Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia–reperfusion injury in rat lung

1998 ◽  
Vol 95 (3) ◽  
pp. 369-376
Author(s):  
Chi-Huei CHIANG ◽  
Kerry WU ◽  
Cheng-Ping YU ◽  
Wann-Cherng PERNG ◽  
Horng-Chin YAN ◽  
...  
Keyword(s):  
Weight Gain ◽  
Lung Injury ◽  
Reperfusion Injury ◽  
Protective Agent ◽  
Ischaemia Reperfusion Injury ◽  
Lung Weight ◽  
Protective Agents ◽  
University Of Wisconsin ◽  
Ischaemia Reperfusion ◽  
Wisconsin Solution

1.An intervention to reduce ischaemia–reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia–reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia–reperfusion-associated lung vascular injury. 2.The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 ;h of cold ischaemia followed by 1 ;h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dex×3, (5) UW+PGE1×3, (6) UW+Bt2-cAMP×3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs. 3.The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs. 4.Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia–reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia–reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

scholarly journals Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury

Thorax ◽  
2017 ◽  
Vol 73 (4) ◽  
pp. 350-360 ◽  
Author(s):  
Kate Colette Tatham ◽  
Kieran Patrick O'Dea ◽  
Rosalba Romano ◽  
Hannah Elizabeth Donaldson ◽  
Kenji Wakabayashi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Reperfusion Injury ◽  
Lung Transplant ◽  
Primary Graft Dysfunction ◽  
Graft Dysfunction ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Lung Dysfunction ◽  
Post Implantation

RationalePrimary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.ObjectiveTo define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.MethodsIsolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.ResultsIn mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.ConclusionsThese results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.

Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury

2013 ◽  
Vol 126 (2) ◽  
pp. 163-174 ◽  
Author(s):  
Ying-Ying Yang ◽  
Pei-Chang Lee ◽  
Yi-Tsau Huang ◽  
Wei-Ping Lee ◽  
Ying-Ju Kuo ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Elevated Serum ◽  
Liver Graft ◽  
Signalling Pathways ◽  
Protective Agent ◽  
Ischaemia Reperfusion Injury ◽  
Positive Effects ◽  
Ischaemia Reperfusion ◽  
Hepatic Congestion ◽  
Pre Treatment

Besides cardioprotective effects, the AT1R (angiotensin-II type 1 receptor) antagonist losartan protects the liver from IRI [IR (ischaemia/reperfusion) injury], but the mechanism has not been fully determined. The HIF (hypoxia inducible factor)-1α and Wnt/β-catenin signalling pathways have been reported to be involved in the mechanism of liver IRI. Therefore the aim of the present study was to determine whether the Wnt/HIF axis is part of the mechanism of the positive effect of AngII inhibition by losartan in liver IRI in rats. Various measurements were made in MCD/HF-NASH (methionine- and choline-deficient-diet/high-fat-diet-induced non-alcoholic steatohepatitis) rats with liver IRI. Acute losartan pre-administration markedly reversed the IR-suppressed levels of the hepatic-protective factors IL (interleukin)-6, IFN (interferon)-γ, Wnt3a, β-catenin and HIF-1α, and decreased hepatic blood flow and IR-elevated serum ALT (alanine aminotransferase), hepatic TNF (tumour necrosis factor)-α, IL-1α, hepatic congestion, vacuolization and necrosis, hepatic Suzuki IRI scores, necrotic index and levels of TBARS (thiobarbituric acid-reacting substances) in MCD/HF-NASH rats. Furthermore, acute Wnt3a pre-treatment significantly inhibited IR-elevated serum ALT, hepatic Suzuki IRI scores and TBARS, and restored the IR-depleted β-catenin/HIF-1α activity in MCD/HF-NASH rats. Simultaneous acute sFRP2 (secreted frizzled-related protein 2; a Wnt3a inhibitor) pre-treatment eliminated the losartan-related beneficial effects in MCD/HF-NASH rats with liver IRI, which was accompanied by a decrease in hepatic HIF-1α/β-catenin activity. Losartan-induced up-regulation of HIF-1α and Wnt/β-catenin signalling was associated with the recovery of IR-inhibited hepatic Bcl-2, Mn-SOD (manganese superoxide), Cu/Zn-SOD (copper/zinc superoxide) and GSH levels, and the suppression of IR-increased hepatic catalase and caspase 3/caspase 8 levels in MCD/HF-NASH rats. In conclusion, up-regulation of the HIF-1α and Wnt/β-catenin signalling pathways are part of the mechanism of the positive effects of losartan-related AngII inhibition in MCD/HF-NASH rats with liver IRI. Our study highlights the potential of the dual-organ protective agent losartan in NASH patients with steatotic livers and cardiovascular risk.

Use of anti-(tumour necrosis factor-α) antibody or 3-deaza-adenosine as additives to promote protection by University of Wisconsin solution in ischaemia/reperfusion injury

2000 ◽  
Vol 99 (3) ◽  
pp. 215-222 ◽  
Author(s):  
Chi-Huei CHIANG ◽  
Chin-Pyng WU ◽  
Wann-Cherng PERNG ◽  
Horng-Chin YAN ◽  
Cheng-Ping YU
Keyword(s):  
Lung Injury ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Α ◽  
University Of Wisconsin ◽  
Ischaemia Reperfusion ◽  
Tnf Α ◽  
Factor Α ◽  
Wisconsin Solution ◽  
Necrosis Factor

Experimental interventions that reduce ischaemia/reperfusion (I/R) lung injury can be used to improve the properties of preservation solutions. We attempted to increase the attenuation of I/R injury by University of Wisconsin solution (UW) by adding an antibody against tumour necrosis factor-α (TNF-α), to neutralize TNF-α, and/or by adding 3-deaza-adenosine (c3-Ado), to inhibit leucocyte adhesion and the biosynthesis of ICAM-1 (intercellular cell-adhesion molecule 1). We examined I/R injury using an isolated rat lung model. Six different solutions were perfused individually, followed by evaluation of I/R injury: (1) 0.9% NaCl (normal saline; NS), (2) NS+anti-TNF-α antibody, (3) UW alone, (4) UW+anti-TNF-α, (5) UW+c3-Ado and (6) UW+anti-TNF-α+c3-Ado. Haemodynamic changes, lung weight gain, capillary filtration coefficient, TNF-α levels and lung pathology were analysed in order to evaluate I/R injury. Compared with lungs perfused with NS, lungs treated with NS+anti-TNF-α showed less I/R injury. The addition of anti-TNF-α and/or c3-Ado to UW reduced I/R injury compared with unmodified UW. Among the six solutions tested, UW containing anti-TNF-α antibody reduced I/R injury to the greatest extent. We conclude that addition of anti-TNF-α antibody or c3-Ado protects against I/R lung injury when using UW. Further investigation of the improved properties of modified UWs would be beneficial with regard to lung transplantation research.

Cytokine up-regulation in ischaemic/reperfused lungs perfused with University of Wisconsin solution and normal saline

2001 ◽  
Vol 101 (3) ◽  
pp. 285-294 ◽  
Author(s):  
Chi-Huei CHIANG ◽  
Cheng-Ping YU ◽  
Chin-Pyng WU ◽  
Horng-Chin YAN ◽  
Wann-Cherng PERNG
Keyword(s):  
Lung Injury ◽  
Pulmonary Oedema ◽  
Normal Saline ◽  
Cytokine Production ◽  
Interleukin 1 ◽  
Lung Weight ◽  
University Of Wisconsin Solution ◽  
University Of Wisconsin ◽  
Tnf Α ◽  
Wisconsin Solution

Ischaemia/reperfusion (I/R) lung injury using University of Wisconsin solution (UW) as perfusate has not been well studied. Isolated rat lungs were challenged with various periods of ischaemia and/or reperfusion. Haemodynamics, lung weight gain (LWG), capillary filtration coefficient (Kfc), tissue pathology, the concentrations of cytokines in the perfusate, and mRNAs for the various cytokines in the lung tissues were measured. I/R induced a permeability type of pulmonary oedema, as reflected by increases in LWG and Kfc. LWG and Kfc in the I45R60(UW) group (45 min of ischaemia followed by 60 min of reperfusion with UW) were only 2% and 5% respectively of those in the I45R60(NS) group (where NS is normal saline). LWG and Kfc in the UW group had both increased by 180 min, to values similar to those in the I45R60(NS) group. However, these findings show that UW was remarkably effective at preventing LWG after 60 min of reperfusion, and was more than 3-fold more effective than NS in delaying LWG. For longer ischaemic times only, or the same period of ischaemia followed by longer reperfusion periods, greater lung injury occurred. I/R lung injury also induced increased concentrations of tumour necrosis factor-α (TNF-α), interleukin 1 and interleukin 6 in the perfusate, and increased the mRNAs for these cytokines in lung tissue. A significant correlation was obtained between TNF-α concentration and LWG. TNF-α production in the I45R60(UW) group was only 7% of that in the I45R60(NS) group. However, TNF-α mRNA expression in the I45R60(UW) group was 80% of that in the I45R60(NS) group. This indicates that transcription/translation do not correlate well with cytokine production, and also suggests that one reason for the effectiveness of UW in delaying LWG may be because it delays TNF-α production. In summary, ischaemia or I/R caused a permeability-type pulmonary oedema that was associated with leucocyte infiltration and the up-regulation of various cytokines, regardless of the perfusion fluid. Except for pulmonary hypertension, less severe I/R lung injury and delayed cytokine production in lungs perfused with UW, the pattern of injury associated with I/R challenge was similar to that in lungs perfused with NS. We propose that more or long-acting protective agents are required as additives in order to modify UW to produce an optimal preservation solution.

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