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PubMed2006

Combined antioxidant (beta-carotene, alpha-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model.

Interactions among beta-carotene (BC), alpha-tocopherol (AT) and ascorbic acid (AA) led to the hypothesis that using a combination of these antioxidants could be more beneficial than using a single antioxidant alone, particularly against smoke-related lung cancer. In this investigation, we have conducted an animal study to determine whether combined BC, AT and AA supplementation (AOX) protects against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis in smoke-exposed (SM) ferrets. Ferrets were treated for 6 months in the following four groups: (i) control, (ii) SM + NNK, (iii) AOX and (iv) SM + NNK + AOX. Results showed that the combined AOX supplementation (i) prevented the SM + NNK-decreased lung concentrations of retinoic acid (RA) and BC; (ii) inhibited the SM + NNK-induced phosphorylation of Jun N-terminal kinase (JNK), extracellular-signal-regulated protein kinase (ERK) and proliferating cellular nuclear antigen proteins in the lungs of ferrets; and (iii) blocked the SM + NNK-induced up-regulation of total p53 and Bax proteins, as well as phosphorylated p53 in the lungs of ferrets. In addition, there were no lesions observed in the lung tissue of ferrets in the control and/or the AOX groups after 6 months of intervention, but combined AOX supplementation resulted in a trend toward lower incidence of both preneoplastic lung lesions and lung tumor formation in SM + NNK + AOX group of ferrets, as compared with the SM + NNK group alone. These data indicate that combined AOX supplementation could be a useful chemopreventive strategy against lung carcinogenesis through maintaining normal tissue levels of RA and inhibiting the activation of mitogen-activated protein kinase pathways, cell proliferation and phosphorylation of p53.

Animals↗
PubMed2005

Baseline chest radiograph for lung cancer detection in the randomized Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

BACKGROUND: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was initiated in 1992 to examine cause-specific mortality reduction from screening for these four cancers in men and women. We report lung cancer detection results of the baseline screening round. METHODS: Of the 154,942 participants enrolled, who were aged 55-74 years with no history of PLCO cancers, 77,465 were randomly assigned to the intervention arm. Current or former smokers and never smokers in this arm received an initial single-view posterior-anterior chest radiograph. RESULTS: In the initial screen, 5991 (8.9%, 95% confidence interval [CI] = 8.7% to 9.2%) of radiographs were suspicious for lung cancer: 8.2% (95% CI = 7.9% to 8.5%) for women and 9.6% (95% CI = 9.3% to 10.0%) for men. Rates were highest for older age groups and for smokers. Among those 5991 participants with a positive screen, 206 (3.4%, 95% CI = 3.0% to 3.9%) underwent biopsy examination, 126 (61.2%, 95% CI = 54.5% to 67.8%) of whom were diagnosed with lung cancer within 12 months of the screen (59 in women and 67 in men). The positive predictive value was 2.1% (95% CI = 1.7% to 2.5%), and 1.9 lung cancers were detected per 1000 screens. Among these cancers, 44% (95% CI = 35% to 52%) were stage I non-small-cell lung cancer. High rates of lung cancer were found in current smokers (6.3 per 1000 screens) and in former smokers who had smoked within the past 15 years (4.9 per 1000 screens). The lung cancer detection rate among never smokers was 0.4 per 1000 screens; this group accounted for 11% (95% CI = 5.6% to 16.6%) of the cancers identified. CONCLUSIONS: In the baseline screen, nearly half the cancers were stage I. Whether this experience results in a reduction in lung cancer mortality is yet to be seen.

Adenocarcinoma↗
PubMed1992

Preexisting lung disease and lung cancer among nonsmoking women.

Preexisting lung disease was examined as a risk factor for lung cancer in a population-based, case-control study of nonsmoking women in Missouri conducted between June 1, 1986, and April 1, 1991. A history of lung disease was reported by approximately 41% of 618 cases and 35% of 1,402 controls (odds ratio (OR) = 1.2; 95% confidence interval (Cl) 1.0-1.5. The risk was more pronounced when next-of-kin interviews were excluded (OR = 1.5). Previous lung disease was significantly related both to adenocarcinoma (OR = 1.4), which accounted for 62% of the cancers, and to all other cell types of lung cancer combined (OR = 1.8). Despite having discontinued smoking for more than 15 years, long-term ex-smokers were at a 2.2-fold risk of lung cancer compared with lifetime nonsmokers. Among lifetime nonsmokers, significant risks were noted for asthma (OR = 2.7) and pneumonia (OR = 1.5). Emphysema (OR = 2.6) and tuberculosis (OR = 2.0) were also significantly related to lung cancer, but only among former smokers. Chronic bronchitis was linked to elevated risks of nonadenocarcinomas only (OR = 2.3). Pleurisy was not reported more frequently by cases than by controls. Approximately 16% of all lung cancers among nonsmoking women could be attributed to previous lung diseases, most notably asthma, pneumonia, emphysema, and tuberculosis.

Adult↗
PubMed2003

Effect of diesel exhaust particulate on bacillus Calmette-Guerin lung infection in mice and attendant changes in lung interstitial lymphoid subpopulations and IFNgamma response.

The effect of exposure to diesel exhaust particulate (DEP) on bacillus Calmette-Guerin (BCG) lung infection in mice was studied. C57Bl/6J female mice were infected with BCG (2.5 x 104 bacteria/mouse) by intrapulmonary instillation, with or without coadministration of DEP (100 microg/mouse). Five weeks later, mice exposed to DEP + BCG had about a four-fold higher BCG load in the lungs than mice exposed only to BCG (p < 0.05). DEP treatment alone had no effect on the total number of lung lymphocytes or numbers of T, B, or NK cells recovered from lungs. In contrast, BCG infection significantly increased (p< 0.05) recovery levels of all types of lymphocytes from lungs. Coexposure to DEP + BCG further increased the recovery of lymphocytes from lungs of BCG-infected mice. The pulmonary lymphocyte subpopulation expressing the greatest levels of mRNA for IFNgamma after BCG infection was CD4+ T cells. Expression levels were similar in mice exposed to BCG or BCG + DEP and were elevated as compared to noninfected mice and mice treated with DEP alone. Recovery of IFNgamma-secreting lymphocytes and IFNgamma-secreting T cells was significantly higher (p < 0.05) from lungs of BCG-infected mice as compared to control or DEP-exposed mice. BCG and BCG + DEP groups of mice did not differ significantly in the numbers of IFNgamma-secreting lymphocytes in lungs. Taken together, these results indicated that coexposure to DEP + BCG did not significantly affect the level of IFNgamma response of mice to BCG infection. However, DEP treatment was found to inhibit IFNgamma-induced nitric oxide (NO) production by mouse alveolar macrophages in vitro. Our results indicate that DEP exposure did not alter the IFNgamma response to BCG infection, but reduced responsiveness of alveolar macrophages to IFNgamma. Reduced sensitivity of DEP-exposed alveolar macrophages to IFNgamma may contribute to a greater load of BCG in the lungs of BCG-infected mice given DEP.

Animals↗
PubMed1992

Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii infections in heart-lung and lung transplantation--how effective and for how long?

Pneumocystis carinii pneumonia (PCP) is a common clinical problem in the setting of organ transplantation, particularly in heart-lung and lung allograft recipients. Without prophylactic measurements, the incidence of P carinii pneumonia can reach up to 88% of heart-lung transplant recipients. We conducted a retrospective analysis of the Stanford heart-lung and lung transplant experience in order to assess the efficacy of the prophylactic therapy and to try to define the duration of therapy necessary for prevention. During a 9-year period 82 heart-lung and 13 single-lung transplants were performed. Of the patients not on prophylaxis therapy 27% (13 patients) developed P carinii infection as compared with 0% of patients on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. The incidence of PCP infection peaked between 3 and 6 months posttransplantation. No case of infection was observed before the 7th week posttransplant. PCP was more common following induction immunosuppression with OKT3 as compared with RATG (P less than 0.05). All cases of infections later than one year posttransplant were associated with recent increase in the immunosuppression regimen with high-dose corticosteroids for treatment of acute or chronic (obliterative bronchiolitis) rejection. Although our study is retrospective and based on various immunosuppressive and diagnostic technique periods, it seems that TMP-SMX is highly effective in preventing PCP infections in heart-lung and lung transplant recipients. Twelve months of therapy is probably a sufficient length of therapy if immunosuppressive therapy is stable. However, whenever augmentation in the immunosuppression regimen is indicated, prophylactic therapy should promptly be restarted.

Adrenal Cortex Hormones↗
PubMed2003

The presence of a local lung transplant center increases lung procurement rates.

BACKGROUND: The availability of cadaveric organs is the major problem in transplantation today. METHODS: A retrospective review of donors in a single organ procurement organization (OPO) was performed. Donors were divided into three eras: before, during, and after the presence of a local lung transplant program. Lung procurement rates by OPO in the United States in 1999 and 2000 were also retrospectively reviewed. RESULTS: Lung transplant rates were higher in the presence of a local lung program: 4.9% at baseline, 19.1% with a local program, and 7.1% after closure of the local lung program (P<0.01). In the United States, 12.4% of lungs available in OPOs with local lung programs are transplanted, versus 8.9% in OPOs without a local program (P<.001). CONCLUSIONS: Even if donor management protocols are maintained, closure of a local lung program decreases lung recovery rates. This observation supports the importance of maintaining local programs to maximize organ recovery rates.

ABO Blood-Group System↗
PubMed1994

Single lung alveolar volume and gas transfer: effect of expansion of the other lung.

BACKGROUND: Temporary occlusion of one mainstem bronchus permits measurement of single lung function. A previous study suggested that the volume at which one lung is occluded may influence the expansion of the other. The effect of ipsilateral occlusion volume on the contralateral effective alveolar volume (VA, EFF,SL), inspired volume (VI,SL), single breath estimated residual volume (RVSB,SL), carbon monoxide (CO) transfer (TLCO,SL) and transfer coefficient (KCO,SL) has been examined. METHODS: Single breath measurements of CO transfer were made in duplicate in 12 healthy subjects aged 19-44 years, without and during occlusion of one mainstem bronchus by a balloon at RV and at total lung capacity (TLC). RESULTS: Mean VA,EFF,SL, VI,SL, and TLCO,SL were lower during occlusion at RV than during occlusion at TLC (2.84 v 3.26 l; 2.18 v 2.54 l; and 4.70 v 5.51 mmol/kPa/min respectively). RVSB,SL was independent of occlusion volume and KCO,SL not different from the KCO of both lungs (KCO,BL). Single lung values during occlusion at TLC were fairly reproducible and were, except for KCO,SL, approximately half the values for both lungs. During occlusion at RV the second TLCO,SL and KCO,SL were lower than the first. CONCLUSIONS: Occlusion of one lung permits reliable determinations of gas transfer indices of the other, provided the lung is occluded at TLC. Occlusion at RV significantly reduces VA,EFF,SL, and hence TLCO,SL, but does not affect KCO,SL of the other lung.

Adult↗
PubMed1997

Metabolism in patients with small cell lung carcinoma compared with patients with non-small cell lung carcinoma and healthy controls.

BACKGROUND: Weight loss is a frequently occurring problem in patients with lung cancer due to an increased resting energy expenditure (REE) and a decreased energy intake. The aim of the present study was to compare the metabolic and inflammatory characteristics of patients with small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). The metabolic parameters of the lung cancer population were compared with those of a healthy control group. METHODS: REE was measured in 66 patients with lung cancer, subdivided according to their histology, and in 33 healthy controls matched for sex, age, and fat free mass (FFM). Inflammatory mediators were measured in the plasma of the patients with lung cancer. RESULTS: An increased REE adjusted for FFM was found in the patients with lung cancer. Those with small cell lung carcinoma (SCLC) had an increased REE adjusted for FFM (mean 1925 kcal/day) compared with those with non-small cell lung carcinoma (NSCLC) (mean 1789 kcal/day, 95% CI for difference 36 to 236). FFM accounted for 69% and 48% of the inter-individual variation in REE in controls and those with NSCLC, respectively, while FFM accounted for only 25% of the variation in REE in patients with SCLC in whom the fat mass (FM) also contributed significantly (28%) to the variation in REE. Increased concentrations of soluble TNF-receptor 75 (sTNF-R75) and cortisol were found in patients with SCLC compared with those with NSCLC. Lipopolyasccharide binding protein (LBP) and sTNF-R55 were related to plasma levels of cortisol. CONCLUSION: An enhanced REE adjusted for FFM occurred in patients with SCLC compared with those with NSCLC.

Aged↗
PubMed1982

Lung inflation, lung solute permeability, and alveolar edema.

A series of experiments in anesthetized rabbits were conducted to determine whether hyperinflation of the lung alone could produce a protein-permeable lung epithelium and whether a protein-permeable lung epithelium allowed accumulation of liquid in the alveolar space. Some animals had their entire lungs subjected to distending pressures; others had only an area of the lung subjected to the high distending pressure. Alveolar liquid was measured by dilution of radioactive solutes upon instillation of saline into atelectatic lung, and protein permeability was determined by the loss of labeled albumin from the alveolar space over 40-60 min. Inflation of the entire lung at 40 cmH2O for 20 min increases air-space gas volume three- to fourfold, does not produce a protein-permeable epithelium, and does not result in accumulation of alveolar liquid. Distension of a small area of the lung by 40 cmH2O pressure for 20 min increases the gas volume 6- to 12-fold and produces a protein-permeable epithelium, but does not result in liquid accumulation in the alveoli. It is concluded that only very high distending volumes cause the lung epithelium to become permeable to protein and that a protein-permeable epithelium alone does not induce alveolar edema.

Animals↗
PubMed1986

Surface forces in lungs. I. Alveolar surface tension-lung volume relationships.

Alveolar surface tension (gamma)-lung volume relationships were obtained for quasi-static and dynamic lung pressure-volume (PV) histories from measurements of PV curves of liquid- and air-filled excised rabbit lungs. PV relationships were measured at room temperature in lungs filled with test liquids with constant liquid-liquid interfacial tensions with alveolar surface-active materials; and air-filled lungs before and after the normal alveolar surface film was covered with test liquids with constant values of liquid- and air-liquid interfacial tensions. Interfacial tensions of test liquids were measured in a surface balance on monolayers of dipalmitoyl phosphatidylcholine. Values of gamma for the normal air-filled lung were obtained either from points of intersection between PV curves with the normal and test liquid interface or from a general relationship between gamma and the component of recoil pressure due to surface tension derived from the data. In contrast to previous analyses that have used PV measurements, this approach does not depend on assumptions about lung microstructural geometry. Surface tension-volume relationships for the normal air-filled lung show a prominent hysteresis with surface tension ranging from near 0 at low volumes during lung deflation to transiently high values near 40 dyn/cm during inflation; value of equilibrium surface tension (gamma EQ) near 28 dyn/cm; and characteristic transitions in surface film compressibility and associated transitions in film kinetic behavior in nonequilibrium film states where gamma deviates from gamma EQ. These features are consistent with the behavior predicted from current models of alveolar surface film behavior.

Animals↗
PubMed1986

Surface forces in lungs. II. Microstructural mechanics and lung stability.

Recent lung microstructural models describing interactions between alveolar surface tension (gamma) and forces in structural elements of the alveolar duct predict that the component of lung recoil pressure due to gamma (P gamma) is proportional to gamma/V1/3, where V is the total lung volume. This relation is tested against experimental data obtained from pressure-volume measurements of excised rabbit lungs with different constant values of gamma. It is found that for values of gamma less than approximately 18 dyn/cm the data generally agree with the model predictions. With higher values of gamma, a mismatch between the data and predictions first occurs at low and high volumes and then spreads over the entire volume range. The mismatch at the lower volumes coincides with the appearance of nonuniformities of lung expansion. The nonuniformities are characterized by a coexistence of under- and overexpanded regions of the parenchyma referred to as a mixture of phases. These nonuniformities, as well as a pressure-volume curve with a shape similar to the shape of measured curves, are predicted from an analysis of lung stability. Results of this work indicate that if the lung expands uniformly, P gamma proportional to gamma/V1/3 is a good approximation over a wide range of volumes. The stability analysis indicates that the equilibrium configurations of the lung parenchyma when gamma is independent of interfacial area and elevated above normal values are nonuniform states of expansion, characterizable as a mixture of phases. This result confirms that a dependence of gamma on surface area is normally required to achieve stable, uniform states of lung expansion.

Animals↗
PubMed1987

Corticosteroids and surfactant increase lung volumes and decrease rupture pressures of preterm rabbit lungs.

We measured the effects of corticosteroids and surfactant individually and in combination on lung pressure-volume relationships, rupture pressures, and rupture volumes. Pregnant does were injected with betamethasone (0.1 mg/kg per day im) or vehicle on days 24 and 25 of gestation, and fetal rabbits were delivered on days 26 and 27. Natural surfactant (50 mg/kg body wt) was instilled intratracheally into half of the lungs after tracheotomy. After nine cycles of inflation with air to 40 cmH2O and deflation, air pressure-volume curves were measured. Then the lungs were filled with air to rupture, and rupture volume and pressure were recorded. Both corticosteroids and surfactant caused an increase in maximal lung volumes (P less than 0.01) and a decrease of lung rupture pressures (P less than 0.01) compared with controls. The effects of corticosteroids plus surfactant on lung volumes were the sum of each effect individually, but rupture pressures were the same as those for corticosteroids or surfactant alone. Surfactant, in addition, caused an increase in lung stability at deflation, an effect that was not evident in the corticosteroid-treated groups. Measurements of saturated phosphatidylcholine in alveolar washes and lung tissue indicated comparable values in the corticosteroid and control groups. We conclude that changes in static properties and rupture pressures presumably reflect changes in lung structure caused by corticosteroids that are independent of a corticosteroid effect on surfactant pool sizes.

Animals↗
PubMed1999

Effects of lung volume on lung and chest wall mechanics in rats.

To investigate the effect of lung volume on chest wall and lung mechanics in the rats, we measured the impedance (Z) under closed- and open-chest conditions at various positive end-expiratory pressures (0-0.9 kPa) by using a computer-controlled small-animal ventilator (T. F. Schuessler and J. H. T. Bates. IEEE Trans. Biomed. Eng. 42: 860-866, 1995) that we have developed for determining accurately the respiratory Z in small animals. The Z of total respiratory system and lungs was measured with small-volume oscillations between 0.25 and 9.125 Hz. The measured Z was fitted to a model that featured a constant-phase tissue compartment (with dissipation and elastance characterized by constants G and H, respectively) and a constant airway resistance (Z. Hantos, B. Daroczy, B. Suki, S. Nagy, and J. J. Fredberg. J. Appl. Physiol. 72: 168-178, 1992). We matched the lung volume between the closed- and open-chest conditions by using the quasi-static pressure-volume relationship of the lungs to calculate Z as a function of lung volume. Resistance decreased with lung volume and was not significantly different between total respiratory system and lungs. However, G and H of the respiratory system were significantly higher than those of the lungs. We conclude that chest wall in rats has a significant influence on tissue mechanics of the total respiratory system.

Airway Resistance↗
PubMed2005

Interpretation of transbronchial lung biopsies from lung transplant recipients: inter- and intraobserver agreement.

BACKGROUND: Transbronchial lung biopsy results are crucial for the management of lung transplant recipients. Little information is available regarding the reliability and reproducibility of the interpretation of transbronchial lung biopsies. OBJECTIVE: To examine the inter-reader variability between two lung pathologists with expertise in lung transplantation. METHODS: Fifty-nine transbronchial lung biopsy specimens were randomly selected. Active infection had been excluded in all cases. The original interpretations (as per the Lung Rejection Study Group) for acute rejection grade included 19 biopsies scored as A0 (none), 14 scored as A1 (minimal), 12 as A2 (mild), 11 as A3 (moderate) and three as A4 (severe). The pathologists worked independently without clinical information or knowledge of the original interpretation. The specimens were graded using the Lung Rejection Study Group criteria for acute rejection (grades A0 to A4), airway inflammation (grades B0 to B4) and bronchiolitis obliterans (C0 absent and C1 present). Between-reader agreement for each category was analyzed using a Kappa statistic. RESULTS: Because many transplant specialists initiate augmented immunosuppression with biopsy grades of A2 or higher, results for each reader were dichotomized as A0/A1 versus A2/A3/A4. Using this dichotomy, there was only moderate agreement (kappa 0.470, P < 0.001) between readers. For categories B and C, the results were dichotomized for the absence or presence of airway inflammation and bronchiolitis obliterans, respectively. The level of agreement between readers was fair for category B (kappa 0.333, P = 0.014) and poor for category C (kappa 0.166, P = 0.108). The intrareader agreement for acute rejection was substantial (kappa 0.795, P = 0.0001; kappa 0.676, P = 0.0001). CONCLUSIONS: Because the agreement between expert pathologists is only modest, optimum clinical decision-making requires that transbronchial lung biopsy results be used in an integrated clinical context.

Biopsy↗
PubMed1999

High-frequency oscillatory ventilation, partial liquid ventilation, or conventional mechanical ventilation in newborn piglets with saline lavage-induced acute lung injury. A comparison of gas-exchange efficacy and lung histomorphology.

It has been reported that, in diseased lungs, either partial liquid ventilation (PLV) or high-frequency oscillatory ventilation (HFOV) can improve oxygenation better and with less lung injury than conventional mechanical ventilation (CMV). This study was intended as a preclinical comparison between the effects of HFOV, PLV and CMV on gas exchange, lung mechanics and histology. Fifteen anesthetized newborn piglets, with respiratory insufficiency due to repeated saline lung lavage, were allocated to either a PLV, HFOV or CMV (n = 5 each) strategy, and treated for 4 h. Within 30 min of commencing therapy, PLV, HFOV, and CMV improved arterial PO2 (Pa,O2), alveoloarterial oxygen gradient (P(A-a),O2), oxygenation index (OI), venous admixture (va), and arterial PCO2 (Pa,CO2). After 4 h, oxygenation parameters (Pa,O2, P(A-a),O2, OI and venous admixture) were significantly better in the HFOV group than in the PLV group; the CMV group showed a higher Pa,O2 and lower OI than the PLV group. Gas exchange at the end of the experiment was not different from baseline in the HFOV and CMV groups. Lung histology and morphometry were performed after perfusion-fixation at endotracheal deflation pressure corresponding to mean airway pressure at the end of the experiment. Lung injury score and mean linear intercept were not different between the three treatment groups. We conclude that in this model, gas exchange improved significantly in all three ventilation strategies. Indices of oxygenation improved less during PLV. The saline lavage-induced acute lung injury model used as in this study, is less stable than previously thought. The final lung injury is not influenced by the ventilation strategy. We speculate that the impaired gas exchange during PLV is an expression of diffusion limitation and ventilation-perfusion mismatch in a recovering lung.

Animals↗
PubMed2005

Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system.

It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11beta-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury.

BACKGROUND: Mechanical ventilation results in acute lung trauma that can stimulate processes that alter lung development. Activation of matrix metalloproteinases (MMPs) and their tissue-produced inhibitors (TIMPs) is initiated by the inflammatory response to mechanical ventilation and are involved in breakdown of the basement membrane and parenchymal modeling. OBJECTIVES: The aim of this study was to test the hypothesis that rhCC10, a lung anti-inflammatory mediator, would foster improved lung function, structural preservation, and a reduction in net MMP activity in a juvenile model of acute lung injury. METHODS: Twenty-four juvenile rabbits were saline-lavage-injured and treated with 100 or 25 mg/kg surfactant (Survanta, Ross Labs) with or without rhCC10 (Claragen, Inc.; n=6 per group). Animals were ventilated for 4 h, then euthanized for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, MMP-7, and MMP-9 and TIMPs 1 and 2 in the lung. RESULTS: Apical lung expansion, reduced with the lower dose of surfactant, was partially restored with the addition of rhCC10. Alveolar septal wall thickness was reduced (p<0.05) with low-dose surfactant plus rhCC10 compared to high-dose surfactant alone. Increased within-group variance in MMP-2 and MMP-9 proteolytic activity was found with the low-dose surfactant and was abolished with rhCC10. MMP-7 was reduced (p<0.05) with rhCC10 administration, independent of surfactant dose. CONCLUSIONS: Intratracheal administration of the anti-inflammatory rhCC10 resulted in preserved lung structure and MMP/TIMP profile after 4 h of mechanical ventilation, in a surfactant dose-dependent manner.

Animals↗
PubMed1996

cAMP-mediated vascular protection in an orthotopic rat lung transplant model. Insights into the mechanism of action of prostaglandin E1 to improve lung preservation.

Prostaglandin E1 (PGE1) is often added to the donor pulmonary flush solution to enhance clinical lung preservation for transplantation. Although PGE1 is thought to act as a pulmonary vasodilator during the harvest period, the precise mechanism(s) of action whereby PGE1 enhances lung preservation is unknown. Because cAMP levels decline in endothelial and vascular smooth muscle cells exposed to hypoxia, we hypothesized that a PGE1-mediated increase in cAMP levels within the preserved lungs might improve pulmonary vascular homeostasis following lung transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantly increased by PGE1 supplementation (approximately 2-fold by 6 hours, P < .0005). To test whether augmenting cAMP levels may enhance lung preservation, experiments were performed using an orthotopic rat left lung transplant model. Compared with controls, supplementing the preservation solution with the membrane-permeable cAMP analogue dibutyryl-cAMP resulted in dose-dependent preservation enhancement, marked by reduced pulmonary vascular resistance (6.0-fold, P < .01), improved arterial oxygenation (3.0-fold, P < .01), reduced graft neutrophil infiltration (1.5-fold, P < .05), and improved recipient survival (7.0-fold, P < .005). Similar preservation enhancement was observed with another cAMP analogue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimulating the cAMP second messenger system by PGE1 supplementation resulted in marked hemodynamic benefits and improved recipient survival, in parallel with reduced graft neutrophil infiltration, vascular permeability, and platelet deposition. These beneficial effects of PGE1 were abrogated by simultaneous administration of the cAMP-dependent protein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (minoxidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE1 and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE1 enhances lung preservation by stimulating the cAMP-dependent protein kinase and promoting non-vasodilatory mechanisms of pulmonary protection.

Alprostadil↗