81 (81mKr) aerosol and technetium-99m (99mTc) were utilized to assess lung ventilation (V) and perfusion (Q), respectively. The digitalized images were trisected to analyze apical, mid-, and basilar lung perfusion and ventilation in both the transplanted and native lung, both at rest and steady-state upright exercise. Results were compared with previously reported data obtained in normal subjects in our laboratory using the identical technique. At rest, 75 +/- 13 percent of perfusion was directed to the transplanted lung; however, the corresponding fractional ventilation was only 67 +/- 14 percent. During exercise, there was no significant change in fractional perfusion or ventilation. Resting apical perfusion in the transplanted lung was higher than normal in four patients and comparable to normal in five patients. In contrast to the augmentation of apical perfusion observed in normal subjects during upright exercise, none of our patients increased the regional perfusion to the apices during exercise in either transplanted or native lungs. These unexpected responses suggest either more maximal allograft apical recruitment at rest due to the increased allograft perfusion or an abnormality in the apical pulmonary vasculature after transplantation. Furthermore, the relative mismatch in ventilation and perfusion in transplanted and native lungs suggests regions of high V/Q in the native, and low V/Q in the transplanted lung. This mismatch is most pronounced in recipients of single lung transplants for pulmonary vascular disease.

Adult↗
PubMed1995

High-resolution computed tomographic findings associated with histologically diagnosed acute lung rejection in heart-lung transplant recipients.

A group of 32 lung (single lung, [n = 14] and double lung [n = 1]) or heart-lung (n = 17) transplant recipients were studied with serial high-resolution computed tomography (HRCT) scans and transbronchial biopsies from the time of surgery. These investigations were carried out routinely every 2 weeks for the first 2 months, every 2 months for a year, every 4 months in the second year, and on any clinical suspicion of acute lung rejection or infection. A total of 190 transbronchial biopsy specimens and concurrent HRCT scans were obtained. Forty (21%) of the biopsy specimens, showed histologic evidence of lung rejection, 111 (58%) were normal, and 39 (21%) were not conclusive. The more frequent HRCT pattern encountered during an acute rejection episode was the presence of patchy "ground-glass" density areas (65%). This finding was sparsely observed during minimal and mild acute rejection episodes. Using histologic diagnosis as a standard for acute rejection, ground-glass opacities on HRCT had a sensitivity of 65% in detecting lung rejection. Although ground-glass opacities were also intermittently observed during cytomegalovirus pneumonia (14%), this finding had a specificity of 85% for detecting occurrence of an acute lung complication. The detection of ground-glass opacities on lung HRCT after lung transplantation, more particularly after the first month after surgery, can aid the decision of when and where to undertake transbronchial lung biopsy.

Acute Disease↗
PubMed1997

Histopathologic diagnosis made in lung tissue resected from patients with severe emphysema undergoing lung volume reduction surgery.

STUDY OBJECTIVES: This study reports histopathologic findings in a group of emphysema patients who underwent thoracoscopic lung volume reduction surgery (75) or sternotomy (five) with the purpose to induce functional improvement and relief of dyspnea. Immediate outcome and complications were correlated to histologic patterns. DESIGN: Histopathologic material obtained in lung volume reduction surgery in 80 consecutive patients was analyzed. Thirty patients who had other histopathologic diagnoses in addition to emphysema were grouped and compared with 50 patients found to have emphysema exclusively. Postoperative outcome and preoperative lung function variables were compared. MEASUREMENTS AND RESULTS: All patients had severe obstructive lung disease and significant air trapping preoperatively documented by pulmonary function testing. All had severe exertional dyspnea. All had chest radiographs, CT, and nuclear medicine lung scans consistent only with emphysema. All portions of resected lung tissue were weighed, lung volume was estimated, and routine histopathologic studies were made. Thirty patients (37.5%) had unsuspected findings such as interstitial fibrosis, noncaseating granulomatosis, chronic inflammation, and unsuspected neoplasia (three carcinomas, one carcinoid). Retrospective review of imaging studies in these patients failed to show infiltrative processes. The average lung weight resected in this group was significantly heavier (65+/-18 g) compared with the other group (56+/-13 g), although both had the same estimated lung volume. Average number of days requiring chest tubes and length of hospitalization was also significantly higher (12.8+/-19 vs 6.4+/-5 days with chest tubes and 17.4+/-22 vs 8.5+/-6 days of hospitalization, respectively). None of the preoperative pulmonary function tests variables were different between the two groups. Serious postoperative complications were more frequent in these patients compared with those who showed only emphysema. CONCLUSIONS: A significant portion of patients diagnosed as having severe emphysema will have other unsuspected histologic findings. When subjected to lung volume reduction surgery, this subgroup will have more serious complications and longer periods of air leaks, requiring longer hospitalization time. Retrospective review of imaging studies and preoperative pulmonary function tests used to select patients for lung volume reduction failed to identify this subgroup.

Adult↗
PubMed2000

Quantitation of regional ventilation during the washout phase of lung scintigraphy: measurement in patients with severe COPD before and after bilateral lung volume reduction surgery.

STUDY OBJECTIVES: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation. DESIGN: Retrospective analysis of routinely acquired data before and after LVRS. SETTING: Large, urban, university medical center. PATIENTS: Twenty-nine patients with severe emphysema. INTERVENTION: Bilateral LVRS. MEASUREMENTS AND RESULTS: (133)Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [m(r)] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [m(s)] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated m(r) and m(s) for each lung region. The mean (+/- SE) baseline FEV(1) was 0.69+/-0.04 L, total lung capacity (TLC) was 139 +/-4% predicted, and the residual volume (RV)/TLC ratio was 65+/-2%. The mean improvement in FEV(1) 3 months post-LVRS was 38%. Post-LVRS, m(r) and m(s) increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in m(s), however, significantly correlated with the increase in FEV(1) (r = 0.66; p<0.0001) and the decrease in RV/TLC (r = -0.67; p<0.0001). An increase in m(s) also correlated with a decrease in PaCO(2) (r = -0.39; p = 0.03), but m(r) showed no relationship with any parameter. CONCLUSIONS: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS.

Administration, Inhalation↗
PubMed2005

CD8 T cell-mediated lung damage in response to the extracellular pathogen pneumocystis is dependent on MHC class I expression by radiation-resistant lung cells.

Pneumocystis, a fungal, extracellular pathogen causes a life-threatening pneumonia in patients with severe immunodeficiencies. In the absence of CD4 T cells, Pneumocystis infection results in vigorous CD8 T cell influx into the alveolar and interstitial spaces of the lung. This response results in lung damage characterized by low pO2 and albumin leakage into the bronchoalveolar lavage fluid similar to other CD8 T cell-mediated interstitial lung diseases. How this extracellular pathogen elicits a CD8 T cell response is not clear, and it was the aim of our study to determine the Ag specificity of the recruited CD8 T cells and to determine whether MHC class I (MHC I) expression was necessary to initiate lung damage. Using an adoptive T cell-transfer model with either polyclonal wild-type CD8 T cells or transgenic influenza virus-specific CD8 T cells we found that CD8 T cell recruitment is Ag-specific and requires the continuous presence of the Pneumocystis pathogen. Bone marrow chimera experiments using Rag-1 and beta2-microglobulin-deficient mice as hosts demonstrated a requirement for MHC I expression on nonbone marrow-derived cells of the lung. This suggests either direct processing of Pneumocystis Ags by nonbone marrow-derived cells of the lung or the induction of lung damage triggered by a lung-specific autoantigen. Using perforin-, Fas-, and IFN-gamma-deficient animals, we showed that these molecules are not directly involved in the CD8-mediated lung damage. However, CD8 T cell-mediated lung damage is Ag-specific is induced by a MHC I-expressing nonbone marrow-derived cell in the lung and is dependent on the continued presence of live Pneumocystis.

Adoptive Transfer↗
PubMed2000

Influence of lung injury on early postoperative survival after lung transplantation.

OBJECTIVES: To identify the various risk factors for early (90 day) mortality after lung transplantation and to evaluate the relationship between lung injury and postoperative survival. METHODS: 152 recipients of single (100) or bilateral (52) lung allografts were evaluated for the presence of postoperative lung injury assessed by a composite four-component lung injury score. Preoperative variables, postoperative course, and mortality were reviewed retrospectively. RESULTS: There was a high risk of death during the first 90 d after transplantation, followed by a decline in risk during the remainder of the first postoperative year. By univariate analysis, lung injury score (p = 0.0001), chest radiograph score (p = 0.0001), and hypoxemia (PaO2/FIO2) ratio (p = 0.0002) were the most statistically significant risk factors for 90-day mortality. Other parameters such as length of intensive care stay (p = 0.0175), length of intubation (p = 0.0212), and preoperative diagnosis of pulmonary fibrosis (p = 0.0123) were also significant risk factors for 90-day mortality. By multivariable analysis, only lung injury score (p = 0.0001) was a statistically significant risk factor for 90-day mortality. The risk of 90-day mortality increased by a factor of 4.4 for each 1 point increment in lung injury score. However, none of the analyzed preoperative or postoperative variables were able to statistically predict lung injury score. CONCLUSIONS: Postoperative lung injury is the most important risk factor for early postoperative mortality after lung transplantation.

Adult↗