scholarly journals Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system

2020 ◽  
Vol 27 (1) ◽  
Author(s):  
K. Walweel ◽  
K. Skeggs ◽  
A. C. Boon ◽  
L. E. See Hoe ◽  
M. Bouquet ◽  
...  
Keyword(s):  
Gas Exchange ◽  
Partial Pressure ◽  
Ex Vivo ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lung Damage ◽  
Endothelin Receptor ◽  
Donor Pool ◽  
Ex Vivo Lung Perfusion ◽  
Tissue Samples

Abstract Background A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). Methods After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). Results Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. Conclusions These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Donation after Brain Death versus Donation after Circulatory Death: Lung Donor Management Issues

2018 ◽  
Vol 39 (02) ◽  
pp. 138-147 ◽  
Author(s):  
Bronwyn Levvey ◽  
Kovi Levin ◽  
Miranda Paraskeva ◽  
Glen Westall ◽  
Gregory Snell
Keyword(s):  
Brain Death ◽  
Ex Vivo ◽  
Scoring Systems ◽  
Donation After Circulatory Death ◽  
Donor Pool ◽  
Ex Vivo Lung Perfusion ◽  
Conversion Rates ◽  
Donor Lung ◽  
Donation After Brain Death ◽  
Circulatory Death

AbstractLung transplantation (LTx) has traditionally been limited by a lack of suitable donor lungs. With the recognition that lungs are more robust than initially thought, the size of the donor pool of available lungs has increased dramatically in the past decade. Donation after brain death (DBD) and donation after circulatory death (DCD) lungs, both ideal and extended are now routinely utilized. DBD lungs can be damaged. There are important differences in the public's understanding, legal and consent processes, intensive care unit strategies, lung pathophysiology, logistics, and potential-to-actual donor conversion rates between DBD and DCD. Notwithstanding, the short- and long-term outcomes of LTx from any of these DBD versus DCD donor scenarios are now similar, robust, and continue to improve. Large audits suggest there remains a large untapped pool of DCD (but not DBD) lungs that may yet further dramatically increase lung transplant numbers. Donor scoring systems that might predict the donor conversion rates and lung quality, the role of ex vivo lung perfusion as an assessment and lung resuscitation tool, as well as the potential of donor lung quality biomarkers all have immense promise for the clinical field.

Primary Graft Dysfunction

2021 ◽  
Vol 42 (03) ◽  
pp. 368-379
Author(s):  
Jake G. Natalini ◽  
Joshua M. Diamond
Keyword(s):  
Risk Factors ◽  
Lung Transplantation ◽  
Ex Vivo ◽  
Significant Risk ◽  
Subsequent Development ◽  
Primary Graft Dysfunction ◽  
Graft Dysfunction ◽  
Donor Pool ◽  
Ex Vivo Lung Perfusion ◽  
Increased Risk

AbstractPrimary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO2:FiO2 less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.

Effect of dietary vitamin A on the mixed function oxidases and the pneumotoxicity of 3-methylindole in goats

1983 ◽  
Vol 61 (8) ◽  
pp. 816-821 ◽  
Author(s):  
F. E. Burley ◽  
T. M. Bray
Keyword(s):  
Vitamin A ◽  
Clinical Signs ◽  
Weight Ratio ◽  
Dry Weight ◽  
Retinyl Palmitate ◽  
Lung Damage ◽  
Dietary Vitamin ◽  
Vitamin A Supplementation ◽  
High Vitamin ◽  
Alveolar Epithelial

To determine the effects of dietary vitamin A on the activity of the mixed function oxidase (MFO) system and on the susceptibility to 3-methylindole (3MI)-induced respiratory disease, goats were fed a high (supplemented with 12 000 IU retinyl palmitate/kg) or a low (no supplementation) vitamin A diet for 14 weeks. Four animals in each dietary group were then challenged with [14C]3MI. The remaining four animals served as controls. Enzyme assays were performed and severity of the 3MI-induced lung damage was scored. Consumption of the low vitamin A diet resulted in a significant reduction in the liver and lung contents of vitamin A; however, serum concentration of vitamin A was unaffected. High vitamin A supplementation did not alter the activity of the MFO system. Clinical signs, lung – body weight ratio and wet – dry weight ratio of the lungs of 3MI-infused goats were not significantly different; however, in the low vitamin A goats, the microscopic lesions such as the extent of alveolar epithelial hyperplasia were judged to be significantly more severe than those observed in the high vitamin A goats.

Attenuation of hyperoxic lung injury by the 21-aminosteroid U-74389G

1995 ◽  
Vol 78 (5) ◽  
pp. 1635-1641 ◽  
Author(s):  
S. Tasaka ◽  
A. Ishizaka ◽  
T. Urano ◽  
K. Sayama ◽  
F. Sakamaki ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Tissue ◽  
Guinea Pigs ◽  
Weight Ratio ◽  
Dry Weight ◽  
Endothelial Damage ◽  
Lung Water ◽  
Tissue Samples ◽  
Cell Accumulation ◽  
Hyperoxic Lung Injury

Hyperoxic lung injury is attributable to oxygen radicals produced under hyperoxic conditions. The 21-aminosteroid (AS), U-74389G, is a potent antioxidant. We examined the effect of U-74389G on lung injury in guinea pigs during exposure to 90% O2 for 48 h. We injected either vehicle or 10 mg/kg of U-74389G 30 min before the O2 exposure and injected the same dose 12, 24, and 36 h later. We performed two series of experiments after exposure. In the first series, we measured the clearance rate of 99mTc-labeled dialdehyde starch (DAS) from the lungs as an index of pulmonary epithelial damage in three experimental groups consisting of 1) control (n = 6) O2 alone (n = 6), and 3) O2 + AS (n = 6). In the second series, pulmonary endothelial injury was estimated by using 28 guinea pigs divided into four experimental groups consisting of 1) control (n = 8), 2) AS alone (n = 5), 3) O2 alone (n = 6), and 4) O2 + AS (n = 9). In the second series, we measured the wet-to-dry weight ratio (W/D) as an index of lung water and the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid compared with plasma (T/P and BAL/P, respectively) as indexes of pulmonary endothelial damage. Cell accumulation in BAL fluid and lung tissue samples was also assessed in the second series.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Tanshinone IIA ameliorates acute lung injury by inhibition of the NLRP3 inflammasome

2019 ◽  
Vol 71 (2) ◽  
pp. 315-320 ◽  
Author(s):  
Tianyu Chen ◽  
Shaoyun Qin ◽  
Ying Dai
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Partial Pressure ◽  
Nlrp3 Inflammasome ◽  
Weight Ratio ◽  
Dry Weight ◽  
Tanshinone Iia ◽  
Inflammasome Activation ◽  
Co2 Partial Pressure ◽  
O2 Partial Pressure

Tanshinone IIA is the phenanthrenequinone derivative extracted from the perennial plant Salvia miltiorrhiza Bunge (red sage). We investigated whether inhibition of the nucleotide-binding oligomerization domain (NOD)-like receptor family protein 3 (NLRP3) inflammasome mediates the protective effect of tanshinone IIA in acute lung injury (ALI) induced in rats by oleic acid (OA) injection. Compared with the control treatment, OA injection induced pulmonary histological impairment, increased the lung wet/dry weight ratio (7.0?1.1 vs 4.?0.6 ) and CO2 partial pressure (PaCO2) (52?6.4 vs 40?3.6 mmHg), decreased arterial O2 partial pressure (PaO2) (63?8.4 vs 100?3.0 mmHg), and increased tumor necrosis factor ? (TNF?) (8.8?2.3 vs 5.2 ?1.5 pg/mL), monocyte chemoattractant protein-1 (MCP-1) (36.1?4.9 vs 25.2?6.6 pg/mL) and interleukin-1? (IL-1?) (15.9?3.2 vs 4.6?1.3 pg/mL) in the bronchoalveolar lavage (BAL) fluid. Tanshinone IIA provided protection against ALI, observed as a reduction in the lung wet/dry weight ratio and CO2 partial pressure, and increased O2 partial pressure. The cytokine increase was also prevented. Tanshinone IIA attenuated increased protein levels of NLRP3, caspase-1 and IL-1? in pulmonary tissues, suggesting that it ameliorates ALI by preventing NLRP3 inflammasome activation.

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models

2020 ◽  
Vol 319 (6) ◽  
pp. L932-L940
Author(s):  
Aizhou Wang ◽  
Aadil Ali ◽  
Shaf Keshavjee ◽  
Mingyao Liu ◽  
Marcelo Cypel
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Small Animal ◽  
Lung Perfusion ◽  
Contributing Factors ◽  
Donor Pool ◽  
Ex Vivo Lung Perfusion ◽  
Advantages And Disadvantages ◽  
Number Of Patients ◽  
End Stage

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.

scholarly journals Calpain inhibition ameliorates scald burn-induced acute lung injury in rats

2018 ◽  
Vol 6 ◽  
Author(s):  
Peng-Ran Du ◽  
Hong-Ting Lu ◽  
Xi-Xiang Lin ◽  
Li-Feng Wang ◽  
Yan-Xia Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Burn Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Membrane Skeleton ◽  
Lung Damage ◽  
Severe Burn ◽  
Calpain Activity ◽  
Ankyrin B

Abstract Background The molecular pattern of severe burn-induced acute lung injury, characterized by cell structure damage and leukocyte infiltration, remains unknown. This study aimed to determine whether calpain, a protease involved in both processes, mediates severe burn-induced acute lung injury. Methods Rats received full-thickness scald burns covering 30% of the total body surface area, followed by instant fluid resuscitation. MDL28170 (Tocris Bioscience), an inhibitor of calpain, was given intravenously 1 h before or after the scald burn. The histological score, wet/dry weight ratio, and caspase-3 activity were examined to evaluate the degree of lung damage. Calpain activity and its source were detected by an assay kit and immunofluorescence staining. The proteolysis of membrane skeleton proteins α-fodrin and ankyrin-B, which are substrates of calpain, was measured by Western blot. Results Time-course studies showed that tissue damage reached a peak between 1 and 6 h post-scald burn and gradually diminished at 24 h. More importantly, calpain activity reached peak levels at 1 h and was maintained until 24 h, paralleled by lung damage to some extent. Western blot showed that the levels of the proteolyzed forms of α-fodrin and ankyrin-B correlated well with the degree of damage. MDL28170 at a dose of 3 mg/kg b. w. given 1 h before burn injury not only antagonized the increase in calpain activity but also ameliorated scald burn-induced lung injury, including the degradation of α-fodrin and ankyrin-B. Immunofluorescence images revealed calpain 1 and CD45 double-positive cells in the lung tissue of rats exposed to scald burn injury, suggesting that leukocytes were a dominant source of calpain. Furthermore, this change was blocked by MDL28170. Finally, MDL28170 given at 1 h post-scald burn injury significantly ameliorated the wet/dry weight ratio compared with burn injury alone. Conclusions Calpain, a product of infiltrating leukocytes, is a mediator of scald burn-induced acute lung injury that involves enhancement of inflammation and proteolysis of membrane skeleton proteins. Its late effects warrant further study.

Involvement of lung interstitial proteoglycans in development of hydraulic- and elastase-induced edema

1998 ◽  
Vol 275 (3) ◽  
pp. L631-L635 ◽  
Author(s):  
Alberto Passi ◽  
Daniela Negrini ◽  
Riccardo Albertini ◽  
Giancarlo De Luca ◽  
Giuseppe Miserocchi
Keyword(s):  
Basement Membrane ◽  
Gel Filtration ◽  
Weight Ratio ◽  
Dry Weight ◽  
Collagen Type Iv ◽  
Tissue Samples ◽  
Type Iv ◽  
Saline Loading ◽  
Intravenous Saline ◽  
Wet Weight

We extracted and isolated proteoglycans from lung tissue samples obtained from three groups of anesthetized rabbits: 1) control animals (C; n= 8) killed by overdose after 180 min; 2) animals receiving an intravenous saline infusion (S; n = 4, 1.5 ml ⋅ kg-1 ⋅ min-1) for 180 min; 3) animals receiving an intravenous bolus of 200 μg of pancreatic elastase (E; n = 4), killed after 200 min. The lung dry weight-to-wet weight ratio in the three groups was 5.2 ± 0.2, 6.0 ± 0.4, and 5.6 ± 0.5, respectively. Gel-filtration analysis showed a massive fragmentation of the versican family of the extracellular matrix (ECM) in the S groups and a marked degradation of heparan sulfate-containing proteoglycans, including perlecan of the basement membrane, in the E group. The binding properties of total proteoglycans to other ECM components were lowered in both groups relative to control. The decrease in proteoglycan binding was more pronounced for collagen type IV in the E group relative to C (−93.5%, P < 0.05) and for hyaluronic acid in the S groups (−85.8%, P < 0.05). These findings suggest that elastase treatment produces a major degree of damage to the organization of basement membrane, whereas saline loading affects more markedly the architecture of interstitial ECM. Qualitative zymography performed on lung extracts showed increased gelatinase activities in both S and E groups, providing direct evidence that the activation of tissue proteinases may play a role in acute lung injury.

scholarly journals 590 Growth and Physiological Characteristics of Diploid and Tetraploid Citrus Rootstock Seedlings Grown at Elevated CO2

HortScience ◽  
1999 ◽  
Vol 34 (3) ◽  
pp. 548D-548 ◽  
Author(s):  
J.P. Syvertsen ◽  
J.W Grosser ◽  
L.S. Lee
Keyword(s):  
Gas Exchange ◽  
Plant Growth ◽  
Water Use ◽  
Root Length ◽  
Weight Ratio ◽  
Dry Weight ◽  
Nutrient Concentrations ◽  
Volkamer Lemon ◽  
Citrus Rootstock ◽  
Leaf N

We grew three diploid (2X) Citrus rootstock seedlings and their autotetraploids (4X) at elevated CO2 to obtain insights into limitations on growth and net gas exchange that have been associated with tetraploidy. Well-nourished Volkamer lemon (Volk), Troyer citrange (Troy), and Cleopatra mandarin (Cleo) were grown in greenhouses at ambient or twice ambient CO2 for 3 months. We measured plant growth, water relations, mineral nutrition, and net gas exchange characteristics of leaves. Overall, tetraploid roots were thicker as 4X had lower root length: dry weight ratio or specific root length (SRL) than 2X roots. Tetraploid plants were smaller and had higher root/shoot ratios, shorter fibrous roots, and lower whole plant transpiration than 2X. Tetraploids also had lower leaf N and P concentrations on a dry weight basis. Since 4X leaves had thicker leaves (more dry weight per area) than 2X leaves, these nutrient differences disappeared when expressed on an leaf area basis. Elevated CO2 increased plant growth but decreased leaf N, P, and K apparently by a growth dilution effect. Elevated CO2 also increased fibrous root thickness, leaf thickness, and net assimilation of CO2 (ACO2) but decreased stomatal conductance and transpiration such that leaf water use efficiency increased. There was no effect of ploidy level on ACO2 but 4X Volk and Troy had lower rates of ACO2 than their diploids at elevated CO2. Hydraulic conductivity of intact root systems (measured in a pressure pot) was correlated to total plant growth but variability obscured effects of CO2 or ploidy on root conductivity. The low SRL of tetraploids were correlated with lower rates of water use and lower leaf nutrient concentrations, which may be operative in determining the growth characteristics associated with tetraploidy.

One-year experience with ex vivo lung perfusion: Preliminary results from a single center

2018 ◽  
Vol 41 (8) ◽  
pp. 460-466 ◽  
Author(s):  
Achim Koch ◽  
Nikolaus Pizanis ◽  
Carolin Olbertz ◽  
Omar Abou-Issa ◽  
Christian Taube ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Lung Perfusion ◽  
Smoking History ◽  
Donor Pool ◽  
Ex Vivo Lung Perfusion ◽  
Extended Criteria Donor ◽  
Ventilation Time ◽  
Postoperative Ventilation ◽  
Lung Transplants ◽  
One Year

Objective: To enlarge the donor pool for lung transplantation, an increasing number of extended criteria donor lungs are used. However, in more than 50% of multi-organ donors the lungs are not used. Ex vivo lung perfusion offers a unique possibility to evaluate and eventually recondition the injured donor lungs. The aim of our study was to assess the enlargement of the donor pool and the outcome with extended criteria donor lungs after ex vivo lung perfusion. Patients and Methods: Data were prospectively collected in our lung transplant database. We compared the results of lung transplants after ex vivo lung perfusion with those after conventional cold static preservation. In total, 11 extended criteria donor lungs processed with ex vivo lung perfusion and 41 cold static preservation lungs transplanted consecutively between May 2016 and May 2017 were evaluated. Normothermic ex vivo lung perfusion was performed according to the Toronto protocol for 4 h. Cold static preservation lungs were stored in low-potassium dextran solution. Results: Ex vivo lung perfusion lungs before procurement had significantly lower PaO2/FiO2 (P/F) ratios and more X-ray abnormalities. There were no statistically significant differences for pre-donation ventilation time, smoking history, or sex. After reconditioning with ex vivo lung perfusion, 9 out of 11 processed lungs were considered suitable and successfully transplanted. The mean postoperative ventilation time and in-hospital stay were not significantly different in ex vivo lung perfusion and cold static preservation recipients. Conclusion: Ex vivo lung perfusion can safely be used in the evaluation of lungs initially considered not suitable for transplantation. The primary outcome was not negatively affected and normothermic ex vivo lung perfusion is a useful tool to increase the usage of potentially transplantable lungs.

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