Lung Ischemia Research Articles

Copenhagen Airport Cohort: air pollution, manual baggage handling and health

PurposeCopenhagen Airport Cohort 1990–2012 presents a unique data source for studies of health effects of occupational exposure to air pollution (ultrafine particles) and manual baggage handling among airport employees. We...

Associations between airflow obstruction and the risks of morbidity on major chronic diseases in Chinese adults: a prospective cohort study

Objective: To examine the prospective associations between airflow obstruction (AFO) and risks of major chronic diseases morbidity in Chinese adults. Methods: Samples of this study were from the China Kadoorie Biobank. A total of 486 996 participants aged 30 to 79 years (mean 51.5 years) at the baseline study, were included after excluding those who self-reported of having heart disease, stroke and cancer at baseline. AFO was defined under the Global Initiative on Obstructive Lung Disease (GOLD) criteria and forced expiratory volume per one second in percentage of the expected one (FEV(1)% P). Cox regression models were used to investigate the associations of AFO with incidence rates of ischemic heart disease, cerebrovascular disease and lung cancer after adjusted for potential confounders. Results: Over a period of 7 years through the follow-up program, the incident cases of ischemic heart disease, cerebrovascular disease and lung cancer appeared as 24 644, 36 336 and 3 218, respectively. Compared with people without AFO, the HR (95% CI) of GOLD-1 to GOLD-4 were 0.89 (0.78-1.01), 1.05 (0.98-1.12), 1.29 (1.18-1.40) and 1.65 (1.42-1.91) respectively for ischemic heart disease. The HR (95%CI) of GOLD-1 to GOLD-4 were 0.96 (0.70-1.26), 1.12 (0.96-1.31), 1.38 (1.14-1.65) and 1.48 (1.05-2.02) respectively for lung cancer. No statistically significant differences in the associations between GOLD level and cerebrovascular disease morbidity were found. However, each 10% decrease in FEV(1)% P was associated with 7.2% (95%CI: 6.4%-8.0%), 3.6% (95%CI: 3.0%-4.3%) and 10.5% (95%CI: 8.4%-12.6%) increased the risks of ischemic heart disease, cerebrovascular disease and lung cancer respectively. The results were persistant when stratified by smoking status. Conclusion: Higher degree of AFO seemed to be associated with the risks of ischemic heart disease, cerebrovascular disease and lung cancer morbidity among the Chinese adults.

Burden of smoking in Lithuania: attributable mortality and years of potential life lost.

High mortality rates from smoking related diseases are a significant public health issue in Lithuania. Study aims to estimate the number of smoking attributable deaths (SADs) and years of potential life lost in Lithuania in 2013. Gender, age and disease specific mortality was calculated by applying the smoking attributable fractions (SAFs) to prevalence estimates of current and former smokers among Lithuanian adults aged ≥35 years that are based on the 2005 Lithuanian Health Interview Survey. Mortality data were obtained from the Institute of Hygiene Health Information Centre. Eight years lag was assumed between smoking rates and subsequent mortality. Sensitivity analysis was used to calculate SAFs applying smoking impact ratio method. In 2013, 13.9% of total mortality or 5771 deaths in Lithuania were attributable to smoking (5181 men and 590 women). The two leading causes of SADs were ischaemic heart disease (2861) and lung cancer (1054) that accounted for 67.8% of the smoking attributable mortality. In the same year, smoking accounted for 39 279 years of potential life lost (34 663 years for men and 4615 years for women). Smoking causes a considerable mortality burden in Lithuania, killing nine times more males than females. Therefore reduction of smoking prevalence is an urgent public health need, which calls for implementation of effective and comprehensive tobacco control measures consistent with the World Health Organization Framework Convention on Tobacco Control Articles and Protocols and The Tobacco Products Directive.

Prevalence-based, disease-specific estimate of the social cost of smoking in Singapore

ObjectiveTo estimate the cost of smoking in Singapore in 2014 from the societal perspective.MethodsA prevalence-based, disease-specific approach was undertaken to estimate the smoking-attributable costs. These include direct and indirect costs...

Apigenin Reduces NF-κB and Subsequent Cytokine Production as Protective Effect in a Rodent Animal Model of Lung Ischemia-Reperfusion Injury

ABSTRACTPurpose: Lung ischemia–reperfusion injury (LIRI) can complicate lung transplantation or cardiac surgery with cardiopulmonary bypass, increasing morbidity and mortality. In LIRI, pro-inflammatory cytokines are activated, reactive oxygen species are generated and nuclear factor-κB (NF-κB) is up-regulated, altering lung mechanics. We tested the effect of the flavonoid apigenin on a rodent model of LIRI. Methods: Thirty-seven Wistar rats were subjected to LIRI with or without a single or double dose of apigenin. Induction of LIRI involved sternotomy and clamping of either the left lung hilum or the pulmonary artery alone for 30 min, followed by 60 min of reperfusion. Control groups consisted of LIRI plus NaCl, a sham group and a baseline group. At the end of the experiments, both lungs were analyzed by RT-PCR, Western blot, and light microscopy. Results: In placebos, the expression levels of pro-inflammatory markers were increased in both lungs significantly, whereas NF-κB was markedly up-regulated. Administration of apigenin reduced the activation of NF-κB and the expression of TNFα, iNOS, and IL-6. These effects were observed in total lung ischemia. Histology showed greater hemorrhage and exudation in the pulmonary periphery of all groups, whereby damage was practically absent in the central lung regions of the apigenin animals. A second dose of apigenin did not outclass a single one. Conclusions: We conclude that apigenin given intraperitoneally can reduce activation of NF-κB and also attenuate the expression of TNFα, IL-6, and iNOS in a surgical model of LIRI. The surgical procedure itself can induce significant damage to the lungs.

Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model.

Lung ischemia reperfusion injury (LIRI) is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD) on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75%) diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR)-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS), proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB) activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF). The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway.

Oxidative and nitrosative stress during pulmonary ischemia-reperfusion injury: from the lab to the OR.

Oxidative and nitrosative stress are an umbrella term for pathophysiological processes that involve free radical generation during inflammation. In this review, the involvement of reactive oxygen and nitrogen species is evaluated during lung ischemia-reperfusion injury (LIRI) from a surgical point of view. The main biochemical and cellular mechanisms behind free radical generation are discussed, together with surgical procedures that may cause reperfusion injury. Finally, different therapeutic strategies are further explored. A literature search was performed, searching for "lung ischemia reperfusion injury", "reperfusion injury", "large animal model" and different search terms for each section: "surgery", "treatment", "cellular mechanism", or "enzyme". Although reperfusion injury is not an uncommon entity and there is a lot of evidence concerning myocardial ischemia-reperfusion injury, in the lung this phenomenon is less extensively described and studies in large animals are not easy to come by. With increasing number of patients on waiting lists for lung transplant, awareness for this entity should all but rise.

Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition.

Dipeptidyl peptidase 4 (DPP4) is a cell surface protease that has been reported to play a role in glucose homeostasis, cancer, HIV, autoimmunity, immunology and inflammation. A role for DPP4 in ischemia-reperfusion injury (IRI) in the heart has been established. Dipeptidyl peptidase 4 inhibition (DPP4i) appeared to decrease infarct size, improves cardiac function and promotes myocardial regeneration. Lung ischemia reperfusion injury is caused by a complex mechanism in which macrophages and neutrophils play an important role. Generation of reactive oxygen species (ROS), uncoupling of nitric oxide synthase (NOS), activation of nuclear factor-κB (NF-κB), activation of nicotinamide adenine dinucleotide phosphate metabolism, and generation of pro-inflammatory cytokines lead to acute lung injury (ALI). In this review we present the current knowledge on DPP4 as a target to treat IRI in the lung. We also provide evidence of the roles of the DPP4 substrates glucagon-like peptide 1 (GLP-1), vasoactive intestinal peptide (VIP) and stromal cell-derived factor-1α (SDF-1α) in protection against oxidative stress through activation of the mitogen-activated protein kinase (MAPK) 1/2 and phosphatidylinositol 3'-kinase (PI3K)/Akt signal transduction pathways.

Oxymatrine on Hsp90a expression and apoptosis in a model of lung ischemia-reperfusion injury.

The protective effects of oxymatrine (OMT) on apoptosis and heat shock protein 90a (Hsp90a) expression in a rabbit model of lung ischemia-reperfusion injury (LIRI) were investigated. The model of LIRI was established in rabbits and they were randomly divided into two groups: The control group (group C, n=10), and experimental group (further divided into groups E1, n=10; and group E2, n=10), to measure the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) activity in lung tissue homogenates at several time points (T0, 0 min; T1, 60 min; T2, 120 min; T3, 180 min; and T4, 240 min), and to measures changes in lung tissue wet/dry weight ratio (W/D), apoptosis index (AI), and Hsp90a expression and organization at T2, T3 and T4. Comparing group C with groups E1 and E2, the levels of SOD activity and MDA were not significantly different at T0 and T1 (P>0.05); W/D ratio and AI were significantly higher than in groups E1 and E2 (P<0.05, P<0.01); 120 min after LIR, MDA, W/D ratio, and AI were lower than in groups E1 and E2 (P<0.05, P<0.01). MDA, W/D ratio and AI were lower in E2 than in E1 (P<0.05), and SOD and Hsp90a expression increased (P<0.05). The ultrastructure in group E showed less injury compared with group C. In conclusion, by scavenging oxygen free radicals, OMT can inhibit apoptosis, increase Hsp90a expression, and reduce the injury caused by lung ischemia reperfusion.

Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia

ABSTRACTPurpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. Materials and Methods: Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague–Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A2A (A2AAR) and A2B adenosine receptor (A2BAR) mRNA and protein were quantified. Results: Twenty-four hours after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A2BAR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A2AAR mRNA and protein concentrations remained unchanged following ischemia. A2BAR protein was increased in PA ligated lungs of SS rats after 7 days, and 4 h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. Conclusion: Increased A2BAR and adenosine following unilateral lung ischemia as well as more BOOP in A2BAR mutant rats implicate a protective role for A2BAR signaling in countering ischemic lung injury.

Prevalence of Exposure to Secondhand Smoke among Higher Secondary School Students in Ernakulam District, Kerala, Southern India.

Introduction:The association between secondhand smoke and health outcomes, such as frequent respiratory infections, ischemic heart disease, lung cancer, asthma, and stroke, has long been established. The study aimed to estimate the prevalence of secondhand smoking exposure among higher secondary school students in Ernakulam district, Kerala, Southern India.Materials and Methods:A structured questionnaire was administered to all students from four randomly selected higher secondary schools in Ernakulam district. Descriptive statistics was done using frequencies and percentages. Univariate and multivariate analyses were done for factors associated with household exposure to tobacco smoke generating odds ratios (ORs) and 95% confidence intervals (CIs).Results:A total of 629 students participated in the study. The prevalence of ever smokers was 11.9% and of current smokers was 5.2%. Among the study participants, 23.2% were exposed to secondhand smoking from a family member and 18.8% from friends. Lower educational status of father was associated with the household exposure to secondhand smoke (adjusted OR 4.51 [95% CI 1.66–12.22]). More than half of the study participants (56.3%) reported that they were exposed to cigarette smoke in past 1 week in a public place and 10.2% in closed public places. Nearly one-third of the students reported that they have seen somebody smoking inside school campus in the past 30 days.Conclusion:Exposure to secondhand smoke at home, schools, and public places was higher among the late adolescent higher secondary school students in Ernakulam district. The findings underscore the urgent need for increased efforts to implement the strategies to reduce secondhand smoke exposure among adolescents.

Lung Ischaemia-Reperfusion Injury: The Role of Reactive Oxygen Species.

Lung ischaemia-reperfusion injury (LIRI) occurs in many lung diseases and during surgical procedures such as lung transplantation. The re-establishment of blood flow and oxygen delivery into the previously ischaemic lung exacerbates the ischaemic injury and leads to increased microvascular permeability and pulmonary vascular resistance as well as to vigorous activation of the immune response. These events initiate the irreversible damage of the lung with subsequent oedema formation that can result in systemic hypoxaemia and multi-organ failure. Alterations in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been suggested as crucial mediators of such responses during ischaemia-reperfusion in the lung. Among numerous potential sources of ROS/RNS within cells, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, nitric oxide synthases and mitochondria have been investigated during LIRI. Against this background, we aim to review here the extensive literature about the ROS-mediated cellular signalling during LIRI, as well as the effectiveness of antioxidants as treatment option for LIRI.

Modeling Long-Term Survival in Chemotherapy-Only Versus Combined Modality Therapy in Patients with Early Stage Unfavorable Hodgkin Lymphoma Involving the Mediastinum

Background: Optimal therapy for patients with early stage Hodgkin lymphoma (HL) is controversial. Combined modality therapy (CMT) utilizes chemotherapy plus consolidative radiotherapy (RT). CMT produces higher initial cure rates, but also increases the long-term risk of radiation toxicity. The most important risks include higher rates of breast and lung cancer, and ischemic heart disease due to mediastinal radiation exposure. Chemotherapy-only (CT) treatment with ABVD produces lower initial cure rates versus CMT, but also yields less long-term toxicity. Furthermore, those CT patients that fail initial therapy can often be salvaged with autologous stem cell transplant (ASCT). To help guide patient-specific strategies, we developed a Markov decision-analytic model to estimate long-term mortality in patients with early stage unfavorable HL involving the mediastinum treated with CMT vs. CT.Methods: We builta decision tree with Markov modeling to compare long-term mortality due to relapse, ischemic heart disease, and breast or lung cancer in hypothetical patients treated with CT or CMT using TreeAge Pro 2016. The model follows a hypothetical cohort of patients from primary therapy through 20-year follow-up. Patients transition between health states (Figure 1) based on probabilities extracted from 13 published studies. Patients that fail therapy then move to survival curves based on early vs. late relapse. The probability of toxicity was based on relative risks found in studies that used ABVD alone or ABVD with involved field or larger RT volumes. Patients who develop a toxicity move to a survival curve specific to that adverse effect. The model estimated 20-year survival in cohorts based on sex, upper vs. lower mediastinal disease, and age (20 y/o vs. 40 y/o) in non-smokers.Results: In 20 y/o patients, CMT showed better long-term survival than CT alone with slightly larger difference in mortality (1.6%) in males with upper mediastinal disease than in females (1.4%) (Table 1). In the cohort of 20 year old males, the causes of death in CMT vs. CT 20 years from starting therapy, respectively, were as follows: HL (4.7% vs. 6.6%); breast cancer (0% vs. 0%); lung cancer (0.1% vs. 0.1%); ischemic heart disease (0.6% vs. 0.3%). In 40 y/o patients, CT showed better long-term survival. The largest difference in mortality was 7.6% in 40 y/o females with lower mediastinal disease (19.9% in CMT vs. 12.3% in CT-only). In this cohort, the causes of death in CMT vs. CT, respectively were: HL (4.6% vs. 6.6%); breast cancer (4.7% vs. 1.0%); lung cancer (2.9% vs. 2.1%); ischemic heart disease (7.8% vs. 2.6%). CT-only also showed a survival benefit of 4.9% in 40 y/o males with lower mediastinal disease. Causes of death in CMT vs. CT, respectively: HL (4.6% vs. 6.6%); lung cancer (3.3% vs. 2.2%); ischemic heart disease (8.5% vs. 2.7%). At 20 years post treatment, CT-only tends to favor older patients, while CMT tends to favor younger patients due to lower baseline risks of dying from second cancers and ischemic heart disease in 40 y/o compared to 60 y/o survivors.Conclusions: This model may help multidisciplinary decision making when determining the optimum strategy for different types of patients based on disease location and risk factors for relapse and toxicity. In this study the benefits of radiation were erased by the higher rates of toxicities in older patients. Of note, the published relative risks used in this model were from studies using outdated large radiation fields rather than modern approaches. The impact of using much smaller "involved site" volumes, intensity modulated RT, and/or proton therapy is unknown but would likely lower long-term mortality from CMT. Further work using probabilistic sensitivity analyses can test these initial conclusions. [Display omitted] [Display omitted] DisclosuresHwang:Novartis: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Schuster:Hoffman-LaRoche: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen Research & Development: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding.

Spatial and temporal trends in the mortality burden of air pollution in China: 2004–2012

While recent assessments have quantified the burden of air pollution at the national scale in China, air quality managers would benefit from assessments that disaggregate health impacts over regions and over time. We took advantage of a new 10×10km satellite-based PM2.5 dataset to analyze spatial and temporal trends of air pollution health impacts in China, from 2004 to 2012. Results showed that national PM2.5 related deaths from stroke, ischemic heart disease and lung cancer increased from approximately 800,000 cases in 2004 to over 1.2 million cases in 2012. The health burden exhibited strong spatial variations, with high attributable deaths concentrated in regions including the Beijing–Tianjin Metropolitan Region, Yangtze River Delta, Pearl River Delta, Sichuan Basin, Shandong, Wuhan Metropolitan Region, Changsha–Zhuzhou–Xiangtan, Henan, and Anhui, which have heavy air pollution, high population density, or both. Increasing trends were found in most provinces, but with varied growth rates. While there was some evidence for improving air quality in recent years, this was offset somewhat by the countervailing influences of in–migration together with population growth. We recommend that priority areas for future national air pollution control policies be adjusted to better reflect the spatial hotspots of health burdens. Satellite-based exposure and health impact assessments can be a useful tool for tracking progress on both air quality and population health burden reductions.

Prevention of Unilateral Pulmonary Edema Complicating Robotic Mitral Valve Operations

Unilateral pulmonary edema (UPE) has been reported after mitral operations performed through the right side of the chest. The clinical presentation is compatible with an ischemia-reperfusion injury. This report describes modifications to robotic mitral valve operations that were designed to reduce UPE. We reviewed 15 patients with UPE after robotic mitral valve operations from 2006 through 2012. Technique modifications to reduce right lung ischemia were used from 2013 through June 2015. Modifications included alterations in patient position, ventilation, and perfusion factors. The incidence of UPE before and aftermodifications was determined, as was perfusion factors and outcomes in a higher-risk patient subgroup with pulmonary hypertension and prolonged bypass procedures. The incidence of UPE was 1.4% (n= 15) in 1,059 consecutive robotic mitral valve procedures using the standard technique and 0.0% in 435 consecutive procedures using the modified technique (p < 0.02). All patients with UPE had pulmonary hypertension and bypass times of greater than 120 minutes. Patients in the higher-risk subgroup had significantly lower systemic temperature (31°C [range, 30°-32°C] versus 34°C [range, 33°-34°C]; p < 0.01) and higher mean perfusion pressure (67mm Hg [range 62-72 mm Hg] versus 54 mm Hg [range, 52-57 mm Hg]; p < 0.01) on bypass using the modified technique. The incidence of UPE in higher-risk patients was significantly reduced using the modified technique (0% versus 5.6%; p < 0.01) without any increase in overall morbidity or mortality. The incidence of UPE in patients undergoing robotic mitral valve operations has been significantly reduced using a modified technique, without increasing the perioperative complication rate. Further work is necessary to validate this protocol and understand the pathophysiology of postoperative UPE.

Burden of disease from major air pollution sources in China

Introduction: Reducing the health impacts of air pollution in highly polluted countries such as China requires understanding the relative impacts of specific source sectors. . Targeted air quality management can lead to substantial health benefits and reductions in climate-forcing emissions. Methods: We combined chemical transport model simulations with estimates of exposure to air pollution and the burden of disease to estimate deaths in China from major air pollution sources in 2013 and under four future scenarios for 2030. Scenarios included future energy mixes and pollution control measures. National and province-level estimates were developed. Results: In China ambient PM2.5 contributed to 916,102 premature deaths in 2013. Coal combustion was the most important contributor to ambient particle (PM2.5) pollution in China in 2013, responsible for 40% of population exposure. 366,000 deaths were attributed to coal combustion in 2013 in China. Industrial (coal and non-coal) emissions contributed 255,000 attributable deaths in 2013 with domestic combustion (biomass and coal) leading to 177,000 attributable deaths, more than the contribution from transportation (137,000), or coal combustion in power plants (86,500). Compared to 2013, deaths attributable to ambient PM2.5 in 2030 were increased by 8 – 38% under scenarios of pollution reduction where population-weighted exposure was decreased by 8 – 50%. These projected mortality increases were due to population aging and increases in ischemic heart disease, stroke, COPD and lung cancer in the Chinese population. Even under the most stringent energy use and pollution control scenario, coal remained the single largest contributor to ambient PM2.5 and attributable burden in 2030. Conclusions: These projections underscore the importance of population dynamics in determining future mortality due to ambient PM2.5. PM levels must be substantially lowered to stabilize or reduce burden given demographic trends.

Close concordance between pulmonary angiography and pathology in a canine model with chronic pulmonary thromboembolism and pathological mechanisms after lung ischemia reperfusion injury

In our paper published in Journal of Thrombosis and Thrombolysis in August this year, we have expressed the concordance between pulmonary angiography and pathology in a canine model with chronic pulmonary thromboembolism (PTE) and pathological mechanisms after lung ischemia reperfusion injury (LIRI). Several highlights could be concerned on this.

Dexmedetomidine protects against lung ischemia-reperfusion injury by the PI3K/Akt/HIF-1α signaling pathway.

To evaluate the role of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1α (HIF-1α) signaling pathway in the protection by dexmedetomidine against lung ischemia-reperfusion injury (IRI) in rats. Forty-eight male Sprague-Dawley rats weighing 250-350g were randomly divided into six groups (n=8 each group): sham group, IRI group, low-dose dexmedetomidine group (LD group), high-dose dexmedetomidine group (HD group), combined low-dose dexmedetomidine and LY294002 group (LDL group), and combined high-dose dexmedetomidine and LY294002 group (HDL group). A 30-min ischemia was induced by occluding the hilum of the left lung, followed by a 120-min reperfusion by removing occlusion of the hilum. After the left lung was removed, the wet/dry weight ratio (W/D) of the lung tissues was determined. Pathological changes of lung tissues were evaluated by light and electron microscopes and the expression of p-Akt and HIF-1α in the lung tissues was determined by western blotting. Compared with the sham group, both the W/D ratio and lung injury were significantly increased, the p-Akt expression was down-regulated and HIF-1α expression was up-regulated in the five experimental groups. Compared with the LD and LDL groups, both the W/D ratio and lung injury were decreased, but the expression of p-Akt and HIF-1α was increased in the HD and HDL groups. Administration of dexmedetomidine before ischemia can provide a protection against lung IRI by re-installing the PI3K/Akt/HIF-1α signaling pathway.

Microparticles: A new insight into lung primary graft dysfunction?

Lung transplantation is the only life-saving treatment for end stage respiratory disease. The immediate outcome is still hampered by primary graft dysfunction. The latter is a form of acute lung injury occurring within the 30min following the unclamping of the pulmonary artery that prompts ischemia reperfusion injury. Severe forms may need prolonged mechanical ventilation and extra-corporeal membrane oxygenation. Overall, primary graft dysfunction accounts for at least one third of the deaths during the first post-operative month. Despite increasing experience and knowledge on the underlying cellular events, there is still a lack of an early marker of ischemia reperfusion graft injuries. Microparticles are plasma membrane vesicles that are released from damaged or stressed cells in biological fluids and remodeling tissues, among which the lung parenchyma during acute or chronic injury. We recently evidenced alveolar microparticles as surrogate markers of strong ischemia injury in ex-vivo reperfusion experimental models. We propose herein new insights on how microparticles may be helpful to evaluate the extent of lung ischemia reperfusion injuries and predict the occurrence of primary graft dysfunction.

Dysregulation of the renin-angiotensin system during lung ischemia-reperfusion injury

ABSTRACTAim/Purpose of the Study: Activation of the renin-angiotensin system leading to increased angiotensin-(1–7) (Ang-(1–7)) and decreased angiotensin 2 (Ang 2) levels may be a new therapeutic approach to reduce acute lung injury. Prolylcarboxypeptidase (PRCP) and prolyloligopeptidase (PREP) are capable of hydrolyzing Ang 2 into Ang-(1–7). However, their relation with circulating Ang 2 levels after lung ischemia–reperfusion injury (LIRI) has never been explored. This study determines whether the activity and expression of PRCP and PREP in plasma and lung tissue is related to circulating Ang 2 levels in a murine model of LIRI. Materials and Methods: LIRI in Swiss mice (6 animals per group) was induced by temporary left lung hilar clamping (1 h) followed by 0, 1 or 24 h of reperfusion. Animals in the sham group received thoracotomy only. PRCP activity was measured via RP-HPLC, PREP activity using a fluorogenic substrate and plasma Ang 2 levels via ELISA. Western blotting was used to determine the PRCP and PREP protein expression profiles in left lung tissue. Results: Plasma Ang 2 levels significantly rise after lung ischemia and remain increased after 1 h and 24 h of reperfusion compared to the sham group. While a significant decrease in plasma PREP activity was found after 24 h of reperfusion, a transient increase in plasma PRCP activity was observed after ischemia. However, no correlation with plasma Ang 2 levels could be demonstrated. The activity profiles of PRCP and PREP and the protein expression of PRCP in the lung tissues remained unchanged after LIRI. Conclusions: LIRI causes a dysregulation of circulating Ang 2 levels and plasma PREP activity, although no direct link between both phenomena could be shown. The activity profile of pulmonary PRCP and PREP was not significantly changed after LIRI, which implies a minor role for local PRCP and PREP in the ischemic lung itself.