Lung Weight Gain Research Articles

VEGF mediates fat embolism-induced acute lung injury via VEGF receptor 2 and the MAPK cascade

Fat embolism (FE) is a lethal medical emergency often caused by fracture of long bones and amputation of limbs. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increases vascular permeability. We tested the hypothesis that VEGF plays a critical role in FE-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Fat tissues were collected from male Sprague-Dawley rats, and animal oil was extracted and mixed with water to form fatty micelles. The micelles were then injected into the tail vein to produce FE and ALI in rats. Lung weight gain was measured as the index of pulmonary edema. The expression of pulmonary VEGF was evaluated by real-time PCR and western blot analysis. Inducible nitric oxide synthase (iNOS) and phosphorylation of mitogen-activated protein kinase (MAPK) were determined by western blot analyses. Interleukin-1β (IL-1β) was quantified by ELISAs. Hematoxylin and eosin staining was used to evaluate the pathological damage of ALI. In this study, we found that animal oil-induced FE significantly increased pulmonary VEGF expression and MAPK phosphorylation. We also evaluated the inflammatory response after FE and found that iNOS and IL-1β significantly increased after FE. Systemic administration of SU-1498, an antagonist of VEGF receptor 2 (VEGFR-2), significantly attenuated the FE-induced inflammatory response and histological damage. This study suggested that VEGF is involved in FE-induced ARDS via the VEGFR-2 and MAPK cascades, which induce IL-1β release and iNOS upregulation. Blockade of could be used to treat FE-induced pulmonary damage.

The Protective Effect of Prone Positioning on Human Rejected Donor Lungs during Cellular Ex Vivo Lung Perfusion

Purpose We previously reported that prone positioning (PP) of porcine lungs during cellular ex vivo lung perfusion (EVLP) diminished inflammatory injury and improved oxygenation and other pulmonary parameters during cellular EVLP. We hypothesized that prone positioning of human lungs during cellular EVLP may diminish injury and improve function, as well. The aim of this study is to validate the previous results with porcine lungs and evaluate the potential benefits of PP EVLP with human rejected donor lungs. Methods Eleven human rejected donor lungs were flushed and stored for 15-16 hours with Perfadex. Lungs were then subjected to 2 hours of cellular EVLP with either maintenance of prone positioning (prone group, n = 6) or supine positioning (control group, n = 5). Lung function was evaluated using blood gas analysis, airway and vascular parameters, visual findings, wet/dry (W/D) ratio and lung weight at 2 hours of EVLP. Results Lung weight (LW) ratio (LW at 2 hours of EVLP/ LW prior to EVLP) was lower in Prone group than in Control group [median (interquartile range)] [1.09 (0.82-1.32) vs. 1.22 (1.01-1.50), p = 0.5] (not statistical significant). The PaO2/FiO2 (P/F) ratio of left atrial blood was significantly higher in Prone group than in Control [335.5 (297.2-392.5) vs. 198.0 (190.5-271.0) mmHg, p Conclusion These results demonstrate that PP during 2 hours of cellular EVLP result in less lung weight gain, and better P/F ratio, especially in the lower lobes. These results were consistent with our previous animal study, and suggest that prone positioning EVLP of rejected human donor lungs also may diminish IRI during EVLP.

Connexin 40 regulates lung endothelial permeability in acute lung injury via the ROCK1-MYPT1- MLC20 pathway.

Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung microvascular endothelium. Yet, the role of Cx40 in the regulation of lung vascular permeability and its underlying mechanisms are unclear. Here, we tested the hypothesis that Cx40 participates in regulation of lung endothelial permeability via a mechanism involving a Rho-associated protein kinase (ROCK) dependent regulation of myosin light chain (MLC). In murine models of intratracheal acid- or LPS-induced lung injury, genetic deficiency of Cx40 attenuated key features of ALI including vascular barrier failure. In human pulmonary microvascular endothelial cells (PMVECs), thrombin-induced loss of transendothelial electrical resistance was attenuated by a Cx40-inhibiting mimetic peptide (40GAP27), Cx40-specific shRNA, or ROCK inhibitor Y27632. In isolated perfused mouse lungs, platelet-activating factor-induced lung weight gain was abrogated by gap junction blocker carbenoxolone, 40GAP27, Y27632, or genetic deficiency of Cx40. Phosphorylation of MLC20 increased drastically in both LPS-treated PMVECs and HCl-treated mouse lungs. Expression of ROCK1 was increased in both LPS-treated PMVECs and HCl-treated mouse lungs, and paralleled by phosphorylation of MLC20. Coimmunoprecipitation experiments revealed protein-protein interaction between ROCK1 and Cx40. LPS-induced upregulation of ROCK1 and phosphorylation of MLC20 were blocked by knockdown of Cx40. LPS caused phosphorylation of myosin phosphatase targeting subunit 1, which could be abrogated by Y27632 or Cx40-shRNA. Our findings reveal a role of Cx40 in regulation of ROCK1 and MLC20 that contributes critically to lung vascular barrier failure in ALI.

Rho-Kinase Inhibition Ameliorates Dasatinib-Induced Endothelial Dysfunction and Pulmonary Hypertension.

The multi-kinase inhibitor dasatinib is used for treatment of imatinib-resistant chronic myeloid leukemia, but is prone to induce microvascular dysfunction. In lung this can manifest as capillary leakage with pleural effusion, pulmonary edema or even pulmonary arterial hypertension. To understand how dasatinib causes endothelial dysfunction we examined the effects of clinically relevant concentrations of dasatinib on both human pulmonary arterial macro- and microvascular endothelial cells (ECs). The effects of dasatinib was compared to imatinib and nilotinib, two other clinically used BCR/Abl kinase inhibitors that do not inhibit Src. Real three-dimensional morphology and high resolution stiffness mapping revealed softening of both macro- and microvascular ECs upon dasatinib treatment, which was not observed in response to imatinib. In a dose-dependent manner, dasatinib decreased transendothelial electrical resistance/impedance and caused a permeability increase as well as disruption of tight adherens junctions in both cell types. In isolated perfused and ventilated rat lungs, dasatinib increased mean pulmonary arterial pressure, which was accompanied by a gain in lung weight. The Rho-kinase inhibitor Y27632 partly reversed the dasatinib-induced changes in vitro and ex vivo, presumably by acting downstream of Src. Co-administration of the Rho-kinase inhibitor Y27632 completely blunted the increased pulmonary pressure in response to dasatinib. In conclusion, a dasatinib-induced permeability increase in human pulmonary arterial macro- and microvascular ECs might explain many of the adverse effects of dasatinib in patients. Rho-kinase inhibition might be suitable to ameliorate these effects.

Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations

BackgroundThe cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non-G551D gating mutations. MethodsPatients with non-G551D gating mutations were recruited to an open-label study evaluating ivacaftor. Primary outcomes included: lung function, sweat chloride, weight gain, and quality of life scores. ResultsTwenty-one subjects were enrolled and completed 6 months follow-up on ivacaftor; mean age was 25.6 years with 52% <18. Baseline ppFEV1 was 68% and mean sweat chloride 89.6 mEq/L. Participants experienced significant improvements in ppFEV1 (mean absolute increase of 10.9% 95% CI = [2.6,19.3], p = 0.0134), sweat chloride (−48.6 95% CI = [−67.4,-29.9], p < 0.0001), and weight (5.1 kg, 95% CI = [2.8, 7.3], p = 0.0002). ConclusionsPatients with non-G551D gating mutations experienced improved lung function, nutritional status, and quality of life. This study supports ongoing use of ivacaftor for patients with these mutations.

Salivary MicroRNA Expression Profiles May Predict Loss of Lung Function and Weight Gain in Asthmatics

Salivary MicroRNA Expression Profiles May Predict Loss of Lung Function and Weight Gain in Asthmatics

Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target.

Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ). Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects. Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5% albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing. In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12% vs. 2% weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH). Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.

A randomised clinical trial of a metaphylactic treatment with tildipirosin for bovine respiratory disease in veal calves

BackgroundBovine respiratory disease (BRD) is a major problem in veal calf rearing units. The objective of this randomised clinical trial was to assess the effectiveness of tildipirosin as a metaphylactic treatment in veal calves on the number of BRD treatments, lung consolidation on thoracic ultrasonography (TUS) and average daily gain (ADG). A total of 209 veal calves from a pre-weaning fattening unit were randomly allocated to receive one of two treatments (tildipirosin 4 mg/kg, subcutaneously, n = 109; placebo 0.9% saline, subcutaneously, n = 100) at day 12 after entry in the pre-weaned unit. The calves were followed for a 70-day period. Occurrence of mortality and BRD treatments were recorded during the pre-weaning period. At days 1, 12 and 30, TUS and clinical scores were performed and ADG was measured during the first and second months of feeding.ResultsThe use of a metaphylactic treatment of tildipirosin 12 days after arrival of the veal calves was not associated with the number of BRD treatments performed by the producer, ultrasonographic lung consolidation or weight gain (P < 0,05). In this cohort of calves, the proportion of calves treated for BRD by the producer was low at 14% (29/209). However, 13% (26/209) of calves included in the study already had ultrasonographic lung consolidation lesions 12 days after their arrival, which was before treatment time, and 27% (56/209) had lung consolidation at day 30.ConclusionIn this study population with a low BRD prevalence, we were not able to detect any benefit of tildipirosin as a metaphylactic treatment of BRD at day 12 after arrival based on BRD treatments, TUS, and ADG.

Protective Effects of Neural Crest-Derived Stem Cell-Conditioned Media against Ischemia-Reperfusion-Induced Lung Injury in Rats.

Current treatments for ischemia-reperfusion (IR)-induced acute lung injury are limited. Mesenchymal stem cell-conditioned medium (CM) has been reported to attenuate lung injury. Neural crest stem cells (NCSCs), a type of multipotent stem cells, are more easily obtained than mesenchymal stem cells. We hypothesize that NCSC-CM has anti-inflammatory properties that could protect against IR-induced lung injury in rats. In this study, NCSC-CM was derived from rat NCSCs. Typical acute lung injury was induced by 30-min ischemia followed by 90-min reperfusion in adult male Sprague–Dawley rats. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to analyze the degree of lung injury after the experiment. NCSC-CM was administered before ischemia and after reperfusion. NCSC-CM treatment significantly attenuated IR-induced lung edema, as indicated by decreases in pulmonary vascular permeability, lung weight gain, wet to dry weight ratio, lung weight to body weight ratio, pulmonary arterial pressure, and protein level in BALF. The levels of tumor necrosis factor-α and interleukin-6 in the BALF were also significantly decreased. Additionally, NCSC-CM improved lung pathology and neutrophil infiltration in the lung tissue, and significantly suppressed nuclear factor (NF)-κB activity and IκB-α degradation in the lung. However, heating NCSC-CM eliminated these protective effects. Our experiment demonstrates that NCSC-CM treatment decreases IR-induced acute lung injury and that the protective mechanism may be attributable to the inhibition of NF-κB activation and the inflammatory response. Therefore, NCSC-CM may be a novel approach for treating IR-induced lung injury.

The Impact of Secondhand Smoke Exposure on Children with Cystic Fibrosis: A Review

Secondhand smoke exposure (SHSe) has multiple adverse effects on lung function and growth, nutrition, and immune function in children; it is increasingly being recognized as an important modifier of disease severity for children with chronic diseases such as cystic fibrosis (CF). This review examines what is known regarding the prevalence of SHSe in CF, with the majority of reviewed studies utilizing parental-reporting of SHSe without an objective biomarker of exposure. A wide range of SHSe is reported in children with CF, but under-reporting is common in studies involving both reported and measured SHSe. Additionally, the impact of SHSe on respiratory and nutritional health is discussed, with potential decreases in long-term lung function, linear growth, and weight gain noted in CF children with SHSe. Immunologic function in children with CF and SHSe remains unknown. The impact of SHSe on cystic fibrosis transmembrane conductance regulator (CFTR) function is also examined, as reduced CFTR function may be a pathophysiologic consequence of SHSe in CF and could modulate therapeutic interventions. Finally, potential interventions for ongoing SHSe are delineated along with recommended future areas of study.

SN50, a Cell-Permeable Inhibitor of Nuclear Factor-κB, Attenuates Ventilator-Induced Lung Injury in an Isolated and Perfused Rat Lung Model.

High tidal volume (VT) ventilation causes the release of various mediators and results in ventilator-induced lung injury (VILI). SN50, a cell-permeable nuclear factor-κB (NF-κB) inhibitory peptide, attenuates inflammation and acute respiratory distress syndrome. However, the mechanisms associated with the effects of SN50 in VILI have not been fully elucidated. We investigated the cellular and molecular mechanisms for the effects of SN50 treatment in VILI. An isolated and perfused rat lung model was exposed to low (5 mL/kg) or high (15 mL/kg) VT ventilation for 6 h. SN50 was administered in the perfusate at the onset of the high-stretch mechanical ventilation. The hemodynamics, lung histological changes, inflammatory responses, and activation of apoptotic pathways were evaluated. VILI was demonstrated by increased pulmonary vascular permeability and lung weight gain, as well as by increased levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), hydrogen peroxide, and macrophage inflammatory protein-2 in the bronchoalveolar lavage fluid. The lung tissue expression of TNF-α, IL-1β, mitogen-activated protein kinases (MAPKs), caspase-3, and phosphorylation of serine/threonine-specific protein kinase (p-AKT) was greater in the high VT group than in the low VT group. Upregulation and activation of NF-κB was associated with increased lung injury in VILI. SN50 attenuated the inflammatory responses, including the expression of IL-1β, TNF-α, MPO, MAPKs, and NF-κB. In addition, the downregulation of apoptosis was evaluated using caspase-3 and p-AKT expression. Furthermore, SN50 mitigated the increases in the lung weights, pulmonary vascular permeability, and lung injury. In conclusion, VILI is associated with inflammatory responses and activation of NF-κB. SN50 inhibits the activation of NF-κB and attenuates VILI.

Pharmacological Reconditioning of Marginal Donor Rat Lungs Using Inhibitors of Peroxynitrite and Poly (ADP-ribose) Polymerase During Ex Vivo Lung Perfusion.

Donor lungs obtained after prolonged warm ischemia (WI) may be unsuitable for transplantation due to the risk of reperfusion injury, but could be reconditioned using ex-vivo lung perfusion (EVLP). Key processes of reperfusion injury include the formation of reactive oxygen species (ROS)/nitrogen species (RNS) and the activation of poly(adenosine diphosphate-ribose) polymerase (PARP). We explored whether rat lungs obtained after WI could be reconditioned during EVLP using the ROS/RNS scavenger Mn(III)-tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the PARP inhibitor 3-aminobenzamide (3-AB). Rat lungs obtained after 3 hours cold ischemia (CI group, control), or 1 hour WI plus 2 hours CI (WI group) were placed in an EVLP circuit for normothermic perfusion for 3 hours. Lungs retrieved after WI were treated or not with 3-AB (1 mg/mL) or MnTBAP (0.3 mg/mL), added to the perfusate. Measurements included physiological variables (lung compliance, vascular resistance, oxygenation capacity), lung weight gain, levels of proteins, lactate dehydrogenase, protein carbonyl (marker of ROS), 3-nitrotyrosine (marker of RNS), poly(adenosine diphosphate-ribose) (PAR, marker of PARP activation) and IL-6, in the bronchoalveolar lavage or the lung tissue, and histology. In comparison to the CI group, the lungs from the WI group displayed higher protein carbonyls, 3-nitrotyrosine, PAR, lactate dehydrogenase and proteins in bronchoalveolar lavage, lung weight gain, perivascular edema, as well as reduced static compliance, but similar oxygenation. All these alterations were markedly attenuated by 3-AB and MnTBAP. After EVLP, lungs obtained after WI exhibit oxidative stress, PARP activation, and tissue injury, which are suppressed by pharmacological inhibitors of ROS/RNS and PARP.

Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.

Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells "rehabilitated" marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.

Advances in the detection and management of cystic fibrosis related diabetes.

This review will outline the screening, diagnosis and management of cystic fibrosis related diabetes (CFRD). It will also discuss advances in the detection of early glucose abnormalities, their clinical significance and the emerging role for early insulin therapy. Before the onset of diabetes (as currently defined), patients with cystic fibrosis (CF) display glucose abnormalities, detectable either by 30-minutely sampled oral glucose tolerance testing (OGTT), or by continuous ambulatory interstitial glucose monitoring (CGM). These early glucose abnormalities are associated with the presence of glucose in airway fluid, potentially promoting the growth of airway pathogens and contributing to the progression of respiratory disease. Progressive insulin deficiency underlies these glucose abnormalities, and insulin deficiency also causes catabolism. Pilot studies of once-daily insulin therapy in the early stages of insulin deficiency show improved lung function and weight gain (important predictors of survival in CF). Early stages of insulin deficiency may be contributing to catabolism and deteriorating lung function in CF. It is plausible that early insulin therapy may prevent this deterioration, a view supported by pilot studies. Randomized controlled trials of early insulin therapy will now determine whether insulin therapy should be commenced earlier than current practice in CF.

Experimental Ex Vivo Lung Perfusion with Sevoflurane: Effect on donors after circulatory death (DCD) lung grafts in a rodent model.

Ischemia-reperfusion injury is a key mechanism of graft damage during lung transplantation, which could be targeted by therapies applied during ex-vivo lung perfusion (EVLP). The inhalational anaesthetic Sevoflurane was found to protect to some degree against ischemia-reperfusion injury1. In this experimental study we wanted to determine the therapeutic potential of volatile Sevoflurane added to the perfusate during EVLP of damaged lung grafts. Two groups of 6 Sprague-Dawley rats were used. After cardiac arrest and a warm ischemic time of 1 hour the lungs were flushed with cold Perfadex®, harvested and kept for 2 hours at 4°C. Normothermic EVLP during 3 hours was performed using a customized circuit primed either with Steen solution® only (control group) or supplemented within the first 30 minutes of EVLP with a gas mixture containing 2% of sevoflurane (treatment group). Differential oxygen partial pressures in the perfusate (ΔvapO2), pulmonary artery pressure (PAP), vascular resistance (PVR), lung compliance (LC), peak airway pressure (PAWP) and lung weight gain (WG) were measured. At the end of EVLP, protein and lactate dehydrogenase (LDH) levels were determined in bronchoalveolar lavage (BAL) and interleukin-6 (IL-6) and protein carbonyl (index of oxidative stress) were measured in lung tissue. Normothermic EVLP of lungs harvested after warm ischemia resulted in markedly declined ΔvapO2, LC, and elevated PAP, PVR, PAWP, WG. In contrast, lungs treated with Sevoflurane during EVLP displayed significantly improved LC, reduced weight gain and significantly lower LDH and protein carbonyl levels as compared to controls. PAWP and IL-6 were diminished in treated lungs, but were not statistically different to controls. The intravascular administration of sevoflurane during EVLP reduces oxidative stress and improves the functional status of DCD rat lungs in this experimental setting.

329 Partial recovery of exocrine pancreatic function and intestinal fat absorption after ivacaftor treatment

Objectives Ivacaftor treatment results in rapid improvement of lung function and weight gain. We hypothesize that the reported ivacaftor induced weight gain is related to recovery of exocrine pancreatic function and improved intestinal fat absorption. Methods We measured fecal elastase-1 (FE), FEV1 and body height and weight, in a 13-year old girl with CF (dF508/S1251N) with proven pancreatic insufficiency (FE Results The patient reported a striking improvement in the general condition and body weight. FEV1 increased from 57% to 89%. Despite a decrease in the total dietary energy intake of 9%, the z-score of the BMI increased from 0.1 to 0.9 (+0.8SDS), after 3 months of ivacaftor treatment compared to baseline. FE increased to 54 ug/g. The CFA without PERT was 88%. Conclusion Our results, based on a single case study, suggest a partial recovery of exocrine pancreatic function, already, after 3 month of ivacaftor treatment. These findings are paralleled by a trend towards normalization of the spontaneous intestinal fat absorption. Noteworthy in this case is the increase in BMI, despite the still below normal CFA and decreased dietary intake. The latter suggests that, besides improved intestinal energy absorption, also lower total daily energy expenditure relates to the observed weight gain in CF patients during successful ivacaftor treatment.

Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States

BackgroundIvacaftor is the first therapeutic agent approved for the treatment of cystic fibrosis (CF) that targets the underlying molecular defect. Patients with severe lung disease were excluded from the randomized Phase 3 trials. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability. MethodsCF patients aged ≥6years with a G551D-CFTR mutation and FEV1≤40% predicted or listed for lung transplant received ivacaftor 150mg every 12h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight. ResultsThe rate of serious adverse events was consistent with disease severity. At 24weeks of treatment with ivacaftor, there was a mean absolute increase in percent predicted FEV1 of 5.5 percentage points and a 3.3kg mean absolute increase in weight from baseline. ConclusionsIn patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.

0990. Role of amplitude and rate of deformation in ventilator-induced lung injury

Methods Twenty-eight healthy piglets were mechanically ventilated for up to 54 hours. Each animal was assigned to one of three groups of VT (300-400 ml; 500-600 ml; 750 ml) and one of two groups of V’. Lower and higher V’ were obtained by setting inspiratory-to-expiratory time ratio as high as 1:2 or as low as 1:9. Respiratory rate was always 15 breaths per minute. Interplay between VT and V’ was assessed at the beginning of the study as airway pressurevolume loop area (or dynamic respiratory system hysteresis). VILI was defined as pulmonary oedema (lung weight gain ≥10% across the study period). Results Main findings are reported in Table 1.

Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome.

Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E2 (PGE2) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC4 and PGE2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC4 and PGE2 than HbAA-perfused lungs: 10.40 ± 0.62 versus 0.92 ± 0.2 ng/g dry lung weight (mean ± SEM; P = 0.0001) for LTC4. Inclusion of autologous platelets (platelet-rich plasma) elevated LTC4 production to 12.6 ± 0.96 and 7 ± 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient's pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC4 and PGE2, both of which may contribute to onset of the acute chest syndrome in SCD.